Large bladder calculus masking a stone in single-system ureterocele

Ureterocele in an elderly is a rare entity. The presence of stone within ureterocele along with a large bladder calculus is an even rarer presentation. This phenomenon has not been reported so far to the best of our knowledge. We present an unusual case of a large bladder calculus with a concomitant stone in the associated ureterocele. The diagnosis was missed in the first instance due to the masking effect by the larger bladder calculus. Herein, we discuss this case and its management.

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Antibiotic-associated haemorrhagic colitis: not always Clostridium difficile

Antibiotic-associated colitis is a gastrointestinal complication of antibiotic use commonly seen in hospitalised patients, with Clostridium difficile (C. difficile) colitis being the most common type. We present a case of haemorrhagic colitis secondary to Klebsiella oxytoca following self-initiated amoxicillin–clavulanic acid use. An 85-year-old woman presented to the emergency department with abdominal pain and mucobloody diarrhoea. History was notable for an ongoing 5-day course of amoxicillin–clavulanic acid use. The CT scan of her abdomen revealed extensive diffuse thickening of the ascending and transverse colon. Stool culture grew K. oxytoca, an established cause of haemorrhagic colitis. She declined colonoscopy but recovered with withdrawal of all antibiotics and conservative treatment. We should be vigilant to haemorrhagic colitis following antibiotic use which is not always C. difficile related.

http://ift.tt/2srh7AI

Vesical dermoid: a rare bladder tumour

Dermoid cysts are benign developmental lesions consisting of tissues of more than one germ cell lineage origin. The urinary bladder is a very rare location of dermoid cysts. We report a case of an 18-year-old woman who presented with suprapubic pain, dysuria and turbid urine. Blood and serum chemistry was normal. Contrast-enhanced CT revealed a heterogeneously enhancing mass of 2.5x2 cm within the urinary bladder infiltrating fundus of urinary bladder with extraluminal extension. At cystoscopy, an irregular mass arising from the dome of the urinary bladder with a covering of hair and whitish scales was seen. The patient was managed by transperitoneal laparoscopic partial cystectomy with left oophorectomy. Histology revealed dermoid cyst arising from the urinary bladder and simple serous cyst in the ovary. Postoperative course was uneventful.

http://ift.tt/2srpvQF

Tension enterothorax and hepatothorax due to a diaphragmatic hernia: successful emergency repair of a life-threatening condition

A 70-year-old female patient presented with acute severe respiratory distress at a district general hospital. Medical history included type 2 diabetes, recurrent pulmonary embolisms and pre-existing diaphragmatic hernia containing part of the liver. Despite initial treatment with steroid inhalers, her clinical picture rapidly deteriorated requiring emergency intubation and positive pressure ventilation. Imaging investigations revealed tension enterothorax and hepatothorax with tracheal deviation. The patient was transferred and underwent an emergency laparotomy at the Regional Oesophagogastric Unit. A large diaphragmatic hernia (central tendon defect) which contained the duodenum, porta hepatis, right lobe of liver, gallbladder and right colon was reduced and successfully repaired. Her postoperative course was uneventful with no signs of recurrence at 2 months follow-up.

This case describes an extremely rare and life-threatening condition of tension enterothorax and hepatothorax, which should be considered in the differential diagnosis of acute respiratory distress with tracheal deviation.

http://ift.tt/2srg43A

McSwain type V appendix intussusception

Description

Intestinal intussusception consists of distal migration of a segment from the intestine to the adjacent intestinal lumen. Appendicular intussusception (AI) is a rare disease that constitutes a clinical challenge. The incidence of AI is estimated at 0.01%.1 It is five times more frequent in men.2 Despite imaging and endoscopic advances, diagnosis remains a difficult challenge. The presentation of AI varies from asymptomatic to chronic pain.3 This case reports a 33-year-old woman with past gastro-oesophageal surgery and complementary appendectomy, which was evaluated for the chronic pain in the right lower quadrant. Colonoscopy (figure 1A,B) revealed intussusception of appendix type V. A laparoscopic caecum resection was performed. The postoperative was uneventful. Histology revealed AI with lumen obliteration by foreign body (suture of previous intervention).

Figure 1

Colonoscopy: (A, B) finger-like polypoid tumour.

McSwain's classification is anatomical...

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Rheumatoid arthritis causing diffuse alveolar haemorrhage: a novel therapeutic approach

Pulmonary vascular involvement due to rheumatoid arthritis, presenting as diffuse alveolar haemorrhage (DAH), is a rare phenomenon, especially if there are no signs of systemic vasculitides. Furthermore, how to proceed with the management of these patients is challenging, as in the case of our patient, who had recurrent DAH. We present a case of a patient with known rheumatoid arthritis who had recurrence of DAH that spanned over several years, often presenting with life-threatening respiratory failure. While her DAH presentation improved with high-dose glucocorticoids, to resolve her recurrence, we opted to initiate treatment with rituximab, with a short course of azathioprine. After the second round of rituximab, the patient continues to do well without any further DAH-related complications. We also summarise prior cases of such patients to highlight variable treatment options.

http://ift.tt/2srwBV8

Staged curative treatment of a complex direct carotid-cavernous fistula with a large arterial defect and an 'oversized' internal carotid artery

This is a case of a high-flow, post-traumatic direct carotid-cavernous fistula with a widened arterial defect and a large-diameter internal carotid artery (ICA). The unique aspect of this case is the oversized ICA, >8mm in diameter, which is both a pathological and a therapeutic challenge, given the lack of available neuroendovascular devices for full vessel reconstruction. We present a planned two-stage embolisation paradigm for definitive treatment. Transarterial coil embolisation is performed as the first stage to disconnect the fistula and normalise flow in the ICA. A 3-month recovery period is then allowed for reduction in carotid diameter. Repair of the large vessel defect and pseudoaneurysm is performed as a second stage in a delayed fashion with a flow-diverting device. Follow-up angiography at 6 months demonstrates obliteration of the fistula and curative ICA reconstruction to a diameter <5mm.

http://ift.tt/2toRM7F

Marjolins squamous cell carcinoma of the hallux following recurrent ingrown toenail infections

Marjolin's squamous cell carcinoma (SCC) affecting the toe is rare. Due to resemblance with benign conditions it can often result in misdiagnosis. We report a case of Marjolin's SCC affecting the proximal hallux in a patient with recurrent ingrown toenail infections. A 58-year-old woman with a background of wedge resections for ingrown toenail and distal phalanx amputation for osteomyelitis presented with pain and hyperkeratotic raised ulcer around the proximal phalanx. MRI scan revealed soft tissue mass infiltrating the proximal phalanx with biopsies confirming a SCC. The patient underwent first ray amputation and made a good clinical recovery and remains disease free. Due to clinical similarities with benign conditions, awareness of Marjolin's SCC as a potential diagnosis when treating patients with recurrent ingrown toenail is imperative. We recommend patients with recurrent ingrown toenail or ulceration with a background of chronic infection have biopsies performed to exclude potential malignancy.

http://ift.tt/2srlnjF

Infectious crystalline keratopathy after Descemeta{euro}™s stripping endothelial keratoplasty

A 68-year-old woman presented with infectious crystalline keratopathy 4 months after she underwent a combined phacoemulsification and Descemet's stripping endothelial keratoplasty for Fuch's endothelial dystrophy in her left eye. After 5 months of topical moxifloxacin 1%, the infiltrate responded well but had not completely resolved, with the resulting endothelial failure requiring a penetrating keratoplasty 9 months after the initial operation. Microbiology identified Enterococcus faecalis with the histopathology demonstrating bacterial colonies within the graft interface. Postoperatively she developed endophthalmitis, needing vitrectomy and intravitreal antibiotics. The infection settled with no recurrence, with topical and oral antibiotics continued for 2 months. A sutured toric piggyback intraocular lens was performed 18 months postvitrectomy for graft astigmatism, achieving a best-corrected vision of 6/15.

Infectious crystalline keratopathy can occur following Descemet's stripping endothelial keratoplasty, requiring long-term topical therapy and potentially leading to graft failure with the necessity for further keratoplasty.

http://ift.tt/2tp8zHD

Twenty-nine-month follow-up of a paediatric zirconia dental crown

The aim of this paper is to present the long-term follow-up of one paediatric zirconia crown on a deciduous molar. Preformed crowns are part of the armamentarium in paediatric dentistry. In recent years, aesthetic alternatives to preformed metal crowns have been developed, first preveneered crowns and then zirconia crowns. This paper describes the restoration of a primary molar with a zirconia crown (EZ-Pedo, Loomis, California, USA) in an 8-year-old boy. In this clinical case, the protocol for the implementation and maintenance of zirconia crowns is detailed. The patient was followed up for 29 months until the natural exfoliation of his primary molar. The adaptation of the zirconia crown, the gingival health and the wear on the opposing tooth were considered. In this case, the paediatric zirconia crown allowed sustainable functional restoration while restoring a natural appearance of the tooth.

