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Πέμπτη 22 Μαρτίου 2018

Case of a fractured human bone fragment as an endobronchial foreign body following a traffic incident

Endobronchial foreign bodies (EFBs) are present in various settings, such as eating or dental procedure. Accidental aspiration of foreign bodies is more common in children; however, cases of adult foreign body aspiration exist. Traumatic incidents can precipitate endobronchial aspiration of foreign bodies. Loss of consciousness, such as in coma, can result in foreign bodies being easily inhaled into the airways. Teeth or vehicle parts have been reported as EFBs following traumatic incidents. We report on a patient with chronic, sustained cough following maxillofacial trauma. Chest CT revealed an abnormal calcified endobronchial opacity. Flexible bronchoscopy confirmed the presence of an endobronchial foreign body in the left main bronchus. Following removal by bronchial forceps, the body was identified as a human bone fragment. Successful removal of the endobronchial bone fragment resulted in complete symptom remission. We concluded that post-traumatic respiratory complaints should be comprehensively evaluated, even if mild.



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What does vanishing bone disease look like?

Description

A previously healthy 44-year-old female presented with an acute history of increasing pain and reduced range of movement in her left shoulder. MRI scan revealed an infiltrative lesion in the proximal humerus, with a degree of cortical thinning and soft tissue involvement; however, initial biopsy provided no definitive diagnosis. Due to the suspicion of underlying malignancy, additional biopsies were organised. A second biopsy provided no diagnosis; however, a third biopsy taken 2 months after presentation revealed a benign vascular lesion with callus formation. This was consistent with the suspicion of our radiologist that a pathological fracture of the proximal humerus had been sustained following a minor fall (figure 1).

Figure 1

Radiograph of left humerus and shoulder at presentation.

Twelve months after presentation, with continued pain and swelling in the arm, further investigations were carried out. Radiographs demonstrated a second...



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Klippel-Trenaunay-Weber syndrome as a cause of chronic thromboembolic pulmonary hypertension

Description

A 52-year-old man was referred to an adult cardiovascular genetic clinic for lifelong venous tortuosity of the left leg. His medical history included recurrent deep venous thromboses of the left leg and pulmonary embolism complicated by oxygen-dependent chronic thromboembolic pulmonary hypertension and right-sided heart failure. He was taking warfarin and reported no family history of similar conditions. On examination, crackles were noted at bibasilar lungs. The left leg was slightly longer than the right leg, and giant tortuous veins were observed on the left side (figure 1A). MRI and angiography of the lower extremities revealed diffuse muscular hypertrophy (figure 1B) and bone elongation of the femur, tibia and fibula, as well as multiple capillary-venous malformations and tortuous deep and superficial veins (figure 1C) on the left leg. Chest tomography angiography showed pulmonary artery dilatation and calcified eccentric thrombus in the right pulmonary...



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Testicular torsion in a patient with Ehlers-Danlos syndrome

We present a 19-year-old man with a diagnosis of Ehlers-Danlos syndrome (EDS) and a delayed presentation of testicular torsion. EDS is a rare and heterogeneous condition affecting collagen synthesis and presents multiple difficulties in a surgical setting. Management of this case of testicular torsion was complicated by impaired cognition of the patient, difficulty with intubation, a contralateral undescended testis and postoperative bleeding. We discuss the specific challenges faced in this case of testicular torsion with longstanding ischaemia and perioperative considerations of EDS.



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Two cases of hypokalaemic rhabdomyolysis: same but different

In this paper, we present two women with hypokalaemic rhabdomyolysis in the context of increased diuretic intake and gastroenteritis, respectively. While their clinical manifestations and laboratory results were strikingly similar, two different underlying disorders were subsequently unveiled. The first patient was diagnosed with Conn syndrome, and adrenalectomy led to significant improvement of hypertension and sustained normokalaemia. The diagnosis in the second patient was Gitelman syndrome. Electrolyte supplements improved long-term lassitude and the frequency of muscle cramps declined significantly. These case vignettes illustrate the importance of establishing the underlying cause of hypokalaemia.



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A rare presentation of haematuria: hip prosthesis in the bladder

An 80-year-old woman presented to our department with visible haematuria and stage II acute kidney injury (AKI). She had stage IIB cervical cancer, for which she received chemotherapy and external beam radiotherapy in 2003. Four years later, she had a left dynamic hip screw for an extracapsular neck of femur fracture following a fall. In 2010, she underwent a right total hip replacement owing to osteoarthritis, and it was subsequently revised in 2012 owing to a right acetabular component failure. In this admission, her AKI improved with intravenous fluid administration and her haematuria settled following catheterisation with a three-way catheter and bladder irrigation with saline. She underwent a flexible cystoscopy which revealed that a part of her right hip prosthesis was in the bladder, having eroded through the right bony pelvis. However, she declined any surgical interventions.



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Importance of source images of time-of-flight magnetic resonance angiography in the diagnosis of low-flow dural arteriovenous fistulae after traumatic brain injury

Three-dimensional time-of-flight (TOF) magnetic resonance angiography (MRA) can reliably detect dural arteriovenous fistula (dAVF); however, TOF source images should be checked in cases with low-flow dAVFs. A 69-year-old woman reported intractable pulsatile tinnitus after head trauma. It was difficult to diagnose dAVF using conventional MRA, but it was confirmed using a TOF source image. Cerebral angiography revealed a dAVF with a small shunted pouch draining into the sigmoid sinus, accompanying the arterial jet flow. Transarterial embolisation of the shunted pouch completely obliterated the dAVF. The patient's tinnitus immediately disappeared after embolisation. This case suggests that a low-flow Borden type I dAVF is undetectable using conventional MRA, and we emphasise the importance of evaluating TOF source images. Transarterial embolisation of the shunted pouch while preserving the normal sinus flow was safe and effective.



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Rhinofacialentomophthoromycosis

Entomopthoromycosis is a rare subcutaneous fungal infection caused by onidiobolus coronatus affecting mainly the upper respiratory mucosa in immunocompetent people.The manifestations of this disease masquerades other clinical entities.Hence, high index of suspicion is required for prompt diagnosis.Histopathological examination and culture are the gold standard diagnostic tools, however no standard treatment protocols ha been mentioned in literature.We present a case of rhinofacial entomopthoromycosis in a yearold ma with a leftsided rhinofacial swelling to highlight the presence of this unusual fungal infection and its treatment.



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Central congenital hypothyroidism caused by maternal thyrotoxicosis

Central congenital hypothyroidism (CCH) is a rare and underdiagnosed disease that sometimes is caused by maternal Graves' disease. We report a case of CCH caused by undiagnosed, initially antibody-negative maternal thyrotoxicosis with possible disruption of fetal hypothalamic-pituitary-thyroid axis maturation. In CCH, maternal thyroid disease should be considered.



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Tarsal buckle with conjunctival prolapse following levator plication for unilateral congenital ptosis

An 8-year-old child underwent uneventful levator plication surgery for unilateral congenital ptosis. Postoperative course for initial few days was uneventful but on day 7, the patient was brought with conjunctival prolapse from the undersurface of upper eyelid due to tarsal kinking and eversion. Early medical management was initiated with frequent surface lubrication to avoid conjunctiva dryness. Under general anaesthesia, right-sided conjunctival repositioning was performed with an eyelid spatula supplemented by three forniceal stay sutures to retain the conjunctiva in its anatomical place. To reverse the tarsal kinking, continued downward traction suture was placed for a period of 2 weeks. At the end of 4 weeks, the conjunctival prolapse was completely resolved with a well-formed superior fornix. At the end of 3 months, the symmetric eyelid position was maintained without any additional complications.



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Complication of intraprosthetic dislocation of dual-mobility hip implant following closed reduction

Total hip replacement is a successful operation for the management of hip pain but there are potential complications, of which dislocation is one of the most common. The management of recurrent dislocation is a challenging problem that requires a multimodal approach and the use of dual-mobility implants is one option. We present a patient who was previously revised with a dual-mobility implant for recurrent dislocation, who had a complication after closed reduction of a subsequent intraprosthetic dislocation. Following a missed radiographical diagnosis, the patient experienced mechanical symptoms on hip flexion caused by a disassociated dual-mobility implant. Subsequent surgical removal of the failed implant and revision was required. Careful study of radiographs revealed an eccentric femoral head and evidence of the disassociated implant within the surrounding soft tissues. Radiographs following closed reduction of intraprosthetic dislocations should be scrutinised closely to detect implant failure to prevent further complications.



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Myocarditis secondary to smallpox vaccination

The development of vaccines ushered in the most profound advancement in 20th century medicine, and have widely been regarded as the one of the most important scientific discovery in the history of mankind. However, vaccines are not without risk; reactions can range from injection site reactions to life-threatening anaphylaxis. Among the more serious vaccine-related sequela is myocarditis. Although myocarditis has been reported following many different vaccines, the smallpox vaccine has the strongest association. We report a case of a 36-year-old active duty service member presenting with progressive dyspnoea, substernal chest pain and lower extremity swelling 5 weeks after receiving the vaccinia vaccination. The aetiology of his acute decompensated heart failure was determined to be from myocarditis. Although the majority of cases of myocarditis resolve completely, some patients develop chronic heart failure and even death. Vaccine-associated myocarditis should always be on the differential for patients that exhibit cardiopulmonary symptoms after recent vaccinations.



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Parkinsons disease with hypocalcaemia: adult presentation of 22q11.2 deletion syndrome

A growing amount of evidence indicates that 22q11.2 deletion syndrome (22q11.2DS) increases the risk of early-onset Parkinson's disease (EOPD). Here, we describe a 36-year-old patient with EOPD. The patient presented with 22q11.2DS features, including associated cognitive disabilities, hypocalcaemia and facial dysmorphia that led us to screen for and confirm this deletion. In addition, hypocalcaemia and vitamin D deficiency were the main factors responsible for severe, painful muscle spasms that were non-levodopa (L-Dopa) responsive and remitted after calcium and vitamin D replacement therapy. Many patients with this deletion remain undiagnosed until adulthood due to the absence of 'major' phenotypic hallmarks, which usually present during early childhood. Later onset problems involving various medical subspecialties are increasingly recognised as important components of 22q11.2DS. Therefore, the multisystem nature and associated burden of morbidities demand a high degree of suspicion for this entity from all clinicians regardless of their medical subspecialty.



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Diffusion-weighted imaging is helpful in the accurate non-invasive diagnosis of breast abscess: correlation with necrotic breast cancer

Clinical differentiation of atypical breast abscesses from necrotic tumour in premenopausal women is challenging and may delay appropriate therapy. In this case report, we present a 36-year-old woman with signs, symptoms and conventional imaging features of malignancy who underwent breast MRI. On diffusion-weighted imaging (DWI), profoundly low apparent diffusion coefficient values were a distinguishing sign of breast abscess from necrotic breast cancer, and helped manage the patient conservatively. We present a companion case of necrotic breast tumour highlighting significant differences in DWI.



