RET fusions in a small subset of advanced colorectal cancers at risk of being neglected

Abstract

Background

Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC).

Patients and methods

In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: 1) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811); 2) cohorts screened at two Italian and one South Korean Institutions; 3) Foundation Medicine Inc. database. Next generation sequencing data were analyzed for RET rearranged cases.

Results

RET fusions were more frequent in older patients (median age of 66 vs. 60 years, p = 0.052), with ECOG PS 1-2 (90% vs. 50%, p = 0.02), right-sided (55% vs. 32%, P=0.013), previously unresected primary tumors (58% vs. 21%, P<0.001), RAS and BRAF wild-type (100% vs. 40%, p < 0.001) and MSI-high (48% vs. 7%, P<0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement.At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 vs. 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P<0.001). In the multivariable model, RET rearrangements were still associated with shorter OS [HR: 2.97; 95% CI, 1.25-7.07; P=0.014], while primary tumor location, RAS and BRAF mutations and MSI status were not.

Conclusions

Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

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Investigating the role of articulatory organs and perceptual assimilation of native and non-native fricative place contrasts

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Compression in Working Memory and Its Relationship With Fluid Intelligence

Abstract

Working memory has been shown to be strongly related to fluid intelligence; however, our goal is to shed further light on the process of information compression in working memory as a determining factor of fluid intelligence. Our main hypothesis was that compression in working memory is an excellent indicator for studying the relationship between working-memory capacity and fluid intelligence because both depend on the optimization of storage capacity. Compressibility of memoranda was estimated using an algorithmic complexity metric. The results showed that compressibility can be used to predict working-memory performance and that fluid intelligence is well predicted by the ability to compress information. We conclude that the ability to compress information in working memory is the reason why both manipulation and retention of information are linked to intelligence. This result offers a new concept of intelligence based on the idea that compression and intelligence are equivalent problems.

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Age, sex, and type of medication predict the effect of anti-VEGF treatment on central retinal thickness in wet age-related macular degeneration

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Serum calcitonin negative mixed medullary-follicular carcinoma initially diagnosed as medullary thyroid carcinoma by fine-needle aspiration cytology: A case report and review of the literatures

Medullary thyroid carcinoma (MTC) is potentially lethal. A prompt and accurate diagnosis is the prerequisite for the treatment of MTC. Fine-needle aspiration (FNA) is a reliable diagnostic tool in the assessment of thyroid nodules. However, cytologic assessment of MTC based on FNA has several drawbacks due to morphological variants. We present a case of MTC diagnosed through FNA cytology, which was eventually histologically confirmed as a mixed medullary-follicular carcinoma with negative serum calcitonin expression. Hence, diagnosis of MTC based on FNA should be applied with caution. Ultrasound characteristics of suspicious thyroid nodules are recommended to be evaluated by FNA. However, calcitonin levels should be measured in both the FNA washout fluid and serum when features of MTC are presented or cytology result is inconclusive. If adequate FNA sample is available, a supplementary immunocytochemical staining of markers such as calcitonin, chromogranin, carcinoembryonic antigen, and thyroglobulin is helpful for a correct diagnosis of MTC.

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Risk factors associated with malignancy and with triage to surgery in thyroid nodules classified as Bethesda category IV (FN/SFN)

Background

Thyroid nodules diagnosed as Bethesda category IV [follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)] are recommended for surgery. However, only 10%-40% of these nodules turn out to be malignant on histopathological examination. Therefore, selection for surgery of nodules diagnosed as Bethesda category IV is important. We aimed to define predictive factors for malignancy and factors associated with triage to surgery.

Methods

The records of all patients with nodules who underwent fine needle aspiration biopsy (FNAB) and classified by Bethesda reporting system as FN/SFN between January 2011 and July 2017 at our institution were reviewed. Univariate and multivariate analysis were performed to select independent factors associated with thyroid cancer, and with triage to surgery. Using independent risk factors for malignancy predictive index categories were created.

Results

Among 6910 nodules that underwent FNAB, 180 (2.6%) were diagnosed as FN/SFN. Of the 180 patients, 139 (77%) underwent surgery with the associated malignancy rate of 37% (51/139) (upper boundary). Risk of malignancy among all FN/SFN nodules was 28% (lower boundary). Solid structure, size ≥ 4 cm, microcalcification, hypoechogenicity, and increased vascularization were found to be significant and independent risk factors associated for malignancy. None of the clinical and ultrasound factors were associated with triage to surgery.

Conclusions

Our findings showed that using predictive factors for malignancy in the Bethesda IV category as risk indices, 17% of patients who had nodules without any risk factors could be spared surgery. Predictive indices could be considered for the malignancy risk and for selection of patients for surgery.

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CSF/serum matrix metallopeptidase-9 ratio discriminates neuro Behçet from multiple sclerosis

Abstract

In neuro Behçet disease with multiple sclerosis-like features, diagnosis could be challenging. Here, we studied the cerebrospinal fluid and serum inflammatory profile of 11 neuro Behçet and 21 relapsing-remitting multiple sclerosis patients. Between the soluble factors analyzed (MMP9, TNFα, IL6, CXCL13, CXCL10, CXCL8, IFNγ, IL10, IL17, IL23, and others) we found MMP9 increased in neuro Behçet serum compared to multiple sclerosis and decreased in cerebrospinal fluid. Furthermore, neuro Behçet analysis of circulating natural killer CD56_DIM subset suggests their potential involvement in increased MMP9 production. We believe that these findings may have a translational utility in clinical practice.

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