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Effects of alternative electron acceptors on the activity and community structure of methane-producing and -consuming microbes in the sediments of two shallow boreal lakes

Abstract

The role of anaerobic CH₄ oxidation in controlling lake sediment CH₄ emissions remains unclear. Therefore, we tested how relevant EAs (SO₄²⁻, NO₃⁻, Fe³⁺, Mn⁴⁺, O₂) affect CH₄ production and oxidation in the sediments of two shallow boreal lakes. The changes induced to microbial communities by the addition of Fe³⁺ and Mn⁴⁺ were studied using next-generation sequencing targeting the 16S rRNA and methyl-coenzyme M reductase (mcrA) genes and mcrA transcripts. Putative anaerobic CH₄ oxidizing archaea (ANME-2D) and bacteria (NC 10) were scarce (up to 3.4% and 0.5% of archaeal and bacterial 16S rRNA genes, respectively), likely due to the low environmental stability associated with shallow depths. Consequently, the potential anaerobic CH₄ oxidation (0–2.1 nmol g⁻¹_{dry weight (DW)}d⁻¹) was not enhanced by the addition of EAs, nor important in consuming the produced CH₄ (0.6–82.5 nmol g⁻¹_DWd⁻¹). Instead, the increased EA availability suppressed CH₄ production via the outcompetition of methanogens by anaerobically respiring bacteria and via the increased protection of organic matter from microbial degradation induced by Fe³⁺ and Mn⁴⁺. Future studies could particularly assess whether anaerobic CH₄ oxidation has any ecological relevance in reducing CH₄ emissions from the numerous CH₄-emitting shallow lakes in boreal and tundra landscapes.

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Complex interactions between potentially pathogenic, opportunistic, and resident bacteria emerge during infection on a reef-building coral

Abstract

Increased bacterial diversity on diseased corals can obscure disease etiology and complicate our understanding of pathogenesis. To untangle microbes that may cause white band disease signs from microbes responding to disease, we inoculated healthy Acropora cervicornis corals with an infectious dose from visibly diseased corals. We sampled these dosed corals and healthy controls over time for sequencing of the bacterial 16S region. Endozoicomonas were associated with healthy fragments from 4/10 colonies, dominating microbiomes before dosing and decreasing over time only in corals that displayed disease signs, suggesting a role in disease resistance. We grouped disease-associated bacteria by when they increased in abundance (primary vs secondary) and whether they originated in the dose (colonizers) or the previously healthy corals (responders). We found that all primary responders increased in all dosed corals regardless of final disease state and are therefore unlikely to cause disease signs. In contrast, primary colonizers in the families Pasteurellaceae and Francisellaceae increased solely in dosed corals that ultimately displayed disease signs, and may be infectious foreign bacteria involved in the development of disease signs. Moving away from a static comparison of diseased and healthy bacterial communities, we provide a framework to identify key players in other coral diseases.

http://ift.tt/2srv8hQ

Physically consistent data assimilation method based on feedback control for patient-specific blood flow analysis

Summary

This paper presents a novel data assimilation method for patient-specific blood flow analysis based on feedback control theory called the physically consistent feedback control-based data assimilation (PFC-DA) method. In the PFC-DA method, the signal, which is the residual error term of the velocity when comparing the numerical and reference measurement data, is cast as a source term in a Poisson equation for the scalar potential field that induces flow in a closed system. The pressure values at the inlet and outlet boundaries are recursively calculated by this scalar potential field. Hence, the flow field is physically consistent because it is driven by the calculated inlet and outlet pressures, without any artificial body forces. As compared with existing variational approaches, although this PFC-DA method does not guarantee the optimal solution, only one additional Poisson equation for the scalar potential field is required, providing a remarkable improvement for such a small additional computational cost at every iteration. Through numerical examples for 2D and 3D exact flow fields, with both noise-free and noisy reference data as well as a blood flow analysis on a cerebral aneurysm using actual patient data, the robustness and accuracy of this approach is shown. Moreover, the feasibility of a patient-specific practical blood flow analysis is demonstrated. This article is protected by copyright. All rights reserved.

http://ift.tt/2ryr1wc

Cost Effectiveness of Pembrolizumab vs. Standard-of-Care Chemotherapy as First-Line Treatment for Metastatic NSCLC that Expresses High Levels of PD-L1 in the United States

Abstract

Objectives

Our objectives were to evaluate the cost effectiveness of pembrolizumab compared with standard-of-care (SoC) platinum-based chemotherapy as first-line treatment in patients with metastatic non-small-cell lung cancer (NSCLC) that expresses high levels of programmed death ligand-1 (PD-L1) [tumour proportion score (TPS) ≥50%], from a US third-party public healthcare payer perspective.

Methods

We conducted a partitioned-survival model with a cycle length of 1 week and a base-case time horizon of 20 years. Parametric models were fitted to Kaplan–Meier estimates of time on treatment, progression-free survival and overall survival from the KEYNOTE-024 randomized clinical trial (patients aged ≥18 years with stage IV NSCLC, TPS ≥50%, without epidermal growth factor receptor (EGFR)-activating mutations or anaplastic lymphoma kinase (ALK) translocations who received no prior systemic chemotherapy) and validated with long-term registry data. Quality-adjusted life-years (QALYs) were calculated based on EuroQoL-5 Dimensions (EQ-5D) utility data collected in the trial. Costs ($US, year 2016 values) for drug acquisition/administration, adverse events and clinical management were included. Costs and outcomes were discounted at 3% per year. A series of deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results.

Results

In the base-case scenario, pembrolizumab resulted in an expected gain of 1.31 life-years (LYs) and 1.05 QALYs and an incremental cost of $US102,439 compared with SoC. The incremental cost per QALY gain was $US97,621/QALY and the incremental cost per LY gain was $US78,344/LY.

Conclusions

Pembrolizumab is projected to be a cost-effective option compared with SoC platinum-based chemotherapy as first-line treatment in adults with metastatic NSCLC expressing high levels of PD-L1.

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Impact of binding mechanism on selective inhibition of histone deacetylase isoforms

Abstract

Industrialized drug screening campaigns usually deliver hundreds of compounds that are active on a particular pharmaceutical target. In the light of high failure rates of drug candidates due to unforeseeable off-target toxicity, the early identification of the most promising compounds with high potential for target selectivity is an urgent need to improve the quality of lead compounds and lower attrition rates in the drug development process. The reliable prediction of the selectivity of active substances for a target protein is a challenging task.

A comprehensive study of the binding kinetics, thermodynamics and selectivity of chemically related ligands of histone deacetylase (HDAC) like amidohydrolase from Pseudomonas aeruginosa (HDAH_pa) reveals one general binding mechanism for all analyzed compounds consisting of a preceding conformational selection step followed by an optional subsequent induced fit. Depending on the chemical structure the ligands bind to one or two of at least three protein conformations with different rate constants. Although these kinetic and mechanistic differences hamper the predictability of selectivity for the HDAC inhibitors, we demonstrate that the enthalpy weighted binding constant K_d^ΔHis a useful metric to predict isoform selectivity of inhibitors against HDAC enzymes and relatively robust toward different but related binding mechanisms.

This article is protected by copyright. All rights reserved.

Depending on their chemical structures ligands recognize different conformers of histone deacetylase (HDAC) like amidohydrolase from P. aeruginosa and bind via a general mechanism consisting of chemical selection and induced fit. Although differences in binding kinetics and reaction pathway may hamper the predictability of selectivity for HDAC inhibitors, the enthalpy weighted binding constant K_d^ΔH proves to be a useful metric to predict isoform selectivity of inhibitors against HDAC enzymes, which is fairly robust toward different but related binding mechanisms.

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Platinum-containing compound platinum pyrithione suppresses ovarian tumor proliferation through proteasome inhibition

Abstract

Background

Ovarian carcinoma is one of the most aggressive gynecological malignant neoplasms and makes up 25–30% of all cancer cases of the female genital tract. Currently, resistance to traditional chemotherapy is a great challenge for patients with Epithelial ovarian cancer (EOC). Therefore, identifying novel agents for EOC treatment is essential and urgent.

Method

MTS assay was used to analyze the cell viability and proliferation of cancer cells. Flow cytometry was employed to analyze cell cycle distribution and cell apoptosis. Protein signaling pathways were detected by western blot and immunohistochemical staining. Nude mouse experiment was performed to test the in vivo effect of platinum pyrithione (PtPT).

Results

PtPT is a chemically well-characterized synthetic complex of platinum that potently inhibits proteasome-associated deubiquitinases USP14 and UCHL5 activity and shows selective cytotoxicity to multiple cancer cells without damaging DNA. We found that PtPT significantly accumulated ubquitinated-proteins and suppressed the proliferation of multiple EOC cells. Additionally, PtPT induced G2 phase arrest and apoptosis in both A2780 and SKOV3 cells. More importantly, animal experiments showed that PtPT dramatically suppressed the growth of EOC xenografts without obvious side effects.

Conclusion

These results suggest that through proteasome inhibition, PtPT significantly suppressed the proliferation of EOC in vitro and in vivo and could be developed as a novel agent for EOC treatment in the future.

http://ift.tt/2sv3LUG

Patterns of venous thromboembolism risk in patients with localized colorectal cancer undergoing adjuvant chemotherapy or active surveillance: an observational cohort study

Abstract

Background

Venous thromoboembolism (VTE) is a frequent and burdensome complication of metastatic colorectal cancer (CRC). However, the epidemiology of VTE in patients with localized CRC after surgery in curative intent is incompletely understood. In this single-center observational cohort study, we investigate patterns of VTE risk in localized CRC, and define its relationship with baseline risk factors, adjuvant chemotherapy and CRC recurrence.

Methods

Five-hundred-sixteen patients with stage II/III CRC were included retrospectively at the time of surgery, and followed until the occurrence of VTE, CRC recurrence, or death (median age = 65.1 years, stage II and III: n = 151 (29.5%), n = 361 (70.5%); adjCTX: n = 339 (65.7%)).