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Combining baseline TMTV and gene profiling for a better risk stratification in diffuse large B cell lymphoma



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Reply: Interim FDG-PET/CT in primary mediastinal diffuse large B-cell lymphoma: really almost useless procedure?



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H. William Strauss, Giuliano Mariani, Duccio Volterrani, Steven M. Larson (editors): Nuclear Oncology: From Pathophysiology to Clinical Applications, second edition



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Value of 18 F–FDG PET/CT for predicting EGFR mutations and positive ALK expression in patients with non-small cell lung cancer: a retrospective analysis of 849 Chinese patients

Abstract

Purpose

Epidermal growth factor receptor (EGFR) mutations and the anaplastic lymphoma kinase (ALK) rearrangement are the two most common druggable targets in non-small cell lung cancer (NSCLC). However, genetic testing is sometimes unavailable. Previous studies regarding the predictive role of 18F–FDG PET/CT for EGFR mutations in NSCLC patients are conflicting. We investigated whether or not 18F–FDG PET could be a valuable noninvasive method to predict EGFR mutations and ALK positivity in NSCLC using the largest patient cohort to date.

Methods

We retrospectively reviewed and included 849 NSCLC patients who were tested for EGFR mutations or ALK status and subjected to 18F–FDG PET/CT prior to treatment. The differences in several clinical characteristics and three parameters based on 18F–FDG PET/CT, including the maximal standard uptake value (SUVmax) of the primary tumor (pSUVmax), lymph node (nSUVmax) and distant metastasis (mSUVmax), between the different subgroups were analyzed. Multivariate logistic regression analysis was performed to identify predictors of EGFR mutations and ALK positivity.

Results

EGFR mutations were identified in 371 patients (45.9%). EGFR mutations were found more frequently in females, non-smokers, adenocarcinomas and stage I disease. Low pSUVmax, nSUVmax and mSUVmax were significantly associated with EGFR mutations. Multivariate analysis demonstrated that pSUVmax < 7.0, female sex, non-smoker status and adenocarcinoma were predictors of EGFR mutations. The receiver operating characteristic (ROC) curve yielded area under the curve (AUC) values of 0.557 and 0.697 for low pSUVmax alone and the combination of the four factors, respectively. ALK-positive patients tended to have a high nSUVmax. Younger age and distant metastasis were the only two independent predictors of ALK positivity.

Conclusion

We demonstrated that low pSUVmax is associated with mutant EGFR status and could be integrated with other clinical factors to enhance the discriminability on the EGFR mutation status in some NSCLC patients whose EGFR testing is unavailable.



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Glioblastoma multiforme: another potential application for 68 Ga-PSMA PET/CT as a guide for targeted therapy



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Yuji Kuge, Tohru Shiga, Nagara Tamaki (editors): Perspectives on nuclear medicine for molecular diagnosis and integrated therapy



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Prediction of outcome using pretreatment 18 F-FDG PET/CT and MRI radiomics in locally advanced cervical cancer treated with chemoradiotherapy

Abstract

Purpose

The aim of this study is to determine if radiomics features from 18fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) images could contribute to prognoses in cervical cancer.

Methods

One hundred and two patients (69 for training and 33 for testing) with locally advanced cervical cancer (LACC) receiving chemoradiotherapy (CRT) from 08/2010 to 12/2016 were enrolled in this study. 18F-FDG PET/CT and MRI examination [T1, T2, T1C, diffusion-weighted imaging (DWI)] were performed for each patient before CRT. Primary tumor volumes were delineated with the fuzzy locally adaptive Bayesian algorithm in the PET images and with 3D Slicer™ in the MRI images. Radiomics features (intensity, shape, and texture) were extracted and their prognostic value was compared with clinical parameters for recurrence-free and locoregional control.

Results

In the training cohort, median follow-up was 3.0 years (range, 0.43–6.56 years) and relapse occurred in 36% of patients. In univariate analysis, FIGO stage (I–II vs. III–IV) and metabolic response (complete vs. non-complete) were probably associated with outcome without reaching statistical significance, contrary to several radiomics features from both PET and MRI sequences. Multivariate analysis in training test identified Grey Level Non UniformityGLRLM in PET and EntropyGLCM in ADC maps from DWI MRI as independent prognostic factors. These had significantly higher prognostic power than clinical parameters, as evaluated in the testing cohort with accuracy of 94% for predicting recurrence and 100% for predicting lack of loco-regional control (versus ~50–60% for clinical parameters).

Conclusions

In LACC treated with CRT, radiomics features such as EntropyGLCM and GLNUGLRLM from functional imaging DWI-MRI and PET, respectively, are independent predictors of recurrence and loco-regional control with significantly higher prognostic power than usual clinical parameters. Further research is warranted for their validation, which may justify more aggressive treatment in patients identified with high probability of recurrence.



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The diagnostic value of 18 F–FDG-PET/CT and MRI in suspected vertebral osteomyelitis – a prospective study

Abstract

Purpose

The aim of this study was to determine the diagnostic value of 18F–fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) and magnetic resonance imaging (MRI) in diagnosing vertebral osteomyelitis.

Methods

From November 2015 until December 2016, 32 patients with suspected vertebral osteomyelitis were prospectively included. All patients underwent both 18F–FDG-PET/CT and MRI within 48 h. All images were independently reevaluated by two radiologists and two nuclear medicine physicians who were blinded to each others' image interpretation. 18F–FDG-PET/CT and MRI were compared to the clinical diagnosis according to international guidelines.

Results

For 18F–FDG-PET/CT, sensitivity, specificity, PPV, and NPV in diagnosing vertebral osteomyelitis were 100%, 83.3%, 90.9%, and 100%, respectively. For MRI, sensitivity, specificity, PPV, and NPV were 100%, 91.7%, 95.2%, and 100%, respectively. MRI detected more epidural/spinal abscesses. An important advantage of 18F–FDG-PET/CT is the detection of metastatic infection (16 patients, 50.0%).

Conclusion

18F–FDG-PET/CT and MRI are both necessary techniques in diagnosing vertebral osteomyelitis. An important advantage of 18F–FDG-PET/CT is the visualization of metastatic infection, especially in patients with bacteremia. MRI is more sensitive in detection of small epidural abscesses.



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Solitary testicular metastasis from prostate cancer. A case report diagnosed by PET/CT with PSMA



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Preoperative prediction of microvascular invasion of hepatocellular carcinoma using 18 F-FDG PET/CT: a multicenter retrospective cohort study

Abstract

Purpose

The aim of this study was to assess the potential of tumor 18F-fluorodeoxyglucose (FDG) avidity as a preoperative imaging biomarker for the prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC).

Methods

One hundred and fifty-eight patients diagnosed with Barcelona Clinic Liver Cancer stages 0 or A HCC (median age, 57 years; interquartile range, 50–64 years) who underwent 18F-FDG positron emission tomography with computed tomography (PET/CT) before curative surgery at seven university hospitals were included. Tumor FDG avidity was measured by tumor-to-normal liver standardized uptake value ratio (TLR) of the primary tumor on FDG PET/CT imaging. Logistic regression analysis was performed to identify significant parameters associated with MVI. The predictive performance of TLR and other clinical variables was assessed using receiver operating characteristic (ROC) curve analysis.

Results

MVI was present in 76 of 158 patients with HCCs (48.1%). Multivariable logistic regression analysis revealed that TLR, serum alpha-fetoprotein (AFP) level, and tumor size were significantly associated with the presence of MVI (P < 0.001). Multinodularity was not significantly associated with MVI (P = 0.563). The area under the ROC curve (AUC) for predicting the presence of MVI was best with TLR (AUC = 0.704), followed by tumor size (AUC = 0.685) and AFP (AUC = 0.670). We were able to build an improved prediction model combining TLR, tumor size, and AFP by using multivariable logistic regression modeling (AUC = 0.756).

Conclusions

Tumor FDG avidity measured by TLR on FDG PET/CT is a preoperative imaging biomarker for the prediction of MVI in patients with HCC.



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Comparison of positron emission tomography/computed tomography and magnetic resonance imaging for posttherapy evaluation in patients with advanced cervical cancer receiving definitive concurrent chemoradiotherapy

Abstract

Purpose

Our purpose was to assess the diagnostic performance of positron emission tomography/computed tomography (PET/CT) and pelvic/abdominal magnetic resonance imaging (MRI) after concurrent chemoradiotherapy (CCRT) for posttherapy evaluation in patients with advanced cervical cancer.

Methods

Patients with cervical squamous cell carcinoma, either with advanced FIGO stage or with positive pelvic or para-aortic lymph node (PALN), received PET/CT using [18F]fluorodeoxyglucose and MRI including diffusion-weighted imaging between 2 and 3 months after CCRT completion. PET/CT were interpreted independently by two nuclear medicine physicians and MRI by two radiologists using the same scoring system. Active residual tumor was proven by pathological confirmation or disease progression on imaging studies within one year after CCRT and the disease regions were classified as local, regional, PALN, or distant. Patient-based and region-based comparison was performed using the receiver operating characteristic curve analysis.

Results

The study included 55 patients and 15 (27%) patients had active residual tumor. The diagnostic performance of PET/CT is significantly superior to that of MRI in patient-based analysis (P = 0.025) and in the detection of local (P = 0.045) and regional (P = 0.014) disease. The patient-based sensitivity, specificity, and accuracy of PET/CT are 60%, 100%, and 89% while those of MRI are 27%, 100%, and 80%.

Conclusions

PET/CT is superior to MRI for posttherapy evaluation in patients with advanced cervical cancer 2–3 months after definitive CCRT, mainly for the detection of residual local and regional disease. Patients with negative or equivocal results should be followed up regularly due to suboptimal sensitivities of imaging.



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Interpretation criteria for FDG PET/CT in multiple myeloma (IMPeTUs): final results. IMPeTUs (Italian myeloma criteria for PET USe)

Abstract

FDG PET/CT (18F-fluoro-deoxy-glucose positron emission tomography/computed tomography) is a useful tool to image multiple myeloma (MM). However, simple and reproducible reporting criteria are still lacking and there is the need for harmonization. Recently, a group of Italian nuclear medicine experts defined new visual descriptive criteria (Italian Myeloma criteria for Pet Use: IMPeTUs) to standardize FDG PET/CT evaluation in MM patients. The aim of this study was to assess IMPeTUs reproducibility on a large prospective cohort of MM patients.