Results

During a median follow-up of 2.7 years, 15 VTEs (2.7%) and 116 recurrences (22.5%) occurred, and 46 patients (8.9%) died. Six-month, 1-year, and 5-year VTE risks were 1.6%, 2.0% and 3.2%, respectively. In competing risk time-to-VTE regression, adjCTX was not associated with an increased risk of VTE (Subdistribution hazard ratio = 0.98, 95% CI:0.33–2.88, p = 0.97). The occurrence of disease recurrence strongly increased the risk of VTE (Multi-state model: Transition hazard ratio (THR) = 13.03, 95% CI:4.39–38.74, p < 0.0001)). Conversely, the onset of VTE did not predict for recurrence (THR = 1.95, 95% CI: 0.62–6.16, p = 0.25).

Conclusion

VTE risk is very low in localized CRC and does not appear to be increased by adjuvant chemotherapy. Thus, primary thromboprophylaxis is unlikely to result in clinical benefit in this population. The strongest determinant of VTE risk appears to be disease recurrence.

http://ift.tt/2sClnxX

Accuracy of non-contrast PMCT for determining cause of death

Abstract

The aim of this study was (1) to compare levels of accuracy regarding the categorization of causes of death between non-contrast post-mortem computed tomography (PMCT) and the final forensic report as well as between autopsy and the final forensic report, and (2) to assess levels of confidence regarding the categorization of causes of death after non-contrast PMCT and after autopsy. This prospective study was conducted over a 5 month period during which 221 cases were admitted to our institute for forensic investigations. Whole-body PMCT and forensic autopsy were performed in every case. Of these, 101 cases were included in the final study population. Inclusion criteria were: (1) age > 18 years, (2) presence of at least one of the two principal investigators at the time of admission. One radiologist and one forensic pathologist independently read all PMCT datasets using a report template. Cause of death category and confidence levels were determined by consensus. Forensic autopsy was performed by two forensic pathologists; both unblinded to imaging results. Both post-imaging and post-autopsy cause of death categorization were compared against the final cause of death, as stated in the forensic expert report, which included findings from histology and/or toxicology. Accuracy of post-imaging cause of death categorization in reference to the final cause of death category was substantial (82%, 83/101 cases, Kappa 0.752). Accuracy of post-autopsy cause of death categorization in reference to the final cause of death category was near perfect (89%, 90/101 cases, Kappa 0.852). Post-imaging sensitivity and specificity regarding the categorization of causes of death were 82% and 97%, respectively. Post-autopsy sensitivity and specificity regarding the categorization of causes of death were 89% and 98%, respectively. There was a high consistency between the accuracy of post-imaging cause of death categorization and post-imaging levels of confidence. There was less consistency between accuracy of post-autopsy cause of death categorization and post-autopsy levels of confidence. In this study categorization of causes of death based on non-contrast enhanced PMCT alone, and on PMCT and macroscopic autopsy together, proved to be consistent with the final cause of death-category as determined based on all available information including PMCT, autopsy, and (if available) histology and/or toxicology in more than 82% and 89% of all cases, respectively. There was higher consistency between levels of confidence and accuracy of causes of death categorization was higher post-imaging than post-autopsy. These results underline the fact that the diagnostic potential of PMCT goes beyond the assessment of trauma cases.

http://ift.tt/2t4b7M7

Black cracks: staining of fracture lines

Abstract

During the investigation of fresh bone fractures, it might be difficult to visualize all the fracture lines that could contribute to the interpretation of the biomechanics behind a fracture. To optimize the examination of the fracture, the bones should first be defleshed to expose the osseous surface. To reveal small fracture lines more clearly, we developed two easy, fast, cheap and non-destructive methods to enhance fracture lines and bone defects by coloring the fracture lines with ink. One method consists of cooking the bone in ink, and the second method uses capillary action for ink penetration. We strongly recommend the use of the latter method with Talens® Black Indian Ink for the clearest results.

http://ift.tt/2suEwSN

Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 1

Although the neurofibromatoses consist of at least three autosomal dominantly inherited disorders, neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and schwannomatosis, NF1 represents a multisystem pleiotropic condition very different from the other two. NF1 is a genetic syndrome first manifesting in childhood; affecting multiple organs, childhood development, and neurocognitive status; and presenting the clinician with often complex management decisions that require a multidisciplinary approach. Molecular genetic testing (see article for detailed discussion) is recommended to confirm NF1, particularly in children fulfilling only pigmentary features of the diagnostic criteria. Although cancer risk is not the major issue facing an individual with NF1 during childhood, the condition causes significantly increased malignancy risks compared with the general population. Specifically, NF1 is associated with highly elevated risks of juvenile myelomonocytic leukemia, rhabdomyosarcoma, and malignant peripheral nerve sheath tumor as well as substantial risks of noninvasive pilocytic astrocytoma, particularly optic pathway glioma (OPG), which represent a major management issue. Until 8 years of age, clinical assessment for OPG is advised every 6 to 12 months, but routine MRI assessment is not currently advised in asymptomatic individuals with NF1 and no signs of clinical visual pathway disturbance. Routine surveillance for other malignancies is not recommended, but clinicians and parents should be aware of the small risks (<1%) of certain specific individual malignancies (e.g., rhabdomyosarcoma). Tumors do contribute to both morbidity and mortality, especially later in life. A single whole-body MRI should be considered at transition to adulthood to assist in determining approaches to long-term follow-up. Clin Cancer Res; 23(12); e46–e53. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.

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Cancer and Central Nervous System Tumor Surveillance in Pediatric Neurofibromatosis 2 and Related Disorders

The neurofibromatoses consist of at least three autosomal-dominant inherited disorders: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. For over 80 years, these conditions were inextricably tied together under generalized neurofibromatosis. In 1987, the localization of NF1 to chromosome 17q and NF2 (bilateral vestibular schwannoma) to 22q led to a consensus conference at Bethesda, Maryland. The two main neurofibromatoses, NF1 and NF2, were formally separated. More recently, the SMARCB1 and LZTR1 genes on 22q have been confirmed as causing a subset of schwannomatosis. The last 26 years have seen a great improvement in understanding of the clinical and molecular features of these conditions as well as insights into management. Childhood presentation of NF2 (often with meningioma) in particular predicts a severe multitumor disease course. Malignancy is rare in NF2, particularly in childhood; however, there are substantial risks from benign and low-grade central nervous system (CNS) tumors necessitating MRI surveillance to optimize management. At least annual brain MRI, including high-resolution images through the auditory meatus, and a clinical examination and auditory assessment are required from diagnosis or from around 10 to 12 years of age if asymptomatic. Spinal imaging at baseline and every 2 to 3 years is advised with more frequent imaging if warranted on the basis of sites of tumor involvement. The malignancy risk in schwannomatosis is not well defined but may include an increased risk of malignant peripheral nerve sheath tumor in SMARCB1. Imaging protocols are also proposed for SMARCB1 and LZTR1 schwannomatosis and SMARCE1-related meningioma predisposition. Clin Cancer Res; 23(12); e54–e61. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.

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18F-Fluoroestradiol PET/CT Measurement of Estrogen Receptor Suppression during a Phase I Trial of the Novel Estrogen Receptor-Targeted Therapeutic GDC-0810: Using an Imaging Biomarker to Guide Drug Dosage in Subsequent Trials

Purpose: Evaluate ¹⁸F-fluoroestradiol (FES) PET/CT as a biomarker of estrogen receptor (ER) occupancy and/or downregulation during phase I dose escalation of the novel ER targeting therapeutic GDC-0810 and help select drug dosage for subsequent clinical trials.

Experimental Design: In a phase I clinical trial of GDC-0810, patients with ER-positive metastatic breast cancer underwent FES PET/CT before beginning therapy and at cycle 2, day 3 of GDC-0810 therapy. Up to five target lesions were selected per patient, and FES standardized uptake value (SUV) corrected for background was recorded for each lesion pretherapy and on-therapy. Complete ER downregulation was defined as ≥90% decrease in FES SUV. The effect of prior tamoxifen and fulvestrant therapy on FES SUV was assessed.

Results: Of 30 patients who underwent paired FES-PET scans, 24 (80%) achieved ≥90% decrease in FES avidity, including 1 of 3 patients receiving 200 mg/day, 2 of 4 patients receiving 400 mg/day, 14 of 16 patients receiving 600 mg/day, and 7 of 7 patients receiving 800 mg/day. Withdrawal of tamoxifen 2 months prior to FES PET/CT and withdrawal of fulvestrant 6 months prior to FES PET/CT both appeared sufficient to prevent effects on FES SUV. A dosage of 600 mg GDC-0810 per day was selected for phase II in part due to decreases in FES SUV achieved in phase I.

Conclusions: FES PET/CT was a useful biomarker of ER occupancy and/or downregulation in a phase I dose escalation trial of GDC-0810 and helped select the dosage of the ER antagonist/degrader for phase II trials. Clin Cancer Res; 23(12); 3053–60. ©2016 AACR.

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Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol

Summary

Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 ± 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.

http://ift.tt/2sd2pvb

Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV+ Patients

Purpose: Human papillomavirus (HPV) 16 plays an etiologic role in a growing subset of head and neck squamous cell carcinomas (HNSCC), where viral expression of the E6 and E7 oncoproteins is necessary for tumor growth and maintenance. Although patients with HPV⁺ tumors have a more favorable prognosis, there are currently no HPV-selective therapies. Recent studies identified differential receptor tyrosine kinase (RTK) profiles in HPV⁺ versus HPV^– tumors. One such RTK, HER3, is overexpressed and interacts with phosphoinositide-3-kinase (PI3K) in HPV⁺ tumors. Therefore, we investigated the role of HPV oncoproteins in regulating HER3-mediated signaling and determined whether HER3 could be a molecular target in HPV⁺ HNSCC.

Experimental Design: HER3 was investigated as a molecular target in HPV⁺ HNSCC using established cell lines, patient-derived xenografts (PDX), and human tumor specimens. A mechanistic link between HPV and HER3 was examined by augmenting E6 and E7 expression levels in HNSCC cell lines. The dependency of HPV⁺ and HPV^– HNSCC models on HER3 was evaluated with anti-HER3 siRNAs and the clinical stage anti-HER3 monoclonal antibody KTN3379.

Results: HER3 was overexpressed in HPV⁺ HNSCC, where it was associated with worse overall survival in patients with pharyngeal cancer. Further investigation indicated that E6 and E7 regulated HER3 protein expression and downstream PI3K pathway signaling. Targeting HER3 with siRNAs or KTN3379 significantly inhibited the growth of HPV⁺ cell lines and PDXs.

Conclusions: This study uncovers a direct relationship between HPV infection and HER3 in HNSCC and provides a rationale for the clinical evaluation of targeted HER3 therapy for the treatment of HPV⁺ patients. Clin Cancer Res; 23(12); 3072–83. ©2016 AACR.

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An interview with Sarah Weckhuysen, 2017 Epilepsia Prize Winner for Clinical Research

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An interview with Tiwalade Sobayo, 2017 Epilepsia Prize Winner for Basic Science Research

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Isolated transient vertigo: posterior circulation ischemia or benign origin?

Isolated transient vertigo can be the only symptom of posterior circulation ischemia. Thus, it is important to differentiate isolated vertigo of a cerebrovascular origin from that of more benign origins, as pa...

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Histone Deacetylase 3 Inhibition Overcomes BIM Deletion Polymorphism-Mediated Osimertinib Resistance in EGFR-Mutant Lung Cancer

Purpose: The BIM deletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non–small cell lung cancer (NSCLC) harboring EGFR mutations. Here, we investigated whether the BIM deletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.

Experimental Design: We used EGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for the BIM deletion polymorphism, to evaluate the effect of osimertinib in vitro and in vivo. Protein expression was examined by Western blotting. Alternative splicing of BIM mRNA was analyzed by RT-PCR.

Results: EGFR-mutated NSCLC cell lines with the BIM deletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage–dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygous BIM deletion–positive cells revealed that vorinostat affected the alternative splicing of BIM mRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors in EGFR-mutated NSCLC cells homozygous for the BIM deletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquired EGFR-T790M mutations.

Conclusions: These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treating EGFR-mutated lung cancers carrying the BIM deletion polymorphism. Clin Cancer Res; 23(12); 3139–49. ©2016 AACR.

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Inhibitor of Pancreatic Cancer by RHIL1RA--Letter

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Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

Gorlin syndrome and rhabdoid tumor predisposition syndrome (RTPS) are autosomal dominant syndromes associated with an increased risk of childhood-onset brain tumors. Individuals with Gorlin syndrome can manifest a wide range of phenotypic abnormalities, with about 5% of family members developing medulloblastoma, usually occurring in the first 3 years of life. Gorlin syndrome is associated with germline mutations in components of the Sonic Hedgehog pathway, including Patched1 (PTCH1) and Suppressor of fused (SUFU). SUFU mutation carriers appear to have an especially high risk of early-onset medulloblastoma. Surveillance MRI in the first years of life in SUFU mutation carriers is, therefore, recommended. Given the risk of basal cell carcinomas, regular dermatologic examinations and sun protection are also recommended. Rhabdoid tumors (RT) are tumors initially defined by the descriptive "rhabdoid" term, implying a phenotypic similarity with rhabdomyoblasts at the microscopic level. RTs usually present before the age of 3 and can arise within the cranium as atypical teratoid/rhabdoid tumors or extracranially, especially in the kidney, as malignant rhabdoid tumors. However, RTs of both types share germline and somatic mutations in SMARCB1 or, more rarely, SMARCA4, each of which encodes a chromatin remodeling family member. SMARCA4 mutations are particularly associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). The outcome following a diagnosis of any of these tumors is often poor, and the value of surveillance is unknown. International efforts to determine surveillance protocols are underway, and preliminary recommendations are made for carriers of SMARCB1 and SMARCA4 mutations. Clin Cancer Res; 23(12); e62–e67. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.

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Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models

Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA-mutant (BRCA^MUT) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression.

Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2^MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2^MUT patient-derived xenograft (PDX) model.

Results: PARPi monotherapy resulted in a decrease in BRCA^MUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2^MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR–CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCA^MUT cells. Notably, PARPi led to G₂ phase accumulation, and the addition of ATRi or CHK1i released cells from G₂ causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2^MUT PDX with the PARPi–ATRi combination inducing tumor regression and in most cases, complete remission.

Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCA^MUT models. Clin Cancer Res; 23(12); 3097–108. ©2016 AACR.

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Von Hippel-Lindau and Hereditary Pheochromocytoma/Paraganglioma Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

Von Hippel–Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the SHDx genes (SDHA, SDHB, SDHC, SDHD, SDHA, and SDHAF2), although other genes also have been described (MAX and TMEM127). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors. Clin Cancer Res; 23(12); e68–e75. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.

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Inhibition of Age-Related Therapy Resistance in Melanoma by Rosiglitazone-Mediated Induction of Klotho

Purpose: Aging is a poor prognostic factor for melanoma. We have shown that melanoma cells in an aged microenvironment are more resistant to targeted therapy than identical cells in a young microenvironment. This is dependent on age-related secreted factors. Klotho is an age-related protein whose serum levels decrease dramatically by age 40. Most studies on klotho in cancer have focused on the expression of klotho in the tumor cell. We have shown that exogenous klotho inhibits internalization and signaling of Wnt5A, which drives melanoma metastasis and resistance to targeted therapy. We investigate here whether increasing klotho in the aged microenvironment could be an effective strategy for the treatment of melanoma.

Experimental Design: PPAR increases klotho levels and is increased by glitazones. Using rosiglitazone, we queried the effects of rosiglitazone on Klotho/Wnt5A cross-talk, in vitro and in vivo, and the implications of that for targeted therapy in young versus aged animals.

Results: We show that rosiglitazone increases klotho and decreases Wnt5A in tumor cells, reducing the burden of both BRAF inhibitor–sensitive and BRAF inhibitor–resistant tumors in aged, but not young mice. However, when used in combination with PLX4720, tumor burden was reduced in both young and aged mice, even in resistant tumors.

Conclusions: Using glitazones as adjuvant therapy for melanoma may provide a new treatment strategy for older melanoma patients who have developed resistance to vemurafenib. As klotho has been shown to play a role in other cancers too, our results may have wide relevance for multiple tumor types. Clin Cancer Res; 23(12); 3181–90. ©2017 AACR.

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PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood

PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76–e82. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.

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Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk

In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83–e90. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.

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Highlights of This Issue

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Involvement of c-Fos in the Promotion of Cancer Stem-like Cell Properties in Head and Neck Squamous Cell Carcinoma

Purpose: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although improvements in surgical techniques, chemotherapy and radiation delivery, and supportive care have improved quality of life for patients with HNSCC, regional and distant recurrence remain common. Recent evidence suggests that cancer stem-like cells (CSC) play a significant role in recurrence and chemoresistance. We previously observed that c-Fos was highly upregulated in the HNSCC sphere–forming cells. Consequences of c-Fos upregulation for the biology of HNSCC-CSCs are poorly understood. In this study, we investigated the role of c-Fos in renewal of stemness of HNSCC and tumor growth.

Experimental Design and Results: We generated stable HNSCC cell lines ectopically expressing the c-Fos gene. Exogenous expression of c-Fos in nontumorigenic MDA1386Tu cells makes these cells tumorigenic in nude mice. Furthermore, subcutaneous transplantation of c-Fos–overexpressing Cal27 cells (tumorigenic) into immunocompromised mice enhanced tumor growth as compared with parental cells. Mechanistic investigations demonstrated that c-Fos overexpression enhanced the epithelial–mesenchymal transition (EMT) state and expression of CSC markers (Nanog, c-Myc, Sox2, and Notch1). Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation. We further observed that overexpression of c-Fos increased the expression of pERK and cyclin D1 in HNSCC cells.

Conclusions: Together, our results strongly suggest a novel role of c-Fos as a regulator of EMT and cancer stem cell reprogramming in HNSCC cells, which may hold potential as a CSC-directed therapeutic approach to improve HNSCC treatment. Clin Cancer Res; 23(12); 3120–8. ©2016 AACR.

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The "Tricky Business" of Identifying Mechanisms of Resistance to Anti-PD-1

Resistance to immune checkpoint inhibitors can vary between patients and among metastases. Understanding the genomic, transcriptomic, and microenvironmental factors that contribute to this variability will reveal the mechanisms that tumors utilize to evade the therapeutic effects of checkpoint inhibitor immunotherapies and will enable us to develop strategies to overcome them. Clin Cancer Res; 23(12); 2921–3. ©2017 AACR.

See related article by Ascierto et al., p. 3168

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PD-L2 Expression in Human Tumors: Relevance to Anti-PD-1 Therapy in Cancer

Purpose: Tumor-associated PD-L1 expression is predictive of clinical response to PD-1–directed immunotherapy. However, PD-L1–negative patients may also respond to PD-1 checkpoint blockade, suggesting that other PD-1 ligands may be relevant to the clinical activity of these therapies. The prevalence of PD-L2, the other known ligand of PD-1, and its relationship to response to anti-PD-1 therapy were evaluated.