Materials and methods

Patients affected by symptomatic MM who had performed an FDG PET/CT at baseline (PET0), after induction (PET-AI), and the end of treatment (PET-EoT) were prospectively enrolled in a multicenter trial (EMN02)(NCT01910987; MMY3033). After anonymization, PET images were uploaded in the web platform WIDEN® and hence distributed to five expert nuclear medicine reviewers for a blinded independent central review according to the IMPeTUs criteria. Consensus among reviewers was measured by the percentage of agreement and the Krippendorff's alpha. Furthermore, on a patient-based analysis, the concordance among all the reviewers in terms of positivity or negativity of the FDG PET/CT scan was tested for different thresholds of positivity (Deauville score (DS 2, 3, 4, 5) for the main parameters (bone marrow, focal score, extra-medullary disease).

Results

Eighty-six patients (211 FDG PET/CT scans) were included in this analysis. Median patient age was 58 years (range, 35–66 years), 45% were male, 15% of them were in stage ISS (International Staging System) III, and 42% had high-risk cytogenetics. The percentage agreement was superior to 75% for all the time points, reaching 100% of agreement in assessing the presence skull lesions after therapy. Comparable results were obtained when the agreement analysis was performed using the Krippendorff's alpha coefficient, either in every single time point of scanning (PET0, PET-AI or PET-EoT) or overall for all the scans together. DS proved highly reproducible with the highest reproducibility for score 4.

Conclusions

IMPeTUs criteria proved highly reproducible and could therefore be considered as a base for harmonizing PET interpretation in multiple myeloma. A prospective clinical validation of IMPeTUs criteria is underway.



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Reply to: “All that glitters is not gold – new reconstruction methods using Deauville criteria for patient reporting”



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Liver metastases from prostate cancer at 11C-Choline PET/CT: a multicenter, retrospective analysis

Abstract

Aim

During our daily clinical practice using 11C-Choline PET/CT for restaging patients affected by relapsing prostate cancer (rPCa) we noticed an unusual but significant occurrence of hypodense hepatic lesions with a different tracer uptake. Thus, we decided to evaluate the possible correlation between rPCa and these lesions as possible hepatic metastases.

Materials and methods

We retrospectively enrolled 542 patients diagnosed with rPCa in biochemical relapse after a radical treatment (surgery and/or radiotherapy). Among these, patients with a second tumor or other benign hepatic diseases were excluded. All patients underwent 11C-Choline PET/CT during the standard restaging workup of their disease. We analyzed CT images to evaluate the presence of hypodense lesions and PET images to identify the relative tracer uptake. In accordance to the subsequent oncological history, five clinical scenarios were recognized [Table 1]: normal low dose CT (ldCT) and normal tracer distribution (Group A); evidence of previously unknown hepatic round hypodense areas at ldCT with normal rim uptake (Group B); evidence of previously known hepatic round hypodense areas at ldCT stable over time and with normal rim uptake (Group C); evidence of previously known hepatic round hypodense areas at ldCT, in a previous PET/CT scan, with or without rim uptake and significantly changing over time in terms of size and/or uptake (Group D); evidence of hepatic round hypodense areas at ldCT with or without rim uptake confirmed as prostate liver metastases by histopathology, triple phase ceCT, ce-ultra sound (CEUS) and clinical/biochemical evaluation (Group E). We evaluated the correlation with PSA level at time of scan, rim SUVmax and association with local relapse or non-hepatic metastases (lymph nodes, bone, other parenchyma).

Results

Five hundred and forty-two consecutive patients were retrospectively enrolled. In 140 of the 542 patients more than one 11C-choline PET/CT had been performed. A total of 742 11C-Choline PET/CT scans were analyzed. Of the 542 patients enrolled, 456 (84.1%) had a normal appearance of the liver both at ldCT and PET (Group A). 19/542 (3,5%) belonged to Group B, 13/542 (2.4%) to Group C, 37/542 (6.8%) to Group D and 18/542 (3.3%) to Group E. Mean SUVmax of the rim was: 4.5 for Group B; 4.2 for Group C; 4.8 for Group D; 5.9 for Group E. Mean PSA level was 5.27 for Group A, 7.9 for Group B, 10.04 for Group C, 10.01 for Group D, 9.36 for Group E. Presence of positive findings at 11C-Choline PET/CT in any further anatomical area (local relapse, lymph node, bone, other extra hepatic sites) correlated with an higher PSA (p = 0.0285). In both the univariate and multivariate binary logistic regression analyses. PSA, SUVmax of the rim, local relapse, positive nodes were not associated to liver mets (Groups D-E) (p > 0.05). On the contrary, a significant correlation was found between the presence of liver metG (group D-E) and bone lesions (p= 0.00193).

Conclusion

Our results indicate that liver metastases in relapsing prostate cancer may occur frequently. The real incidence evaluation needs more investigations. In this case and despite technical limitations, Choline PET/CT shows alterations of tracer distribution within the liver that could eventually be mistaken for simple cysts but can be suspected when associated to high trigger PSA, concomitant bone lesions or modification over time. In this clinical setting an accurate analysis of liver tracer distribution (increased or decreased uptake) by the nuclear medicine physician is, therefore, mandatory.



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Favorable versus unfavorable prognostic groups by post-chemoradiation FDG-PET imaging in node-positive esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy

Abstract

Purpose

Our purpose was to examine the prognostic value of post-CRT PET based on the presence or absence of FDG-avid metastatic lymph node(s) and metabolic response of the primary tumor in patients with clinically node-positive ESCC treated with definitive chemoradiotherapy (dCRT).

Methods

We identified 108 eligible patients treated by chemoradiotherapy (CRT) with or without resection from our prospectively collected database. Absence of FDG-avid metastatic lymph node with at least partial response of the primary tumor on PET scan after initial CRT was defined as the Post-CRT PET favorable group (yPET-F), and otherwise as unfavorable group (yPET-U). The Kaplan-Meier method and Cox regression were performed for survival analyses and multivariable analysis, respectively.

Results

The study cohort was comprised of 59 patients receiving dCRT. Forty-five patients receiving trimodality therapy (TMT) comprised the comparative group and four patients were excluded from further analyses for developing interval distant metastasis detected on post-CRT PET scan. The median follow-up for the study cohort was 41 months. On K-M analysis of the study cohort, yPET-F was found to have significantly better OS (2-year: 72.5% vs 13.7%, p < 0.01) and DMFS (2-year: 71.6% vs 36.6%, p = 0.01) than yPET-U. In multivariable analysis, yPET-F remained as a strong independent favorable prognosticator on both OS (HR 0.08, p < 0.01) and DMFS (HR 0.14, p = 0.02) for the dCRT cohort. Compared with TMT cohort, for yPET-U patients, TMT had better OS (p = 0.03) than dCRT-Operable and dCRT-Operable had superior OS (p = 0.04) than dCRT-Unresectable. For yPET-F patients, there was no difference in both OS (p > 0.99) and DMFS (p = 0.92) between these three groups.

Conclusions

Absence of FDG-avid metastatic lymph node with at least partial response of the primary tumor on PET scan after CRT (i.e., yPET-F status) prognosticate for excellent OS and DMFS in cN+ ESCC patients treated with dCRT, and might be comparable to TMT.



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EANM guideline for radionuclide therapy with radium-223 of metastatic castration-resistant prostate cancer

Abstract

Radium Ra-223 dichloride (radium-223, Xofigo®) is a targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. Radium-223 is the first targeted alpha therapy in this indication providing a new treatment option, with evidence of a significant survival benefit, both in overall survival and in the time to the first symptomatic skeletal-related event. The skeleton is the most common metastatic site in patients with advanced prostate cancer. Bone metastases are a clinically significant cause of morbidity and mortality, often resulting in bone pain, pathologic fracture, or spinal cord compression necessitating treatment. Radium-223 is selectively accumulated in the bone, specifically in areas of high bone turnover, by forming complexes with the mineral hydroxyapatite (the inorganic matrix of the bone). The alpha radiation generated during the radioactive decay of radium-223 produces a palliative anti-tumour effect on the bone metastases. The purpose of this guideline is to assist nuclear medicine specialists in evaluating patients who might be candidates for treatment using radium-223, planning and performing this treatment, understanding and evaluating its consequences, and improving patient management during therapy and follow-up.



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Life is not black and white, nor just Shades of Gray



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EANM guidelines for radionuclide therapy of bone metastases with beta-emitting radionuclides

Abstract

The skeleton is the most common metastatic site in patients with advanced cancer. Pain is a major healthcare problem in patients with bone metastases. Bone-seeking radionuclides that selectively accumulate in the bone are used to treat cancer-induced bone pain and to prolong survival in selected groups of cancer patients. The goals of these guidelines are to assist nuclear medicine practitioners in: (a) evaluating patients who might be candidates for radionuclide treatment of bone metastases using beta-emitting radionuclides such as strontium-89 (89Sr), samarium-153 (153Sm) lexidronam (153Sm-EDTMP), and phosphorus-32 (32P) sodium phosphate; (b) performing the treatments; and ©) understanding and evaluating the treatment outcome and side effects.



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Melanoma and Immune Checkpoint Inhibitors

Abstract

Purpose of Review

Prognosis of patients with advanced melanoma is dismal with a median overall survival of about 8 months and 5-year overall survival from a diagnosis of metastatic disease of roughly 10%. However, immune checkpoint inhibitors have brought indispensable benefits to melanoma patients. Here we will review the recent clinical efficacy and adverse events of immune checkpoint inhibitors for melanoma patients.

Recent Findings

The immune checkpoint inhibitors increase confirmed objective response and prolong progression-free and overall survival of the afflicted patients in association with maintaining their quality of life. Although diverse immune-related adverse events occur, most of them are manageable by appropriate immunomodulating agents. Clinical efficacy of immune checkpoint inhibitors continues even after discontinuation of drugs.

Summary

Compared with conventional therapeutic options, the immune checkpoint inhibitors appear to prolong the survival of patients with advanced melanoma. Further clinical trials are warranted to determine whether their combinatory use with other treatment options may augment benefits or not.



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Mucosal Melanoma: a Literature Review

Abstract

Purpose of review

Mucosal melanoma is of great interest due to its aggressive behavior and less favorable prognosis. The literature is mainly case reports and case series. Here, we will collect the knowledge on mucosal melanoma from the last decade and review the literature. The main focus is being site-specific clinical features, treatment, and prognosis.

Recent findings

The use of immunotherapy gain ground as for others subsets of melanoma. Anti-CTLA-4 and anti-PD-1/ PD-L1 blockade in mucosal melanoma have been evaluated in recent studies. Clinical trials are ongoing.