Experimental Design: PD-L2 expression was assessed in archival tumor tissue from seven indications using a novel immunohistochemical assay. In addition, relationships between clinical response and PD-L2 status were evaluated in tumor tissues from patients with head and neck squamous cell carcinoma (HNSCC) with recurrent or metastatic disease, treated with pembrolizumab.

Results: PD-L2 expression was observed in all tumor types and present in stromal, tumor, and endothelial cells. The prevalence and distribution of PD-L2 correlated significantly with PD-L1 (P = 0.0012–<0.0001); however, PD-L2 was detected in the absence of PD-L1 in some tumor types. Both PD-L1 and PD-L2 positivity significantly predicted clinical response to pembrolizumab on combined tumor, stromal and immune cells, with PD-L2 predictive independent of PD-L1. Response was greater in patients positive for both PD-L1 and PD-L2 (27.5%) than those positive only for PD-L1 (11.4%). PD-L2 status was also a significant predictor of progression-free survival (PFS) with pembrolizumab independent of PD-L1 status. Longer median times for PFS and overall survival were observed for PD-L2–positive than PD-L2–negative patients.

Conclusions: Clinical response to pembrolizumab in patients with HNSCC may be related partly to blockade of PD-1/PD-L2 interactions. Therapy targeting both PD-1 ligands may provide clinical benefit in these patients. Clin Cancer Res; 23(12); 3158–67. ©2017 AACR.

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Western Diet Deregulates Bile Acid Homeostasis, Cell Proliferation, and Tumorigenesis in Colon

Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer. Here, we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to colorectal cancer. WD increased colon tumor numbers, and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation. Despite increased luminal BA, colonocytes from WD-fed mice exhibited decreased expression of the BA transporters FABP6, OSTβ, and ASBT and decreased concentrations of secondary BA deoxycholic acid and lithocholic acid, indicating reduced activity of the nuclear BA receptor FXR. Overall, our results suggest that WD increases cancer risk by FXR inactivation, leading to BA deregulation and increased colon cell proliferation. Cancer Res; 77(12); 3352–63. ©2017 AACR.

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p62/SQSTM1 Cooperates with Hyperactive mTORC1 to Regulate Glutathione Production, Maintain Mitochondrial Integrity, and Promote Tumorigenesis

p62/sequestosome-1 (SQSTM1) is a multifunctional adaptor protein and autophagic substrate that accumulates in cells with hyperactive mTORC1, such as kidney cells with mutations in the tumor suppressor genes tuberous sclerosis complex (TSC)1 or TSC2. Here we report that p62 is a critical mediator of TSC2-driven tumorigenesis, as Tsc2+/− and Tsc2f/f Ksp-CreERT2+ mice crossed to p62−/− mice were protected from renal tumor development. Metabolic profiling revealed that depletion of p62 in Tsc2-null cells decreased intracellular glutamine, glutamate, and glutathione (GSH). p62 positively regulated the glutamine transporter Slc1a5 and increased glutamine uptake in Tsc2-null cells. We also observed p62-dependent changes in Gcl, Gsr, Nqo1, and Srxn1, which were decreased by p62 attenuation and implicated in GSH production and utilization. p62 attenuation altered mitochondrial morphology, reduced mitochondrial membrane polarization and maximal respiration, and increased mitochondrial reactive oxygen species and mitophagy marker PINK1. These mitochondrial phenotypes were rescued by addition of exogenous GSH and overexpression of Sod2, which suppressed indices of mitochondrial damage and promoted growth of Tsc2-null cells. Finally, p62 depletion sensitized Tsc2-null cells to both oxidative stress and direct inhibition of GSH biosynthesis by buthionine sulfoximine. Our findings show how p62 helps maintain intracellular pools of GSH needed to limit mitochondrial dysfunction in tumor cells with elevated mTORC1, highlighting p62 and redox homeostasis as nodal vulnerabilities for therapeutic targeting in these tumors. Cancer Res; 77(12); 3255–67. ©2017 AACR.

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FOXM1 in Cancer: Interactions and Vulnerabilities

FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers, and it has been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to transactivate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an oncogenic role by interacting with other proteins, such as β-catenin or SMAD3 to induce oncogenic WNT and TGFβ signaling pathways, respectively. In this review, I will discuss the protein–protein interactions of FOXM1 that are critical for cancer development and may represent novel targets for anticancer drugs. Cancer Res; 77(12); 3135–9. ©2017 AACR.

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Nature and Nurture: What Determines Tumor Metabolic Phenotypes?

Understanding the genetic basis of cancer has led to therapies that target driver mutations and has helped match patients with more personalized drugs. Oncogenic mutations influence tumor metabolism, but other tumor characteristics can also contribute to their metabolic phenotypes. Comparison of isogenic lung and pancreas tumor models suggests that use of some metabolic pathways is defined by lineage rather than by driver mutation. Lung tumors catabolize circulating branched chain amino acids (BCAA) to extract nitrogen for nonessential amino acid and nucleotide synthesis, whereas pancreatic cancer obtains amino acids from catabolism of extracellular protein. These differences in amino acid metabolism translate into distinct pathway dependencies, as genetic disruption of the enzymes responsible for utilization of BCAA nitrogen limits the growth of lung tumors, but not pancreatic tumors. These data argue that some cancer metabolic phenotypes are defined by cancer tissue-of-origin and environment and that these features constrain the influence of genetic mutations on metabolism. A better understanding of the factors defining tumor nutrient utilization could be exploited to help improve cancer therapy. Cancer Res; 77(12); 3131–4. ©2017 AACR.

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Oncogenic Role of SND1 in Development and Progression of Hepatocellular Carcinoma

SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3′, 5′-deoxythymidine bisphosphate (pdTp), inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC. Cancer Res; 77(12); 3306–16. ©2017 AACR.

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Highlights from Recent Cancer Literature

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Human Subjects Protection and Cancer Surveillance Research: Revised Regulations, Expanded Opportunities

On January 19, 2017, the United States federal government issued revisions to the Common Rule under which scientists who receive federal funding conduct research involving human subjects. The revised Common Rule expressly addresses public health surveillance in relation to scientific research and the protection of human subjects, and its impacts are anticipated to contribute to the efficiency of activities, including cancer registration and surveillance, and research that uses cancer registry data. Cancer Res; 77(12); 3140–3. ©2017 AACR.

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Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer

PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin β1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin β1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition. Cancer Res; 77(12); 3280–92. ©2017 AACR.

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Interaction between Tumor Cell Surface Receptor RAGE and Proteinase 3 Mediates Prostate Cancer Metastasis to Bone

Human prostate cancer often metastasizes to bone, but the biological basis for such site-specific tropism remains largely unresolved. Recent work led us to hypothesize that this tropism may reflect pathogenic interactions between RAGE, a cell surface receptor expressed on malignant cells in advanced prostate cancer, and proteinase 3 (PR3), a serine protease present in inflammatory neutrophils and hematopoietic cells within the bone marrow microenvironment. In this study, we establish that RAGE–PR3 interaction mediates homing of prostate cancer cells to the bone marrow. PR3 bound to RAGE on the surface of prostate cancer cells in vitro, inducing tumor cell motility through a nonproteolytic signal transduction cascade involving activation and phosphorylation of ERK1/2 and JNK1. In preclinical models of experimental metastasis, ectopic expression of RAGE on human prostate cancer cells was sufficient to promote bone marrow homing within a short timeframe. Our findings demonstrate how RAGE–PR3 interactions between human prostate cancer cells and the bone marrow microenvironment mediate bone metastasis during prostate cancer progression, with potential implications for prognosis and therapeutic intervention. Cancer Res; 77(12); 3144–50. ©2017 AACR.

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Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling

Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells with KRAS and additional alterations to CDKN2A, TP53, or SMAD4 genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection, followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual. Cancer Res; 77(12); 3325–35. ©2017 AACR.

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Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice

Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Coexpression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with ATOH1. MCPyV sT, when coexpressed with ATOH1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. Cancer Res; 77(12); 3151–7. ©2017 AACR.

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TLR-3/9 Agonists Synergize with Anti-ErbB2 mAb—Letter

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Increased T-cell Infiltration Elicited by Erk5 Deletion in a Pten-Deficient Mouse Model of Prostate Carcinogenesis

Prostate cancer does not appear to respond to immune checkpoint therapies where T-cell infiltration may be a key limiting factor. Here, we report evidence that ablating the growth regulatory kinase Erk5 can increase T-cell infiltration in an established Pten-deficient mouse model of human prostate cancer. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared with control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression. A comparative transcriptomic analysis revealed upregulation in prostate DKO mice of the chemokines Ccl5 and Cxcl10, two potent chemoattractants for T lymphocytes. Consistent with this effect, we observed a relative increase in a predominantly CD4+ T-cell infiltrate in the prostate epithelial and stroma of tumors from DKO mice. Collectively, our results offer a preclinical proof of concept for ERK5 as a target to enhance T-cell infiltrates in prostate cancer, with possible implications for leveraging immune therapy in this disease. Cancer Res; 77(12); 3158–68. ©2017 AACR.

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Micellar Delivery of miR-34a Modulator Rubone and Paclitaxel in Resistant Prostate Cancer

Treatment of prostate cancer with paclitaxel often fails due to the development of chemoresistance caused by downregulation of the tumor suppressor gene miR-34a. In this study, we demonstrate that codelivery of paclitaxel and 2'-hydroxy-2,4,4',5,6'-pentamethoxychalcone (termed rubone) drives upregulation of miR-34a and chemosensitizes paclitaxel-resistant prostate cancer cells, killing both cancer stem–like cells (CSC) and bulk tumor cells. Rubone upregulated miR-34a and reversed its downstream target genes in DU145-TXR and PC3-TXR cells. Paclitaxel and rubone combination therapy inhibited tumor cell growth, migration, and CSC population growth. We synthesized poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol; PEG-PCD) to prepare micelles. The drug-loading capacities were 9.70% ± 0.10% and 5.34% ± 0.02% for paclitaxel and rubone, respectively, controlling a drug release of 60.20% ± 2.67% and 60.62% ± 4.35% release of paclitaxel and rubone at 24 hours. Delivery of miR-34a and rubone decreased PC3-TXR cell viability with increasing paclitaxel concentration. Coincubation with a miR-34a inhibitor diminished the effect of rubone. Paclitaxel IC50 in PC3 and PC3-TXR cells was 55.6 and 2,580 nmol/L, respectively, but decreased to 49.8 and 93.2 nmol/L when treated in combination with rubone, demonstrating a reversal of paclitaxel resistance by rubone. Systemic administration of micelles carrying paclitaxel and rubone inhibited orthotopic prostate tumor growth in nude mice, compared with monotherapy, by reversing the expression of miR-34a, SIRT1, cyclin D1, and E-cadherin. In summary, our results showed how rubone acts as an efficient small-molecule modulator of miR-34a to reverse chemoresistance and further enhance the therapeutic efficacy of paclitaxel in paclitaxel-resistant prostate cancer. Cancer Res; 77(12); 3244–54. ©2017 AACR.

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Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response

The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair. Tumors expressing phosphomimetic Mre11 were more sensitive to the PARP inhibitor olaparib, compared with those expressing unphosphorylatable Mre11, suggesting that patients with elevated Plk1 expression might benefit from olaparib treatment. Cancer Res; 77(12); 3169–80. ©2017 AACR.

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IL4 Primes the Dynamics of Breast Cancer Progression via DUSP4 Inhibition

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor–positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24− cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268–79. ©2017 AACR.

http://ift.tt/2scJ25p

TWIST1-WDR5-Hottip Regulates Hoxa9 Chromatin to Facilitate Prostate Cancer Metastasis

TWIST1 is a transcription factor critical for development that can promote prostate cancer metastasis. During embryonic development, TWIST1 and HOXA9 are coexpressed in mouse prostate and then silenced postnatally. Here we report that TWIST1 and HOXA9 coexpression are reactivated in mouse and human primary prostate tumors and are further enriched in human metastases, correlating with survival. TWIST1 formed a complex with WDR5 and the lncRNA Hottip/HOTTIP, members of the MLL/COMPASS–like H3K4 methylases, which regulate chromatin in the Hox/HOX cluster during development. TWIST1 overexpression led to coenrichment of TWIST1 and WDR5 as well as increased H3K4me3 chromatin at the Hoxa9/HOXA9 promoter, which was dependent on WDR5. Expression of WDR5 and Hottip/HOTTIP was also required for TWIST1-induced upregulation of HOXA9 and aggressive cellular phenotypes such as invasion and migration. Pharmacologic inhibition of HOXA9 prevented TWIST1-induced aggressive prostate cancer cellular phenotypes in vitro and metastasis in vivo. This study demonstrates a novel mechanism by which TWIST1 regulates chromatin and gene expression by cooperating with the COMPASS-like complex to increase H3K4 trimethylation at target gene promoters. Our findings highlight a TWIST1–HOXA9 embryonic prostate developmental program that is reactivated during prostate cancer metastasis and is therapeutically targetable. Cancer Res; 77(12); 3181–93. ©2017 AACR.

http://ift.tt/2rtvPb3

Multifunctional Telodendrimer Nanocarriers Restore Synergy of Bortezomib and Doxorubicin in Ovarian Cancer Treatment

We have developed multifunctional nanoparticles for codelivery of bortezomib and doxorubicin to synchronize their pharmacokinetic profiles and synergize their activities in solid tumor treatment, a need still unmet in the clinic. Micellar nanoparticles were formed by a spatially segregated, linear-dendritic telodendrimer containing three segments: a hydrophilic polyethylene glycol (PEG), a bortezomib-conjugating intermediate, and a dendritic doxorubicin-affinitive interior. Bortezomib-conjugated telodendrimers, together with doxorubicin, self-assembled into monodispersed micelles [NP(BTZ-DOX)] with small particle sizes (20–30 nm) for dual drug delivery. NP(BTZ-DOX) displayed excellent drug-loading capacity and stability, which minimized premature drug leakage and synchronized drug release profiles. Bortezomib release was accelerated significantly by acidic pH, facilitating drug availability in the acidic tumor microenvironment. Synergistic anticancer effects of combined bortezomib and doxorubicin were observed in vitro against both multiple myeloma and ovarian cancer cells. NP(BTZ-DOX) prolonged payload circulation and targeted tumors in vivo efficiently with superior signal ratios of tumor to normal organs. In vitro and in vivo proteasome inhibition analysis and biodistribution studies revealed decreased toxicity and efficient intratumoral bortezomib and doxorubicin delivery by nanoformulation. NP(BTZ-DOX) exhibited significantly improved ovarian cancer treatment in SKOV-3 xenograft mouse models in comparison with free drugs and their combinations, including bortezomib and Doxil. In summary, tumor-targeted and synchronized delivery system elicits enhanced anticancer effects and merits further development in the clinical setting. Cancer Res; 77(12); 3293–305. ©2017 AACR.

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tRF/miR-1280 Suppresses Stem Cell-like Cells and Metastasis in Colorectal Cancer

Several studies have shown that tRNAs can be enzymatically cleaved to generate distinct classes of tRNA-derived fragments (tRF). Here, we report that tRF/miR-1280, a 17-bp fragment derived from tRNALeu and pre-miRNA, influences Notch signaling pathways that support the function of cancer stem-like cells (CSC) in colorectal cancer progression. tRF/miR-1280 expression was decreased in human specimens of colorectal cancer. Ectopic expression of tRF/miR-1280 reduced cell proliferation and colony formation, whereas its suppression reversed these effects. Mechanistic investigations implicated the Notch ligand JAG2 as a direct target of tRF/miR-1280 binding through which it reduced tumor formation and metastasis. Notably, tRF/miR-1280–mediated inactivation of Notch signaling suppressed CSC phenotypes, including by direct transcriptional repression of the Gata1/3 and miR-200b genes. These results were consistent with findings of decreased levels of miR-200b and elevated levels of JAG2, Gata1, Gata3, Zeb1, and Suz12 in colorectal cancer tissue specimens. Taken together, our results established that tRF/miR-1280 suppresses colorectal cancer growth and metastasis by repressing Notch signaling pathways that support CSC phenotypes. Furthermore, they provide evidence that functionally active miRNA can be derived from tRNA, offering potential biomarker and therapeutic uses. Cancer Res; 77(12); 3194–206. ©2017 AACR.

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Immune Gene Expression Is Associated with Genomic Aberrations in Breast Cancer

The presence of tumor-infiltrating lymphocytes (TIL) is a favorable prognostic factor in breast cancer, but what drives immune infiltration remains unknown. Here we examine if clonal heterogeneity, total mutation load, neoantigen load, copy number variations (CNV), gene- or pathway-level somatic mutations, or germline polymorphisms (SNP) are associated with immune metagene expression in breast cancer subtypes. Thirteen published immune metagenes correlated separately with genomic metrics in the three major breast cancer subtypes. We analyzed RNA-Seq, DNA copy number, mutation and germline SNP data of 627 ER+, 207 HER2+, and 191 triple-negative (TNBC) cancers from The Cancer Genome Atlas. P-values were adjusted for multiple comparisons, and permutation testing was used to assess false discovery rates. Increased immune metagene expression associated significantly with lower clonal heterogeneity estimated by MATH score in all subtypes and with a trend for lower overall mutation, neoantigen, and CNV loads in TNBC and HER2+ cancers. In ER+ cancers, mutation load, neoantigen load, and CNV load weakly but positively associated with immune infiltration, which reached significance for overall mutation load only. No highly recurrent single gene or pathway level mutations associated with immune infiltration. High immune gene expression and lower clonal heterogeneity in TNBC and HER2+ cancers suggest an immune pruning effect and equilibrium between immune surveillance and clonal expansion. Thus, immune checkpoint inhibitors may tip the balance in favor of immune surveillance in these cancers. Cancer Res; 77(12); 3317–24. ©2017 AACR.

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Erratum to: Early gastric adenocarcinoma arising within foveolar-type dysplasia in a patient with Muir-Torre variant Lynch syndrome

http://ift.tt/2srkmIh

Clinical development of PD-1/PD-L1 immunotherapy for gastrointestinal cancers: facts and hopes

Gastrointestinal (GI) cancers are among the most deadly malignancies. Whereas serial incremental survival benefits have been made with cytotoxic chemotherapy with metastatic disease, a plateau of achievement has been reached. Applying modern integrative genomic technology, distinct molecular subgroups have been identified in GI cancers. This not only highlighted the heterogeneity in tumours of each primary anatomical site, it also identified novel therapeutic targets in distinct molecular subgroups and might improve the yield of clinical success. Molecular characteristics of tumours and their interaction with tumour microenvironment would further impact on development of combination therapy, including immunotherapy. Currently immune checkpoint blockade attracts the most intense research and the successful integration of these novel agents in GI cancers in the treatment paradigm requires an in-depth understanding of the diverse immune environment of these cancers.

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Prevalence of and risk factors for HBV infection in a metropolitan Southern Italian area: Evidence for the effectiveness of universal Hepatitis B vaccination.