Summary

The etiology of mucosal melanomas remains unknown. Head and neck mucosal melanomas are most common. Wide excision surgery is the treatment of choice. The effect of adjuvant therapy on survival remains questionable due to the limited knowledge. Radiotherapy seems to give better local control. The overall five-year survival rate for mucosal melanomas is 0–45%. Recent data indicates that this may be improved by the immunotherapy in the years to come.



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Reassembling a shattered life: A study of posttraumatic growth in displaced Cambodian community leaders.

The present study explored the concept of posttraumatic growth (PTG) and transformation among 12 Cambodian community leaders who are survivors of the Khmer Rouge genocide. Based on a phenomenological qualitative paradigm, this study used the conceptual models of PTG to explore coping, meaning making, and positive growth as both a process and an outcome. Four core themes emerged for the PTG process: (a) separation, loss, enslavement, and other dehumanizing experiences, (b) distress and psychological responses to trauma, (c) methods of coping used to manage debilitating distress, and (d) process of healing and meaning making. Five core themes emerged for the PTG outcome: (a) gratitude and greater appreciation of life, (b) new priorities and goals, (c) importance of family and interpersonal relationships, (d) increased personal strength, and (e) effective leadership. Principal findings in this study highlighted the importance of trauma disclosure (e.g., sharing traumatic experiences through writing, conversations, public speaking, etc.), the reconstruction of trauma narrative, religious coping, and community activism as the foundation of recovery and growth. Findings also suggest that these factors greatly influence the participants' posttraumatic outcomes, particularly in positive changes related to priorities and goals, interpersonal relationships, personal strength, and leadership effectiveness. Theoretical, societal, and clinical implications of findings as well as future directions are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Reactive and proactive ethnic–racial socialization practices of second-generation Asian American parents.

Studies of Asian American parenting have primarily focused on first-generation immigrant parents. Few studies have examined the experiences of second-generation Asian American adults who now have children of their own. The purpose of this qualitative study, then, is to better understand the values, practices, and concerns of second-generation Asian American parents regarding ethnic and racial socialization. The sample included 34 Asian American parents from seven different cities across the United States. Using interviews and a focus group, the results show that (a) place, specific contexts, and transitions were important to second-generation parents' motivation behind ethnic and racial socialization, (b) parents are reactive and proactive, especially with regard to promoting an awareness of discrimination, in the racial socialization of their children, (c) parents engage in predominantly proactive ethnic socialization when passing on heritage culture, which they believe is important, but also difficult to do, (d) in contrast to ethnic socialization, passing on American culture and passing on important values (that they did not see as solely "American" or "Asian") came easily, and (e) parents consider the intersection of race and culture with religion and disability when socializing their children. Our findings highlight unique aspects of how second-generation Asian American parents engage in ethnic and racial socialization in an increasingly socially diverse world. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Qualitative methods in Asian American psychology: Part II.

Qualitative methods provide opportunities for researchers to capture the diverse experiences and perspectives of Asian Americans from a variety of historical and contemporary contexts, as they affect a complex array of intersecting identities. Part II of this special issue on qualitative research begins with two articles that explored aspects of ethnic socialization. The first study used interviews and a focus group to examine reactive and proactive ethnic–racial socialization practices of Asian American second-generation parents. The second study incorporating a mixed-methods design examined the interrelations between reports of parental ethnic–racial socialization, ethnic identity, affirmation/belonging to one's ethnic group, model minority pride and pressure, and model minority achievement orientation in a sample of South Asian Americans. The third study used a mixed-qualitative-methods design including an online survey and focus group methods. Consensual qualitative research–modified and thematic content analysis were used to explore experiences of racialized sexism/sexualized racism among Asian American women. The fourth study applying a phenomenological qualitative paradigm examined posttraumatic growth among a group of displaced Cambodian community leaders. The fifth study using a community-based participatory research framework illustrated the cultural adaptation of a parent training program. The final study applied a sequential explanatory mixed-methods design to understand Asian American social media use. Taken together, the content of this issue highlights a variety of qualitative methods that explore the diverse experiences of Asian Americans. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Racialized sexism/sexualized racism: A multimethod study of intersectional experiences of discrimination for Asian American women.

This article presents findings from a multimethod qualitative study on the intersectional experiences of discrimination for Asian American women. Participants included 94 women from various Asian American ethnic groups (Mdnage = 25) who participated in an online survey analyzed through consensual qualitative research–modified and 13 women (Mdnage = 29) from different Asian American ethnic groups who participated in focus group interviews analyzed using thematic content analysis. Results revealed 15 themes that illuminated the types of discrimination experienced by participants as Asian American women, namely, tokenist representative of Asian Americans, mislabeled/assumed ethnicity, foreigner, excluded, smart and/or inevitably successful, culture-based discrimination, criminal, bad driver, denying experiences of discrimination, exotic, not a leader, submissive and passive, cute and small, invisible, and service worker. Experiences of discrimination occurred in a variety of personal and professional contexts. Research and clinical implications as well as directions for future research are discussed. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Asian American social media use: From cyber dependence and cyber harassment to saving face.

Nationally representative studies have found significant racial differences in social media use; however, most of these investigations do not disaggregate Asian American findings due to the relatively small proportion of Asian Americans in representative samples. Most purposive studies specifically about Asian social media use have been conducted in Asian countries and have used primarily quantitative methods. Using a sequential explanatory mixed-method design, we analyze data from a large (N = 1,872) purposive online survey of adolescents and emerging adults aged 18–25 years old and follow-up interviews with 24 adult Asian American women. This is the first study of its kind to examine the relative prevalence of social media behaviors across racial/ethnic groups with Asian Americans disaggregated as a unique subgroup and as the racial group of reference. It provides more descriptive and detailed accounts of how, when, and why cyber dependence, cyber harassment, and saving face/impression management behaviors occur within Asian American women's social networking communities. We discuss the overarching themes of maintenance of privacy and limiting loss of face, avoiding stigma related to negative emotional states, and personal conceptualizations of cyber harassment. Finally, we provide practical suggestions for clinical practitioners and future directions for social media use and racial/ethnic disparities. (PsycINFO Database Record (c) 2018 APA, all rights reserved)

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Cardiac-Specific Expression of ΔH2-R15 Mini-Dystrophin Normalized All Electrocardiogram Abnormalities and the End-Diastolic Volume in a 23-Month-Old Mouse Model of Duchenne Dilated Cardiomyopathy

Human Gene Therapy, Ahead of Print.


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A Case of Subacute Infantile Mountain Sickness in a Kyrgyz Child

High Altitude Medicine &Biology, Ahead of Print.


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Chronic Intermittent Hypobaric Hypoxia (4600 M) Attenuates Pulmonary Vasodilation Induced by Acetylcholine or Sodium Nitroprusside

High Altitude Medicine &Biology, Ahead of Print.


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A brave new world

Abstract

Whereas up to 1950s the two major activities of academic Pathology—diagnostic and experimental—were both practiced by a single individual, thereafter, scientific, academic and economic factors created the conditions that favored monothematic practitioners. In this white paper, I argue that now, at the beginning of the 21st century, this separation is detrimental to the discipline, and I propose changes that would reunite the two strands.



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Acta Neurologica Scandinavica, Ahead of Print.

Acta Neurologica Scandinavica, Ahead of Print.


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Acta Neurologica Scandinavica, Ahead of Print.

Acta Neurologica Scandinavica, Ahead of Print.


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Advanced Materials, Ahead of Print.

Advanced Materials, Ahead of Print.


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Advanced Materials, Ahead of Print.

Advanced Materials, Ahead of Print.


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Population attributable fractions continue to unmask the power of prevention

Population attributable fractions continue to unmask the power of prevention

Population attributable fractions continue to unmask the power of prevention, Published online: 23 March 2018; doi:10.1038/s41416-018-0062-5

Population attributable fractions continue to unmask the power of prevention

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The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015, Published online: 23 March 2018; doi:10.1038/s41416-018-0029-6

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015

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Partial breast irradiation with CyberKnife after breast conserving surgery: a pilot study in early breast cancer

Abstract

Background

Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer.

Methods

This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result.

Results

Mean pathological tumor size was 10.5 mm (±4.3, range 3–18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched.

Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107–213; range:56–325) with a median PTV isodose prescription of 86.0% (IQR 85.0–88.5; range:82–94). The median PTV was 88.1 cm3 (IQR 63.8–108.6; range:32.3–238.8). The median breast V100 and V50 was 0.6 (IQR 0.1–1.5; range:0–13) and 18.6 (IQR 13.1–21.7; range:7.5–37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7–27.6; range 22.3–29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients' evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer.

Conclusions

These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results.

Trial registration

The present study is registered at Clinicaltrial.gov (NCT02896322). Retrospectively egistered August 4, 2016.



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Targeting Brain-Adaptive Cancer Stem Cells Prohibits Brain Metastatic Colonization of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) exhibits more traits possessed by cancer stem cells (CSC) than other breast cancer subtypes and is more likely to develop brain metastases. TNBC patients usually have shorter survival time after diagnosis of brain metastasis, suggesting an innate ability of TNBC tumor cells in adapting to the brain. In this study, we establish novel animal models to investigate early tumor adaptation in brain metastases by introducing both patient-derived and cell line–derived CSC-enriched brain metastasis tumorsphere cells into mice. We discovered astrocyte-involved tumor activation of protocadherin 7 (PCDH7)-PLCβ-Ca2+-CaMKII/S100A4 signaling as a mediator of brain metastatic tumor outgrowth. We further identified and evaluated the efficacy of a known drug, the selective PLC inhibitor edelfosine, in suppressing the PCDH7 signaling pathway to prohibit brain metastases in the animal models. The results of this study reveal a novel signaling pathway for brain metastases in TNBC and indicate a promising strategy of metastatic breast cancer prevention and treatment by targeting organ-adaptive cancer stem cells.Significance: These findings identify a compound to block adaptive signaling between cancer stem cells and brain astrocytes. Cancer Res; 1–13. ©2018 AACR.