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The novel association of circulating tumor cells and circulating megakaryocytes with prostate cancer prognosis

Purpose: To develop an approach for the investigation of different subtypes of circulating tumor cells (CTCs) and other cells to evaluate their potential prognostic value of prostate cancer.<br /><br />Experimental Design: Malignancy of CTCs undergoing epithelial to mesenchymal transition (EMT) was confirmed by repeated Fluorescence in situ hybridization. Subgroups of CTCs in 81 patients with prostate cancer (43 castration resistant and 38 untreated localized) were correlated to disease aggressiveness parameters. Area under curve analysis was applied to compare the performance for metastasis prediction between serum PSA level alone and a combined risk score using both PSA and EMTing CTC count. Circulating megakaryocytes and cancer patient survival association was performed using Cox model.<br /><br />Results: The majority of vimentin(VIM)+/CD45- cells were malignant with genomic alterations in several genomic regions. The number of cytokeratin(CK)-/VIM+/CD45- CTCs correlated with disease burden, tumor aggressiveness and poorer survival. Meanwhile, CK+/VIM+/CD45- CTCs were associated with metastases better than other subtypes of CTCs in these limited samples. Combination of PSA level and the number of CK+/VIM+/CD45- CTCs enhanced the prediction of cancer metastases (AUC 0.921, 95%CI: 0.858-0.985). The number of circulating megakaryocytes was potentially associated with good patient survival in advanced prostate cancer (HR:0.849, 95%CI:0.628-1.146, per cell increase) and the difference between the number of mesenchymal CTCs and megakaryocytes strongly correlated to poor survival (HR:10.17, 95%CI:2.164-47.789, if score ≥2.0).<br /><br />Conclusions: This CTC analysis approach and the potential association of megakaryocytes with cancer prognosis may greatly enhance our ability to investigate the cancer metastasis process and to predict/monitor cancer progression.

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A Phase 1b Open Label Multicentre Study of AZD4547 in Patients with Advanced Squamous Cell Lung Cancers

Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in ~20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with anti-tumor activity in FGFR1 amplified SQCLC cell lines and patient-derived xenografts. <br /><br />Experimental Design: Based on these data, we performed a phase 1 study of AZD4547 in patients with previously treated stage IV FGFR1 amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included anti-tumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses. <br /><br />Results: 15 FGFR1 amplified patients were treated. The most common related AEs were gastrointestinal and dermatologic. Grade ≥ 3 related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). 2/15 (13.3%) patients were progression free at 12 weeks and the median overall survival was 4.9 months. Molecular tests including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in the 8p11 amplicon. <br /><br />Conclusions:AZD4547 was tolerable at the 80mg po bid dose with modest anti-tumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational co-variates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease.

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MOLECULAR PATHWAYS: TARGETING THE MICROENVIRONMENT OF LIVER METASTASES

Curative treatment for metastatic solid cancers remains elusive. The liver, which is nourished by a rich blood supply from both the arterial and portal venous systems is the most common site of visceral metastases, particularly from cancers arising in the gastrointestinal (GI) tract, with colorectal cancer (CRC) being the predominant primary site in Western countries. A mounting body of evidence suggests that the liver microenvironment (LME) provides autocrine and paracrine signals originating from both parenchymal and non-parenchymal cells, that collectively create both pre-and pro-metastatic niches for the development of hepatic metastases. These resident cells and their molecular mediators represent potential therapeutic targets for the prevention and/or treatment of liver metastases (LM). This review summarizes: 1) the current therapeutic options for treating LM with a particular focus on CRC LM (CRCLM); 2) the role of the LME in LM at each of its phases 3) potential targets in the LME identified through pre-clinical and clinical investigations and 4) potential therapeutic approaches for targeting elements of the LME before and/or after the onset of LM, as the basis for future clinical trials.

http://ift.tt/2towfvS

Cardioprotection against Heart Failure by Shenfu Injection via TGF-β/Smads Signaling Pathway

Objective. To explore the potential cardioprotective mechanism of Shenfu injection (SFI) against heart failure (HF) by attenuating myocardial fibrosis and cardiac remodeling. Methods and Results. Four weeks after myocardial infarction (MI), adult male Sprague Dawley rats were randomized for 4-week treatment with Valsartan, SFI, or vehicle. Echocardiography and hemodynamics were applied to evaluate cardiac functions. Myocardia of coronary artery ligated (CAD) rats were observed to investigate changes in cardiac structure and function. Our findings suggest that treatment with SFI could inhibit progression of myocardial fibrosis and attenuate cardiac remodeling. In addition, SFI decreased expression of Smad2 and Smad3, while increasing the expression of Smad7 through regulation of TGF-β/Smads signaling pathway. Conclusion. Treatment with SFI in Sprague Dawley rats improves ventricular structure and function and reduces cardiac fibrosis by ameliorating TGF-β/Smads signaling pathway after ventricular remodeling.

http://ift.tt/2s3yzuv

Informing Reimbursement Decisions Using Cost-Effectiveness Modelling: A Guide to the Process of Generating Elicited Priors to Capture Model Uncertainties

Abstract

In informing decisions, utilising health technology assessment (HTA), expert elicitation can provide valuable information, particularly where there is a less-developed evidence-base at the point of market access. In these circumstances, formal methods to elicit expert judgements are preferred to improve the accountability and transparency of the decision-making process, help reduce bias and the use of heuristics, and also provide a structure that allows uncertainty to be expressed. Expert elicitation is the process of transforming the subjective and implicit knowledge of experts into their quantifiable expressions. The use of expert elicitation in HTA is gaining momentum, and there is particular interest in its application to diagnostics, medical devices and complex interventions such as in public health or social care. Compared with the gathering of experimental evidence, elicitation constitutes a reasonably low-cost source of evidence. Given its inherent subject nature, the potential biases in elicited evidence cannot be ignored and, due to its infancy in HTA, there is little guidance to the analyst wishing to conduct a formal elicitation exercise. This article attempts to summarise the stages of designing and conducting an expert elicitation, drawing on key literature and examples, most of which are not in HTA. In addition, we critique their applicability to HTA, given its distinguishing features. There are a number of issues that the analyst should be mindful of, in particular the need to appropriately characterise the uncertainty associated with model inputs and the fact that there are often numerous parameters required, not all of which can be defined using the same quantities. This increases the need for the elicitation task to be as straightforward as possible for the expert to complete.

http://ift.tt/2toQD02

Serum Zonulin, Gut Permeability, and the Pathogenesis of Autism Spectrum Disorders: Cause, Effect, or an Epiphenomenon?

Autism is not a single disorder, but a spectrum of related disorders (autism spectrum disorders [ASD]) with a shared core of symptoms defined by deficits in communication, social reciprocity, and repetitive, stereotypic behaviors.

http://ift.tt/2scGowu

Utility of Neurovascular Imaging in Acute Neonatal Arterial Ischemic Stroke

To evaluate the prevalence of magnetic resonance angiography (MRA) findings and clinically characterize neonates with arterial ischemic stroke (AIS) who have abnormal or variable vasculature.

http://ift.tt/2rtsTv2

Midostaurin for the treatment of acute myeloid leukemia

Future Oncology Ahead of Print.


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Regorafenib: a newly approved drug for advanced hepatocellular carcinoma

Future Oncology Ahead of Print.


http://ift.tt/2rya4lB

Exploiting natural killer group 2D receptors for CAR T-cell therapy

Future Oncology Ahead of Print.


http://ift.tt/2s3elB4

Methods to analyze big data in pharmacogenomics research

Pharmacogenomics Ahead of Print.


http://ift.tt/2s3h9ht

Standard versus Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Prospective Randomized Study

Symptomatic spondylolisthesis patients may benefit from surgical decompression and stabilization. The standard (S) technique is a transforaminal lumbar interbody fusion (TLIF). Newer, minimally invasive (MI) techniques seem to provide similar results with less morbidity. We enrolled patients with at least 6 months of symptoms and image-confirmed low-grade spondylolisthesis, at a single academic institution, between 2011 and 2015. The patients were randomized to either S or MI TLIF. The primary outcome measure was the Oswestry Disability Index (ODI) improvement at 1 year. Secondary outcome measures included length of operation, estimated blood loss, length of hospitalization, and fusion rates at 1 year. Forty patients were enrolled in each group. The differences in mean operative time and estimated blood loss were not statistically significant between the two groups. The patients were discharged after surgery at 4.12 days for the S TLIF group and 1.92 days for the MI TLIF group. The ODI improvement was similar and statistically significant in both groups. The fusion was considered solid in 36 (90%) of patients at 1 year in both groups. In conclusion, the two techniques provided similar clinical and radiological outcomes at 1 year. The patients undergoing MI TLIF had a shorter hospital stay. This trial is registered with NCT03155789.

http://ift.tt/2sqKF1s

CT radiomics predicts HPV status and local tumor control after definitive radiochemotherapy in head and neck squamous cell carcinoma

This study shows that higher pre-treatment tumor heterogeneity, quantified using radiomics of contrast-enhanced CT imaging, is associated with worse prognosis in head and neck squamous cell carcinoma and the absence of HPV infection. Overall, our analysis provides an evidence that a radiomic signature might be a useful input in risk assessment in addition to clinical parameters (tumor stage, tumor volume and HPV status).

http://ift.tt/2t4frev

Clinical Research Ethics: Considerations for the Radiation Oncologist

Consideration of clinical research ethics in radiation oncology is underexplored relative to other areas of oncology. A number of ethical challenges related to informed consent, randomization, conflicts of interest, and scientific validity and social value are shared with other areas of medicine, although their exact inflections are specific to radiation oncology. In addition, there are unique concerns in radiation oncology arising from: the rapid evolution and uneven distribution of radiation technologies; the greater unfamiliarity of the general public and research oversight committees in regards to radiation oncology clinical practice; and the high complexity of managing most radiation oncology research, much of which is carried out in high-acuity multidisciplinary oncologic settings.

http://ift.tt/2sunbJn

Subclinical white matter lesions and medial temporal lobe atrophy are associated with EEG slowing in a memory clinic cohort

As the world's population ages, the identification of subjects at increased risk of Alzheimer's dementia and the early detection of Alzheimer's disease (AD) are key topics in research and are also of increasing relevance in clinical care and patient counselling. Newly refined diagnostic criteria for AD now better define clinical phenotype and integrate neuroimaging and cerebrospinal fluid biomarkers into the diagnostic process. They cover the full staging of the disease from the subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) to clinically obvious dementia (Dubois et al., 2014).

http://ift.tt/2sCdJ6H

Macrophages Promote Resistance to Checkpoint Inhibitors [News in Brief]

Researchers find that macrophages remove PD-1–blocking antibodies from T cells.

http://ift.tt/2rsQ4pz

High glucose increases action potential firing of catecholamine neurons in the nucleus of the solitary tract by increasing spontaneous glutamate inputs.

Glucose is a crucial substrate essential for cell survival and function. Changes in glucose levels impact neuronal activity and glucose deprivation increases feeding. Several brain regions have been shown to respond to glucoprivation, including the nucleus of the solitary tract (NTS) in the brainstem. The NTS is the primary site in the brain that receives visceral afferent information from the gastrointestinal tract. The catecholaminergic (CA) subpopulation within the NTS modulates many homeostatic functions including cardiovascular reflexes, respiration, food intake, arousal and stress. However, it is not known if they respond to changes in glucose. Here we determined whether NTS-CA neurons respond to changes in glucose concentration and the mechanism involved. We found that decreasing glucose concentrations from 5mM to 2mM to 1mM, significantly decreased action potential firing in a cell-attached preparation, while increasing it back to 5 mM increased the firing rate. This effect was dependent on glutamate release from afferent terminals and required presynaptic 5-HT3Rs. Decreasing the glucose concentration also decreased both basal and 5-HT3R-agonist induced increase in the frequency of spontaneous glutamate inputs onto NTS-CA neurons. Low glucose also blunted 5-HT induced inward currents in nodose ganglia neurons, which are the cell bodies of vagal afferents. The effect of low glucose in both nodose ganglia cells and in NTS slices was mimicked by the glucokinase inhibitor glucosamine. This study suggests that NTS-CA neurons are glucosensing through a presynaptic mechanism that is dependent on vagal glutamate release, 5-HT3R activity, and glucokinase.

http://ift.tt/2suRoIi

Nkx2.5 is Essential to Establish Normal Heart Rate Variability in the Zebrafish Embryo

Heart rate variability (HRV) has become an important clinical marker of cardiovascular health and a research measure for the study of the cardiac conduction system and its autonomic controls. While zebrafish (Danio rerio) is an ideal vertebrate model for understanding heart development, HRV has only recently been investigated in this system. We have previously demonstrated that nkx2.5 and nkx2.7, two homologues of Nkx2-5 expressed in zebrafish cardiomyocytes, play vital roles in maintaining cardiac chamber-specific characteristics. Given observed defects in ventricular and atrial chamber identities in nkx2.5^-/- embryos coupled with conduction system abnormalities in murine models of Nkx2.5 insufficiency, we postulated that reduced HRV would serve as a marker of poor cardiac health in nkx2.5 mutants and in other zebrafish models of human congenital heart disease. Using live video image acquisition, we derived beat-to-beat intervals to compare HRV in wild-type and nkx2.5^-/- embryos. Our data illustrate that the nkx2.5 loss-of-function model exhibits increased heart rate and decreased HRV when compared to wild type during embryogenesis. These findings validate HRV analysis as a useful quantitative tool for assessment of cardiac health in zebrafish and underscore the importance of nkx2.5 in maintaining normal heart rate and HRV during early conduction system development.

http://ift.tt/2t473LF

Efficacy and optimal duration of metallic stent in the management of refractory anastomotic stricture after liver transplantation

Anastomotic bile duct stricture (ABS) remains as one of the most common complications in liver transplant patients. Current practice of endoscopic retrograde cholangiopancreatography (ERCP) with insertion of plastic stent (PS) often requires multiple procedures before achieving stricture resolution. To date, studies utilizing covered self-expandable metallic stent (cSEMS) in ABS management reported varying degree of efficacy. The aim of this study was to analyze long term efficacy of cSEMS in patients with ABS, and identifying factor(s) influencing the probability of stricture resolution.

http://ift.tt/2rxLtgI

Comparing EUS-Fine Needle Aspiration and EUS-Fine Needle Biopsy for Solid Lesions: A Multicenter, Randomized Trial

Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) is the standard of care for tissue sampling of solid lesions adjacent to the GI tract. Fine needle biopsy (FNB) may provide higher diagnostic yield with fewer needle passes. The aim of this study was to assess the difference in diagnostic yield between FNA and FNB.

http://ift.tt/2s2Z0jM

Colon Pathology Characteristics in Li-Fraumeni Syndrome

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Diffuse Enlargement of the Pancreas: An Unusual Radiologic Presentation of a Pancreatic Neuroendocrine Tumor

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Lifestyle behaviour change in patients with non-alcoholic fatty liver disease: A qualitative study of clinical practice

http://ift.tt/2rxMcyI

Association of transferrin saturation with the arthropathy of hereditary haemochromatosis

http://ift.tt/2s31vTo

Controlling the Cost of Medicaid

The federal–state Medicaid program is facing the possibility of the largest and most consequential changes to its funding since its inception in 1965. The American Health Care Act (AHCA), H.R. 1628, as adopted by the House of Representatives on May 4, would replace the current federal matching…

http://ift.tt/2tom6PS

Alternative Science and Human Reproduction

Human reproduction has become the victim of alternative science, rife with alternative definitions of well-understood medical conditions and characterized by rejection of the scientific method as the standard for generating and evaluating evidence. Alternative science begins with alternative facts…

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Raman-encoded molecular imaging (REMI) with topically applied SERS nanoparticles for intraoperative guidance of lumpectomy

Intraoperative identification of carcinoma at lumpectomy margins would enable reduced re-excision rates, which are currently as high as 20-50%. While imaging of disease-associated biomarkers can identify malignancies with high specificity, multiplexed imaging of such biomarkers is necessary to detect molecularly heterogeneous carcinomas with high sensitivity. We have developed a Raman-encoded molecular imaging (REMI) technique in which targeted nanoparticles are topically applied on excised tissues to enable rapid visualization of a multiplexed panel of cell surface biomarkers at surgical margin surfaces. A first-ever clinical study was performed in which 57 fresh specimens were imaged with REMI to simultaneously quantify the expression of four biomarkers HER2, ER, EGFR and CD44. Combined detection of these biomarkers enabled REMI to achieve 89.3% sensitivity and 92.1% specificity for the detection of breast carcinoma. These results highlight the sensitivity and specificity of REMI to detect biomarkers in freshly resected tissue, which has the potential to reduce the rate of re-excision procedures in cancer patients.

http://ift.tt/2toxRGa

Enhanced therapeutic efficacy and memory of tumor specific CD8 T cells by ex-vivo PI3K-{delta} inhibition

Inhibition of specific Akt isoforms in CD8+ T cells promotes favored differentiation into memory versus effector cells, the former of which are superior in mediating anti-tumor immunity. In this study, we investigated the role of upstream PI3K isoforms in CD8+ T cell differentiation and assessed the potential use of PI3K isoform-specific inhibitors to favorably condition CD8+ T cells for adoptive cell therapy. The phenotype and proliferative ability of tumor antigen specific CD8+ T cells was assessed in the presence of PI3K-α, -β, or -δ inhibitors. Inhibition of PI3K-δ, but not PI3K-α or PI3K-β, delayed terminal differentiation of CD8+ T cells and maintained the memory phenotype, thus enhancing their proliferative ability and survival while maintaining their cytokine and granzyme B production ability. This effect was preserved in vivo after of ex vivo PI3K-δ inhibition in CD8+ T cells destined for adoptive transfer, enhancing their survival and also the anti-tumor therapeutic activity of a tumor-specific peptide vaccine. Our results outline a mechanism by which inhibitions of a single PI3K isoform can enhance the proliferative potential, function and survival of CD8+ T cells, with potential clinical implications for adoptive cell transfer and vaccine-based immunotherapies.

http://ift.tt/2sqPVSt

Risk of second malignancies in solid organ transplant recipients who develop keratinocyte cancers

Solid organ transplant recipients have increased risk for developing keratinocyte cancers (KC), including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, KC are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on KC occurrence, with 15 state cancer registries. Risk of developing malignancies after KC was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n=6169) was associated with 1.44-fold increased risk [95% confidence interval (CI): 1.31-1.59] for developing later malignancies. Risks were particularly elevated for non-cutaneous SCC, including those of the oral cavity/pharynx [hazard ratio (HR)=5.60, 95%CI: 4.18-7.50] and lung (HR=1.66, 95%CI: 1.16-2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR=2.77, 95%CI: 1.29-5.96) and female genital cancers (HR=3.43, 95%CI: 1.44-8.19). In contrast, BCC (n=3669) was not associated with overall risk of later malignancy (HR=0.98, 95%CI: 0.87-1.12) including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk.

http://ift.tt/2tobuAj