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Estradiol: A Steroid with Multiple Facets

Horm Metab Res
DOI: 10.1055/s-0044-100920

Seventy-five glorious years have passed since estradiol was discovered by Edward Doisy. From discovery in the ovaries to delineation of diverse physiological effects, research on estrogens has covered a lot of ground. Estrogen receptors that mediate estrogenic effects, have been detected not only in reproductive organs, but also in other body organs. Estrogen receptors function either as conventional transcription factors or as rapid signal transducers. These different modes of action are opted by estrogens to elicit an array of reproductive and non-reproductive functions. It is well established that estrogens promote cell proliferation in various tissues and hence are also linked to carcinogenesis. Anti-estrogens are being used as adjunct therapies for cancers since several years. On the other hand, estrogen-based strategies are used to alleviate adverse effects of menopause. Apart from estrogens synthesized in various organs, exposure to environmental estrogens can also impact physiology. Thus, too much or too less of estrogens can tip the balance and lead to unfavorable consequences. Multiple estrogen receptors with their tissue- or cell type-specific expression eliciting dose-dependent effects make it perplexing to 'unify' estrogenic actions in diverse tissues/organs. This warrants more research on estrogen-mediated effects and their regulation in somatic and reproductive tissues. This review presents physiological and pathological aspects of estrogens thus highlighting the good, bad, and ugly facets of estrogens.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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False positive plasma genotyping due to clonal hematopoiesis

Purpose: Plasma cell-free DNA (cfDNA) genotyping is increasingly used in cancer care, but assay accuracy is debated. Because most cfDNA is derived from peripheral blood cells (PBC), we hypothesized that nonmalignant mutations harbored by hematopoietic cells (clonal hematopoiesis, CH) could be a cause of false positive plasma genotyping.  Experimental Design: We identified patients with advanced NSCLC with KRAS, JAK2, or TP53 mutations identified in cfDNA. With consent, PBC DNA was tested using droplet digital PCR (ddPCR) or next-generation sequencing (NGS) to test for CH-derived mutations.  Results: We first studied plasma ddPCR results from 58 EGFR-mutant NSCLC patients. Two had KRAS G12X detected in cfDNA and both were present in PBC, including one where the KRAS mutation was detected serially for 20 months. We then studied 143 plasma NGS results from 122 NSCLC patients, and identified 5 JAK2 V617F mutations derived from PBC. Additionally, 108 TP53 mutations were detected in cfDNA; for 33 of the TP53 mutations, PBC and tumor NGS were available for comparison, and 5 were present in PBC but absent in tumor, consistent with CH. Conclusions: We find that most JAK2 mutations, some TP53 mutations, and rare KRAS mutations detected in cfDNA are derived from CH not tumor. Clinicians ordering plasma genotyping must be prepared for the possibility that mutations detected in plasma, particularly in genes mutated in CH, may not represent true tumor genotype. Efforts to use plasma genotyping for cancer detection may need paired PBC genotyping so that CH-derived mutations are not misdiagnosed as occult malignancy.



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Epigenome-wide SRC-1 mediated gene silencing represses cellular differentiation in advanced breast cancer

Purpose:Despite the clinical utility of endocrine therapies for estrogen receptor positive (ER) breast cancer, up to 40% of patients eventually develop resistance, leading to disease progression. The molecular determinants that drive this adaptation to treatment remain poorly understood. Methylome aberrations drive cancer growth yet the functional role and mechanism of these epimutations in drug resistance are poorly elucidated. Experimental design: Genome-wide multi-omics sequencing approach identified a differentially methylated hub of pro-differentiation genes in endocrine resistant breast cancer patients and cell models. Clinical relevance of the functionally validated methyl-targets was assessed in a cohort of endocrine treated human breast cancers and patient-derived ex vivo metastatic tumours. Results:Enhanced global hypermethylation was observed in endocrine treatment resistant cells and patient metastasis relative to sensitive parent cells and matched primary breast tumor respectively. Using paired methylation and transcriptional profiles we found that SRC-1-dependent alterations in endocrine resistance lead to aberrant hyper-methylation that resulted in reduced expression of a set of differentiation genes. Analysis of ER positive endocrine treated human breast tumors (n=669) demonstrated that low expression of this pro-differentiation gene set significantly associated with poor clinical outcome (p=0.00009). We demonstrate that the re-activation of these genes in vitro and ex vivo reverses the aggressive phenotype. Conclusion: Our work demonstrates that SRC-1-dependent epigenetic remodeling is a 'high level' regulator of the poorly differentiated state in ER-positive breast cancer. Collectively these data revealed an epigenetic reprograming pathway, whereby concerted differential DNA methylation is potentiated by SRC-1 in the endocrine resistant setting.



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Role of Salt Valency in the Switch of H-NS Proteins between DNA-Bridging and DNA-Stiffening Modes

This work investigates the interactions of H-NS proteins and bacterial genomic DNA through computer simulations performed with a coarse-grained model. The model was developed specifically to study the switch of H-NS proteins from the DNA-stiffening to the DNA-bridging mode, which has been observed repeatedly upon addition of multivalent cations to the buffer but is still not understood. Unraveling the corresponding mechanism is all the more crucial, as the regulation properties of H-NS proteins, as well as other nucleoid proteins, are linked to their DNA-binding properties.

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Impact of Radiation Therapy Dose Escalation on Prostate Cancer Outcomes and Toxicities

imageObjectives: Freedom from biochemical failure (FFBF) is a common primary outcome of randomized-controlled trials of prostate cancer (PCa). We aimed to determine how increasing the PCa biologically equivalent dose (BED) of external radiation therapy (RT) is correlated with FFBF and overall patient outcomes: overall survival (OS), distant metastasis (DM), and cancer-specific mortality (CSM); as well as genitourinary (GU), and gastrointestinal toxicities. Materials and Methods: We performed a meta-analysis of 6884 PCa patients from 12 randomized-controlled trials of external beam RT. Mixed effects regression models were used to estimate weighted linear relationships between BED and observed percentages of 5- and 10-year outcomes. For toxicities, a subset analysis of using 3-dimensional conformal RT (3D-CRT) versus intensity-modulated RT (IMRT) was performed. Results: Increasing BED correlated with improved FFBF: 10-year absolute improvement of 9.6% and 7.2% for low-risk and intermediate-risk patients, respectively (P

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EGFR Exon 19 Deletion is Associated With Favorable Overall Survival After First-line Gefitinib Therapy in Advanced Non–Small Cell Lung Cancer Patients

imageObjectives: Exon 19 deletion and L858R mutation in exon 21 of the epidermal growth factor receptor (EGFR) are both common mutations that predict a good response to EGFR tyrosine kinase inhibitors in non–small cell lung cancer (NSCLC). However, the existence of clinically significant difference in sensitivity to EGFR tyrosine kinase inhibitors among different EGFR mutation subtypes is still a matter of debate. Materials and Methods: The outcome of 60 EGFR mutation-positive advanced NSCLC patients who received first-line gefitinib therapy (250 mg/d) was retrospectively analyzed according to EGFR mutation subtypes. Results: The median progression-free survival (PFS) and overall survival (OS) after the initiation of gefitinib therapy for all patients was 11 and 26 months, respectively. Univariate analysis showed that patients with exon 19 deletion (n=28) had significantly longer median PFS (20 vs. 8 mo, P=0.004) and OS (36 vs. 22 mo, P=0.001) compared with those with L858R mutation (n=25) and uncommon or dual mutations (n=7). Multivariate analysis revealed that exon 19 deletion (P=0.007) was an independent prognostic factor of favorable PFS, with an independent association with poor PFS of male sex (P=0.049). Exon 19 deletion was also independently associated with favorable OS (P

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Phase I Trial of Dose-escalated Whole Liver Irradiation With Hepatic Arterial Fluorodeoxyuridine/Leucovorin and Streptozotocin Followed by Fluorodeoxyuridine/Leucovorin and Chemoembolization for Patients With Neuroendocrine Hepatic Metastases

imageObjectives: We have previously shown that refractory neuroendocrine tumors can respond to moderate doses of chemoradiotherapy. We completed a dose-escalation phase I/II trial combining hepatic arterial (HA) chemotherapy, chemoembolization, and dose-escalated whole liver radiotherapy to determine the maximum safe dose of radiation that could be delivered and to make a preliminary assessment of response. Materials and Methods: From 2002 to 2009, 19 patients with symptomatic neuroendocrine liver metastases who failed somatostatin analog therapy were enrolled. HA fluorodeoxyuridine, leucovorin, and streptozotocin were delivered, as concurrent whole liver radiotherapy was dose escalated from 24 to 32 Gy in 2 Gy fractions, with a target rate of dose-limiting grade ≥3 radiation-induced liver disease of 10%. Eight weeks later, for patients without grade ≥3 liver or grade ≥4 any toxicity, a 72-hour infusion of HA fluorodeoxyuridine and leucovorin was given, followed by transarterial chemoembolization. Results: Eleven patients completed the entire protocol and received 24 to 32 Gy. No patients developed radiation-induced liver disease; 7 had grade 3 to 4 transiently increased liver function tests, and 4 had other grade 4 toxicities. Three patients (14%) had partial response, 16 (84%) stable disease. Median freedom from local progression and overall survival were 35.3 and 54.6 months, respectively. Conclusions: Thirty-two in 2 Gy daily fractions can be delivered safely when combined with HA chemotherapy and subsequent transarterial chemoembolization. However, although objective responses were observed, this combination was not significantly better than our prior approaches. Further treatment intensification strategies, including individualized dose escalation for radiation-tolerant livers, and improved radiosensitization should be investigated, along with improved systemic therapy.

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Early-stage Uterine Pure and Mixed Clear Cell Carcinoma: Outcomes and Recurrence With and Without Adjuvant Therapy

imageObjective: Clear cell carcinoma (CCC) of the uterus is a rare but aggressive histology for which the role of adjuvant therapy for stage I-II disease is unclear. Our study investigated outcomes and patterns of failure in these patients. Methods: We found 64 cases of CCC, including 26 of pure CCC, 22 mixed with endometrioid adenocarcinoma, and 16 mixed with uterine papillary serous carcinoma. Adjuvant treatment was given to 55%. Results: Median follow-up was 51.9 months. By Kaplan-Meier estimate, 5-year vaginal recurrence-free survival (RFS) was 91.3%, pelvic RFS was 92.6%, distant metastasis RFS was 81.6%, disease-free survival was 79.6%, and overall survival was 79.7%. Median time to recurrence was 20.7 months (range, 2 to 40.5 mo). Patients treated adjuvantly had higher proportion of stage II disease (40% vs. 6.9% observed, P=0.0031) and 20% (7/35) recurred. There were no significant differences in outcomes by histologic subtypes but numerically more recurrences with uterine papillary serous involvement. By univariate analysis, higher stage, presence of lymphovascular invasion, and lack of lymph node dissection were predictive of worse overall survival. Age 65 years and above was predictive of worse cancer-specific survival. Of 12 who progressed, only 1 was salvaged and 11 died of disease. Of progressors, 10 had documented distant metastasis. Median time from recurrence to death was 4.5 months (range, 0.2 to 21.2 mo). Conclusions: Given aggressive and often unsalvageable nature of recurrence, consideration of adjuvant treatment (including chemotherapy and radiation) is warranted for early-stage CCC, particularly for stage II or those with poor prognostic factors.

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Efficacy, Safety, and Potential Biomarkers of Sunitinib and Transarterial Chemoembolization (TACE) Combination in Advanced Hepatocellular Carcinoma (HCC): Phase II Trial

imageObjectives: To evaluate the safety/efficacy and explore biomarkers for a rationally designed combination of sunitinib and transarterial chemoembolization (TACE) in a prospective phase 2 study of advanced hepatocellular carcinoma (HCC). Methods: Inoperable HCC patients with Child-Pugh A disease received 37.5 mg sunitinib from days 1 to 7 followed by TACE on day 8. Sunitinib was resumed from days 15 to 36 followed by 2 weeks off. Patients received subsequent sunitinib cycles of 4 weeks on and 2 weeks off. Dynamic contrast-enhanced magnetic resonance imaging and circulating soluble biomarkers were assessed at baseline, day 8, day 10, and day 36. Results: Sixteen patients with liver only (n=10) and extrahepatic disease (n=6) were enrolled. After a median follow-up of 12.8 months, 2 partial responses, 11 stable disease, and 3 clinical deteriorations were seen for a clinical benefit rate of 81%. Median progression-free survival (PFS) was 8 months (95% CI, 4.3-9.3) and overall survival was 14.9 months (95% CI, 6.3-27.1). Eleven of 16 patients (69%) had grade 3/4 toxicities attributable to sunitinib, the most frequent being thrombocytopenia, amylase/lipase elevations, lymphopenia, and fatigue. Mean Ktrans (volume transfer constant) and viable tumor percent in consented patients decreased by 27% and 14.8%, respectively, with combination therapy. Soluble vascular endothelial growth factor receptor-2 (sVEGFR2) levels, cytokines (interleukin-8, interleukin-21), and monocytes decreased with combination therapy. Estimated sunitinib IC50 values of 15 and 10 ng/mL modulated Ktrans and AUC90. sVEGFR2 levels decreased with Ktrans and AUC90. Conclusions: Encouraging progression-free survival and overall survival were seen with acceptable toxicity in our study of sunitinib and TACE combination in advanced HCC. Potential imaging and serum biomarkers showed increased benefit with combination therapy.

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Utility of the ACE Inhibitor Captopril in Mitigating Radiation-associated Pulmonary Toxicity in Lung Cancer: Results From NRG Oncology RTOG 0123

imageObjectives: The primary objective of NRG Oncology Radiation Therapy Oncology Group 0123 was to test the ability of the angiotensin-converting enzyme inhibitor captopril to alter the incidence of pulmonary damage after radiation therapy for lung cancer; secondary objectives included analyzing pulmonary cytokine expression, quality of life, and the long-term effects of captopril. Materials and Methods: Eligible patients included stage II-IIIB non–small cell lung cancer, stage I central non–small cell lung cancer, or limited-stage small cell. Patients who met eligibility for randomization at the end of radiotherapy received either captopril or standard care for 1 year. The captopril was to be escalated to 50 mg three times a day. Primary endpoint was incidence of grade 2+ radiation-induced pulmonary toxicity in the first year. Results: Eighty-one patients were accrued between June 2003 and August 2007. Given the low accrual rate, the study was closed early. No significant safety issues were encountered. Eight patients were ineligible for registration or withdrew consent before randomization and 40 patients were not randomized postradiation. Major reasons for nonrandomization included patients' refusal and physician preference. Of the 33 randomized patients, 20 were analyzable (13 observation, 7 captopril). The incidence of grade 2+ pulmonary toxicity attributable to radiation therapy was 23% (3/13) in the observation arm and 14% (1/7) in the captopril arm. Conclusions: Despite significant resources and multiple amendments, NRG Oncology Radiation Therapy Oncology Group 0123 was unable to test the hypothesis that captopril mitigates radiation-induced pulmonary toxicity. It did show the safety of such an approach and the use of newer angiotensin-converting enzyme inhibitors started during radiotherapy may solve the accrual problems.

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A Phase I/II Study of Docetaxel, Oxaliplatin, and Fluorouracil (D-FOX) Chemotherapy in Patients With Untreated Locally Unresectable or Metastatic Adenocarcinoma of the Stomach and Gastroesophageal Junction

imageBackground: A randomized phase III study established docetaxel, cisplatin, and 5-fluorouracil (DCF) as one of the standard treatments for patients with untreated advanced gastric cancer (AGC). However, DCF use is limited due toxicity. With the purpose to evaluate a less toxic regimen, we conducted a single arm, phase I/II trial of modified DCF (oxaliplatin, 5-fluorouracil, and docetaxel [D-FOX]) for untreated AGC patients. The primary objective of the phase I study was to determine the maximum tolerated dose of docetaxel and for the phase II study was to assess the progression-free survival (PFS) at 6 months and overall survival (OS). Patients and Methods: We enrolled a total of 98 patients with AGC. Docetaxel and oxaliplatin were administered intravenously on day 1 and 5-fluorouracil was infused starting on day 1 over 48 hours. Cycles were repeated every 2 weeks and patients were monitored for toxicities. Kaplan-Meir curve was used to estimate unadjusted OS and PFS. Results: The maximum tolerated dose of docetaxel was 50 mg/m2. In total, 24 (45%) patients experienced grade 2 adverse events, 22 (41%) experienced grade 3, and 1 (1.9%) experienced grade 4 toxicity. The median PFS in the phase II portion of the study was approximately 6.5 (95% confidence interval, 5.5-9.5) months and the median OS was 11.1 (95% confidence interval, 9.4-18.8) months. Conclusions: D-FOX administered every 2 weeks is a well-tolerated and active regimen in untreated AGC patients.

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A Meta-Analysis of the Association Between Radiation Therapy and Survival for Surgically Resected Soft-Tissue Sarcoma

imageObjectives: Radiotherapy for soft-tissue sarcoma (STS) has been shown to reduce local recurrence, but without clear improvement in survival. We conducted a meta-analysis to study the association between radiotherapy and survival in patients undergoing surgery for STS. Methods: A systematic review was conducted from PubMed, EMBASE, Web of Science, and Cochrane databases. Our population of interest consisted of adults with primary extremity, chest wall, trunk, or back STS. Our metameters were either an odds or hazard ratio for mortality. A bias score was generated for each study based on margin status and grade. Results: Of 1044 studies, 30 met inclusion criteria for final analysis. The pooled odds ratio in patients receiving radiation was 0.94 (95% confidence interval [CI], 0.78-1.14). The pooled estimate of the hazards ratio in patients receiving radiation was 0.87 (95% CI, 0.73-1.03) overall and 0.65 (95% CI, 0.52-0.82) for studies judged to be at low risk of bias. Significant publication bias was not seen. Conclusions: High-quality studies reporting adjusted hazard ratios are associated with improved survival in patients receiving radiotherapy for STS. Studies in which odds ratios are calculated from event data and those that do not report adjusted outcomes do not show the same association, likely due to confounding by indication.

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Chemotherapy is of Value in Second Line and Beyond, Relapsed High-grade, Serous Epithelial Ovarian Cancer: An Analysis of Outcomes Obtained With Oral Etoposide

imageBackground: Epithelial ovarian cancer is chemotherapy responsive, and multiple lines of chemotherapy are often given. However, there are few data with regard to its effectiveness in later lines. Our aim was to assess its benefit in the high-grade, serous subtype relative to the line of therapy, using etoposide as the example. Methods: Women treated with oral etoposide at the British Columbia Cancer Agency upon recurrence/progression in the years 2000 to 2010 were reviewed. Kaplan-Meier and Cox regression methods were used to correlate line of therapy with overall survival, progression-free survival, and interval between etoposide initiation and next progression or death (EPFS). Results: A total of 219 women, median age 61, received etoposide as second (17%), third (30%), fourth (26%), fifth (17%), and sixth to eighth (11%) lines of therapy. The median number of cycles was 2 to 4. Patients who received etoposide as fourth-line to eighth-line treatment had a significantly longer median overall survival and initial progression-free survival (from diagnosis to first relapse) when compared with those who received it as second-line to third-line treatment (47.8 vs. 25.8 mo, P

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Analysis of the Relationship Between Response to Chemotherapy and Response to Radiation Therapy in Patients With Non–Small Cell Lung Cancer Receiving Sequential Treatment

imageObjectives: We examine whether induction chemotherapy response predicts thoracic radiotherapy response in locally advanced or oligometastatic non–small cell lung cancer. Materials and Methods: Between January 2001 to August 2010, 25 consecutive patients were identified who received systemic dose chemotherapy followed by definitive thoracic radiotherapy alone. All patients had measurable disease after chemotherapy that was evaluable for response to radiotherapy. Response to each modality was scored by RECIST as stable disease (SD), progressive disease (PD), partial response (PR), or complete response (CR). Results: Patients had adenocarcinoma (n=13), squamous cell carcinoma (n=8), or other histologies (n=4). They had stage IIIA (n=6), IIIB (n=14), and IV (n=5) disease. Patients received 2 to 6 cycles (median 4) of platinum-based chemotherapy followed by radiotherapy (median 66.6/1.8 Gy [range 50 to 84 Gy]). Median time between chemotherapy end and radiotherapy start was 6.7 weeks (range, 1.6 to 53.4 wk). Twelve patients responded to chemotherapy (all were PRs) and 13 did not (SD+PD). Fifteen patients responded to radiotherapy (7 CR, 8 PR) and 10 did not (SD+PD). Of the 12 patients who responded to chemotherapy, 8 also responded to radiotherapy (4 CR, 4 PR). Of the 13 chemotherapy nonresponders, 7 responded to radiotherapy (3 CR, 4 PR). χ2 analysis did not find any association between chemotherapy and radiotherapy response (P=0.513). Regression analysis also failed to identify any correlation between chemotherapy and radiotherapy response (r2=0.008). Conclusions: This study suggests that response to chemotherapy does not predict response to radiotherapy in locally advanced or oligometastatic non–small cell lung cancer. Lack of response to chemotherapy, therefore, should not preclude treatment with definitive radiotherapy.

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Prognostic Impact of Missed Chemotherapy Doses During Chemoradiation Therapy for Non–Small Cell Lung Cancer

imageObjective: The aim of this study is to investigate the impact of missed chemotherapy administrations (MCA) on the prognosis of non–small cell lung cancer (NSCLC) patients treated with definitive chemoradiation therapy (CRT). Materials and Methods: In total, 97 patients with NSCLC treated with definitive CRT were assessed for MCA due to toxicities. Logistic regression was used to determine factors associated with MCA. Kaplan-Meier curves, log-rank tests, and Cox Proportional Hazards models were conducted. Results: MCA occurred in 39% (n=38) of the patients. Median overall survival was 9.6 months for patients with MCA compared with 24.3 months for those receiving all doses (P=0.004). MCA due to decline in performance status was associated with the worst survival (4.6 mo) followed by allergic reaction (10.0 mo), hematologic toxicity (11 mo), and esophagitis (17.2 mo, P=0.027). In multivariate models, MCA was associated with higher mortality (hazard ratio, 1.97; P=0.01) and worse progression-free survival (hazard ratio, 1.96; P=0. 009). Conclusions: MCA correlated with worse prognosis and increased mortality. Methods to reduce toxicity may improve administration of all chemotherapy doses and increase overall survival in NSCLC treated with CRT.

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Age Bias in Time From Diagnosis Comparisons of Prostate Cancer Treatment

imageObjectives: Observational studies of prostate cancer treatment have demonstrated a major survival benefit with prostatectomy; randomized trials have been less certain in this regard. This discrepancy is hypothesized to be due to the use survival calculations based on time from diagnosis (TFD), which can bias toward better survival for younger cohorts. Attained age is an alternative timescale that can mitigate this effect. A Surveillance, Epidemiology and End Results comparison of prostatectomy, radiotherapy (XRT), and conservative management for localized prostatic cancer was conducted to compare these 2 timescales. Methods: Kaplan-Meier analysis was used to contrast overall survival based on TFD and attained age from 279,064 prostate cancer cases. Proportional hazards models were constructed and baseline hazard functions estimated. Results: The prostatectomy cohort averaged 9 to 12 years younger than the radiotherapy or conservative management cohorts, and the baseline hazard depended more strongly upon age than TFD. Survival calculations based on TFD demonstrated a major benefit with prostatectomy compared with XRT and conservative management, consistent with prior observational studies. Calculations based on attained age, however, demonstrated lesser differences between treatment cohorts and were more consistent with published randomized trials. Conclusions: The survival benefit apparent to prostatectomy in conventional observational cohort studies could reflect an age-related bias attributable to their use of TFD analysis. Care is warranted in the choice of timescale in observational analysis if large age differences exist between treatment cohorts. Randomized controlled trials remain the most reliable means to compare prostate cancer treatments.

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Pre-ESRD Care and Mortality in Incident ESRD Patients With Multiple Myeloma

imageObjectives: The relationship between mortality and pre-ESRD (end-stage renal disease) nephrology care in incident ESRD patients with multiple myeloma (MM) as the primary cause of renal failure has not been examined. Materials and Methods: Among 439,206 incident US hemodialysis patients with MM as the primary cause of ESRD (June 1, 2005 to May 31, 2009) identified using the US Renal Data System, adjusted odds ratios (OR) for reported pre-ESRD nephrology care for ESRD due to MM (n=4561) versus other causes (n=434,645) were calculated. The association of pre-ESRD nephrology care with subsequent mortality in MM-ESRD patients was examined. Results: MM-ESRD patients were less likely to have any predialysis nephrology care in the year before initiation of dialysis (34.8% vs. 58.5%; OR=0.38; 95% confidence interval [CI], 0.34-0.43) compared with patients with ESRD due to other causes. MM-ESRD patients compared with others were more likely to have catheters on first dialysis (91.8% vs. 75.6%; OR=4.15; 95% CI, 3.54-4.86). Incident MM-ESRD patients receiving predialysis care for ≥6 months had significantly lower 1-year mortality (hazard ratio 0.89; 95% CI, 0.82-0.97 and 0.88; 95% CI, 0.80-0.96, respectively), relative to those without this care. A catheter for dialysis access was associated with a 1.6-fold increase in 1-year mortality in incident MM-ESRD (hazard ratio 1.55; 95% CI, 1.32-1.83). Conclusions: MM-ESRD patients were less likely to have predialysis nephrology care and more likely to use catheters on first dialysis. However, predialysis care is independently associated with lower mortality in MM-ESRD patients. Predialysis care should be prioritized in MM patients approaching ESRD.

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Thyroid Paraganglioma: Our Experience and Systematic Review of the Literature on a Rare Tumor

imageIntroduction: Primary paraganglioma (PG) of the thyroid gland is an extremely rare neuroendocrine tumor with potential for misdiagnosis. We describe 2 cases of thyroid PG, suggest a possible diagnostic and therapeutic management strategy, and present a systematic review of the literature. Case Reports: Two 67-year-old women presented similarly with asymptomatic but rapidly growing thyroid nodules in which malignancy was suspected after fine needle aspiration biopsy, "THY 4" according to the 2014 SIAPEC classification, both undergoing total thyroidectomy. Unexpectedly, immunohistochemistry showed neuroendocrine cellular architecture that was negative for common markers of well-differentiated follicular neoplasms, thyroglobulin, thyroid transcription factor 1, cytokeratins and medullary thyroid cancer, calcitonin, carcinoembryonic antigen, whereas neuron-specific enolase, synaptophysin, chromogranin A, and S-100 protein were highly expressed, confirming the diagnosis of primary thyroid PG. The patients were both discharged on postoperative day 2, without any other therapy and are currently well without evidence of local recurrence of metastatic disease, after 4 years and 3 months of follow-up, respectively. Discussion: These are the only 2 cases of thyroid PG experienced in our center which specializes in thyroid surgery. Thyroid PG is a rare neuroendocrine neoplasm first described by Van Miert in 1964 with just over 50 cases reported in the literature. Our experience is concordant with the literature that the diagnosis of the primary PG of the thyroid is challenging, due to its low prevalence and the cytologic and histopathologic similarities with other more frequently diagnosed benign and malignant thyroid tumors. Immunohistochemistry is required for definitive diagnosis but gross tumor characteristics are also helpful for diagnosis. Surgical resection is the recommended standard treatment.

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The characteristics of ctDNA reveal the high complexity in matching the corresponding tumor tissues

Abstract

Background

Next-generation sequencing (NGS) is an efficient and sensitive method to detect mutations from ctDNA. Many features and clinical conditions could significantly affect the concordance between ctDNA and corresponding tumor tissues. Our goal was to systematically investigate the critical factors contributing to different concordance between ctDNA and corresponding tumor tissues.

Methods

We recruited two groups of IIIB or IV lung cancer patients: The standard group to evaluate the accuracy of our method and the concordance between ctDNA and tumor tissues, and the study group with various clinical conditions. We applied our unique identification (UID) indexed capturing-based sequencing (UC-Seq) to ctDNA samples, and confirm the results by Droplet digital PCR (ddPCR).

Results

Considering mutations detected from NGS of tumor tissues as golden standard, UC-Seq achieved overall 93.6% sensitivity for SNVs and Indels, and 0.8 Pearson correlation between tumor TMB and bTMB. Efficacious treatments, long sampling date (more than 2 weeks) between tumor tissues and ctDNA and low concentrations of cfDNA (less than 9 ng/ml) could significantly decrease the concordance between ctDNA and tumor tissues. About 84% mutations showed shorter mutant fragment length than that of wild-type fragments, and the AFs of mutations could be significantly enriched in small-size ctDNA.

Conclusions

In late-stage lung cancer patients, ctDNA generally has high concordance with tumor tissues. However it could be significantly affected by three clinical conditions which could dynamically change the content of ctDNA. Moreover, the detection limit could be further extended by enriching small-size ctDNA in the preparation of samples.



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Punch biopsies shorten time to clearance of high-risk human papillomavirus infections of the uterine cervix

Abstract

Background

The primary objective was to determine human papilloma virus (HPV) clearance rate after cervical biopsy among women with persistent high-risk HPV infection compared with spontaneous HPV clearance rate in the absence of biopsy.

Methods

We collected data from a dedicated screening program of women aged 30–70 years old. Inclusion criteria for the baseline non-interventional cohort were a positive HPV test (hybrid capture 2, HC2) and normal cytology. In the baseline cohort women were followed with approximately yearly HPV-tests and cytology until HPV regressed (one negative HPV test) or interventions in the form of diagnostic biopsies or therapy. Women who had a diagnostic biopsy were included in the biopsy cohort and followed until HPV regression or therapy. Observed HPV regression rates and time to HPV regression were compared between baseline and biopsy cohorts. For the comparison, we used Fisher's exact test for the HPV regression rates and interval-censored, accelerated failure time model for time to HPV regression.

Results

Among the 1079 women included in the baseline cohort, 499 (46.3%) had HPV clearance and 475 were referred for colposcopy with biopsy. The biopsy cohort comprised all women who were not treated and had at least one HC2 test after biopsy (201/475; 42.3%). Of those, 138 (68.7%) experienced HPV regression. In the biopsy cohort, time to clearance of HPV infection was approximately halved (0.46, 95% CI 0.38–0.56) compared with the baseline cohort. This result was robust in a wide range of sensitivity analyses.

Conclusions

A higher proportion of women cleared their HPV infection, and time to HPV clearance was shorter in the biopsy cohort than in the baseline cohort. It is reassuring for clinicians to know that conservative management of patients with HPV persistency is successful when colposcopy with biopsies excludes high-grade disease.



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The DNA methylation profile of liver tumors in C3H mice and identification of differentially methylated regions involved in the regulation of tumorigenic genes

Abstract

Background

C3H mice have been frequently used in cancer studies as animal models of spontaneous liver tumors and chemically induced hepatocellular carcinoma (HCC). Epigenetic modifications, including DNA methylation, are among pivotal control mechanisms of gene expression leading to carcinogenesis. Although information on somatic mutations in liver tumors of C3H mice is available, epigenetic aspects are yet to be clarified.

Methods

We performed next generation sequencing-based analysis of DNA methylation and microarray analysis of gene expression to explore genes regulated by DNA methylation in spontaneous liver tumors of C3H mice. Overlaying these data, we selected cancer-related genes whose expressions are inversely correlated with DNA methylation levels in the associated differentially methylated regions (DMRs) located around transcription start sites (TSSs) (promoter DMRs). We further assessed mutuality of the selected genes for expression and DNA methylation in human HCC using the Cancer Genome Atlas (TCGA) database.

Results

We obtained data on genome-wide DNA methylation profiles in the normal and tumor livers of C3H mice. We identified promoter DMRs of genes which are reported to be related to cancer and whose expressions are inversely correlated with the DNA methylation, including Mst1r, Slpi and Extl1. The association between DNA methylation and gene expression was confirmed using a DNA methylation inhibitor 5-aza-2′-deoxycytidine (5-aza-dC) in Hepa1c1c7 cells and Hepa1-6 cells. Overexpression of Mst1r in Hepa1c1c7 cells illuminated a novel downstream pathway via IL-33 upregulation. Database search indicated that gene expressions of Mst1r and Slpi are upregulated and the TSS upstream regions are hypomethylated also in human HCC. These results suggest that DMRs, including those of Mst1r and Slpi, are involved in liver tumorigenesis in C3H mice, and also possibly in human HCC.

Conclusions

Our study clarified genome wide DNA methylation landscape of C3H mice. The data provide useful information for further epigenetic studies of mice models of HCC. The present study particularly proposed novel DNA methylation-regulated pathways for Mst1r and Slpi, which may be applied not only to mouse HCC but also to human HCC.



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Age greater than 60 years portends a worse prognosis in patients with papillary thyroid cancer: should there be three age categories for staging?

Abstract

Background

Age is an important prognostic factor in papillary thyroid cancer (PTC), with better survival observed in patients < 45 years of age, regardless of stage. Although the impact of increasing age on PTC-related survival is well-known, previous studies have focused on survival relative to age 45 years only. As the number of patients entering their 7th decade of life increases, PTC-related survival in this demographic becomes increasingly important. Survival in patients ≥ 60 years specifically compared to other groups has not previously been examined. We sought to determine whether age ≥ 60 years is an adverse prognostic factor for disease-specific survival and recurrence in patients with PTC.

Methods

The California Cancer Registry database was linked to inpatient and ambulatory patient records from the Office of Statewide Health Planning and Development for the years 2000–2011. This linked database was queried for patients diagnosed with papillary thyroid cancer and treated with surgery. We then identified prognostic factors related to both 5-year and 10-year disease-specific survival and disease-free survival in patients ≤ 45, 45–59, and ≥ 60 years. Multivariable Cox proportional hazard models were created to test the effect of age ≥ 60 on disease-specific and disease-free survival, controlling for clinical, treatment, and demographic factors.

Results

The final cohort included 15,675 patients. Of the group, 46.3% were between 18 and 44 years of age, 33.6% were 45–59 years, and 20.1% were ≥ 60. Univariate analysis showed that compared to other groups, patients ≥ 60 were more likely to be male (p < 0.001), present with tumors > 5 cm (p < 0.001), more likely to have metastatic disease (p < 0.001), less likely to receive radioactive iodine (p < 0.001), and more likely to receive external beam radiation therapy (p < 0.001). In multivariable Cox proportional hazards models for 5 and 10-year disease-free survival, age ≥ 60 was associated with higher risk of disease at 5 and 10-years (HR 2.3 and 1.9 respectively, p < 0.001). Similar results were observed for 5 and 10-year disease-specific survival (HR 38.0 and 30.0 respectively, p < 0.001) after controlling for gender, race, co-morbidity, stage, surgical procedure, radioactive iodine, insurance, and hospital volume.

Conclusions

Patients ≥ 60 years of age have worse DSS and DFS after a diagnosis of PTC, across all stages of disease. Given that patients over the age of 45 years have progressively worse survival as they age, these data support having three age groups, 18–44 years of age, 45–59 years, and ≥ 60 as an independent predictor of survival and recurrence to current staging guidelines.



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The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015



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Population attributable fractions continue to unmask the power of prevention



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Reply to “Relationship between age and nerve dimensions in Charcot-Marie-Tooth disease. Do we know the reality?”

We read with great interest the letter by Coraci and collaborators (2018) in response to our recent electrodiagnostic, nerve ultrasound and histological study on Charcot-Marie-Tooth disease (CMT) due to myelin protein zero (Fabrizi et al., 2018). In an attempt to reconcile discrepancies on the relationship between age and nerve size in previous reports, Coraci and coworkers explored the correlation between age and cross sectional area (CSA) in a group of 49 patients with genetically confirmed CMT, namely 27 CMT1 and 22 CMT2 patients with local polynomial regression fitting (LOESS), a very flexible non-parametric regression analysis method that does not require the specification of a function to fit a model to all of the data in the sample, making it ideal for modelling complex processes for which no theoretical models exist (NIST, 2018).

http://ift.tt/2pu84wD

CT-Based Nodal Radiomic Biomarkers Predictive of Patient Outcome in Head and Neck Squamous Cell Carcinoma

Non-invasive radiomic biomarkers involve high-throughput extraction of imaging data and may provide important complementary information. We investigated the association between pretreatment nodal radiomic features and clinical outcome for head neck cancer (HNC).

http://ift.tt/2px9R45

British Journal of Surgery, Ahead of Print.

British Journal of Surgery, Ahead of Print.


http://ift.tt/2pzxBnr

Methadone

Methadone is a valuable opioid in the management of patients who have cancer with pain. Methadone is a mu-, kappa-, and delta-opioid agonist, and an N-methyl-D-aspartate receptor antagonist. These mechanisms of action make methadone an attractive option for complex pain syndromes. It is critically important that providers consider a patient's risk status before beginning methadone. Careful consideration must be given to dosing methadone in both opioid-naïve and opioid-tolerant patients, with vigilant monitoring for therapeutic effectiveness and potential toxicity until the patient achieves steady state.

http://ift.tt/2pwYclQ

Mechanisms of, and Adjuvants for, Bone Pain

Metastatic bone pain is a complex, poorly understood process. Understanding the unique mechanisms causing cancer-induced bone pain may lead to potential therapeutic targets. This article discusses the effects of osteoclast overstimulation within the tumor microenvironment; the role of inflammatory factors at the tumor-nociceptor interface; the development of structural instability, causing mechanical nerve damage; and, ultimately, the neuroplastic changes in the setting of sustained pain. Several adjuvant therapies are available to attenuate metastatic bone pain. This article discusses the role of pharmacologic therapies, surgery, kyphoplasty, vertebroplasty, and radiofrequency ablation.

http://ift.tt/2u8dimA

Cancer Pain Syndromes

Patients with cancer experience many acute and chronic pain syndromes, the identification of which may be helpful in the assessment and treatment of pain. Syndromes are defined by the relationship with the cancer, the pain pathophysiology, and the clinical characteristics of the pain. The most common pain syndromes are directly related to the tumor; bone pain syndromes are most common. Neuropathic pain syndromes may involve cancer-related injury at any level of the peripheral nervous system. Treatment-related pain syndromes may follow any type of antineoplastic therapy. This article reviews the phenomenology of common acute and chronic cancer pain syndromes.

http://ift.tt/2pvBYAy

Raymond E. Meyn, Jr., Ph.D.; 1942–2017

Radiation Research, Volume 189, Issue 4, Page 447-448, April 2018.


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Response to the ‘Comments on “Cellular Therapies for Treatment of Radiation Injury after a Mass Casualty Incident” (Radiat Res 2017; 188:242-45)' by Drouet et al. (Letters to the Editor, Radiat Res 2017; 188:463)

Radiation Research, Volume 189, Issue 4, Page 446-446, April 2018.


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An Assessment of Radiation-Associated Risks of Mortality from Circulatory Disease in the Cohorts of Mayak and Sellafield Nuclear Workers

Radiation Research, Volume 189, Issue 4, Page 371-388, April 2018.


http://ift.tt/2HV4ceM

Cognitive Science, Ahead of Print.

Cognitive Science, Ahead of Print.


http://ift.tt/2pvlybo

Beliefs and expectations of rural hospital practitioners towards a developing trauma system: a qualitative case study

Publication date: Available online 22 March 2018
Source:Injury
Author(s): Ryan D.F. Adams, Elaine Cole, Susan I. Brundage, Zoe Morrison, Jan O. Jansen
BackgroundAn understanding of stakeholders' views is key to the successful development and operation of a rural trauma system. Scotland, which has large remote and rural areas, is currently implementing a national trauma system. The aim of this study was to identify key barriers and enablers to the development of an effective trauma system from the perspective of rural healthcare professionals.MethodsThis is a qualitative study, which was conducted in rural general hospitals (RGH) in Scotland, from April to June 2017. We used an opportunistic sampling strategy to include hospital providers of rural trauma care across the region. Semi-structured interviews were conducted, recorded, and transcribed. Thematic analysis was used to identify and group participant perspectives on key barriers and enablers to the development of the new trauma system.ResultsWe conducted 15 interviews with 18 participants in six RGHs. Study participants described barriers and enablers across three themes: 1) quality of care, 2) interfaces within the system and 3) interfaces with the wider healthcare system. For quality of care, enablers included confidence in basic trauma management, whilst a perceived lack of change from current management was seen as a barrier. The theme of interfaces within the system identified good interaction with other services and a single point of contact for referral as enablers. Perceived barriers included challenges in referring to tertiary care. The final theme of interfaces with the wider healthcare system included an improved transport system, increased audit resource and coordinated clinical training as enablers. Perceived barriers included a rural staffing crisis and problematic patient transfer to further care.ConclusionsThis study provides insight into rural professionals' perceptions regarding the implementation of a trauma system in rural Scotland. Barriers included practical issues, such as retrieval, transfer and referral processes. Importantly, there is a degree of uncertainty, discontent and disengagement towards trauma system development, and concerns regarding staffing levels and governance. These issues are unlikely to be unique to Scotland and warrant further study to inform service planning and the effective delivery of rural trauma systems.



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Should we bury K-wires after metacarpal and phalangeal fracture osteosynthesis?

Publication date: Available online 22 March 2018
Source:Injury
Author(s): Mads Terndrup, Thomas Jensen, Søren Kring, Martin Lindberg-Larsen
BackgroundBurying Kirschner wires (K-wires) under the skin after metacarpal and phalangeal fracture osteosynthesis may reduce risk of infection, but it might also complicate later removal.Purpose/Aim of StudyTo examine infection and reoperation rates after metacarpal and phalangeal fracture osteosynthesis with buried versus exposed K-wires.Materials and MethodsMetacarpal and phalangeal fractures treated with K-wire osteosynthesis at our institution from 1 st of January 2009 to 1 st of February 2015 were identified retrospectively. The final study population included 444 patients, 331 with metacarpal, 109 phalangeal and 4 with mixed fractures. Surgical and patient records were examined 90 days postoperatively.Findings/Results337 patients (75.9%) were treated with buried K-wires and 107 patients (24.1%) with exposed (non-buried) K-wires. 14 patients (4.1%) treated with buried K-wires presented with postoperative infection, opposed to 7 patients (6,5%) treated with non-buried K-wires (p = 0.311). None of the postoperative infections caused re-operation. Only one case of deep/severe infection was recorded in a patient treated with buried K-wires requiring intravenous antibiotic treatment. In 58 of 337 patients (17.2%) treated with buried K-wires, removal was not possible in the outpatient clinic and required readmission for removal in the operation theatre. All exposed K-wires could be removed in the out-patient clinic without re-operation.ConclusionsWe found no difference in postoperative infection rate between metacarpal and phalangeal fracture osteosynthesis with buried versus exposed K-wires. However, the high readmission and reoperation rate (17.2%) after burying K-wires should call for reconsideration of surgical strategies.



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