Clinicopathological correlations in 38 cases of gastroenteropancreatic high-grade neuroendocrine neoplasms.

Objective: Diagnosis and treatment of gastroenteropancreatic high-grade neuroendocrine neoplasms (GEP-HG-NENs), particularly G3 well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) relies on histopathological morphology, immunohistochemistry, and molecular biological markers, which are lacking especially in cases with ambiguous histomorphology. In this study to contribute to the development of more targeted treatment strategies, we examined various immunohistochemical and molecular biological markers and their association with clinicopathological features in GEP-HG-NENs. Methods: We included 38 patients with GEP-HG-NENs in this study, with their retrospective follow-up data. The expression of tumour protein p53 (TP53), RB transcriptional corepressor 1 (RB1), somatostatin receptor 2 (SSTR2), clusterin (CLU), and marker of proliferation Ki-67 (MKI67) was immunohistochemically analysed. KRAS proto-oncogene, GTPase (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E expression was evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). The relationships between immunohistochemical and molecular biological markers and clinicopathological characteristics were examined using a Cox risk regression model, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses. Results: SSTR2, RB, TP53, and CLU expression differed between NET G3 and NECs, with variations among the NET G3 and small- and large-cell NEC (SCNEC and LCNEC, respectively) groups (p < 0.05). The median MKI67 proliferative index was approximately 40% and 70% in G3 NETs and NECs, respectively. The NET G3 group exhibited a median survival of 25 months, indicating a relatively better prognosis than that of the NECs group (median survival, 11 months). Both Kaplan-Meier survival analysis and the Cox risk regression model indicated a statistical correlation among treatment methods, CLU expression, and prognosis (p < 0.05). The BRAF V600E mutation rate was 32.4% in G3 NETs and SCNEC, demonstrating a significant difference between both types (p = 0.0086). Furthermore, ROC curve analysis highlighted the diagnostic significance of the positive expression of the immunohistochemical markers CLU, SSTR2, and RB in identifying NET G3. Conclusion: To guide more suitable treatment strategies, it is essential to develop and apply valuable and more targeted immunohistochemical and molecular pathological markers for a comprehensive analysis.

Extended 73-month survival in an elderly patient with BRAF V600E-mutated lung adenocarcinoma: A case report.

BRAF is a mediator that activates the mitogen-activated protein kinase pathway. A mutation in BRAF can cause abnormal pathway activation, leading to cell proliferation. In a Phase II study, the combination therapy of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib was found to be effective in non-small cell lung cancer (NSCLC) patients with the BRAF mutation. However, this study has limited efficacy and safety data for elderly patients. We present a case of a patient who started treatment at 87 years old and showed a good prognosis, remaining alive 73 months from the start of treatment with no significant adverse events. The patient also maintained a partial response (PR) according to RECIST 1.1 at the last follow-up. This case suggests that the dabrafenib and trametinib combination therapy is safe and effective for elderly NSCLC patients with the BRAF mutation.

Association between microsatellite instability status, clinicopathological features and mitochondrial DNA amplification in patients with colorectal cancer.

The relationship between BRAF-V600E mutations, mitochondrial DNA amplification and microsatellite instability-high (MSI-H) in colorectal cancer (CRC) has yet to be fully elucidated. The aim of the present study was to assess the association between the MSI status and BRAF-V600E gene mutations/clinicopathological features/mitochondrial DNA amplification in CRC. A non-interventional study analysis was performed using the clinicopathological features of 455 patients with CRC. Immunohistochemistry was used to evaluate four mismatch repair proteins (MutS homolog 2, MutS homolog 6, MutL homolog 1 and postmeiotic segregation increased 2), Ki-67 index, and programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) expression. Additionally, PCR coupled with capillary electrophoresis were used to ascertain the MSI status. Moreover, amplification refractory mutation system-PCR was used to detect BRAF-V600E gene mutation and fluorescence in situ hybridization analysis was used to assess mitochondrial DNA. A total of 455 patients were divided into the MSI high (MSI-H) group (n=52) and microsatellite stability (MSS) group (n=403) based on their MSI status. Compared with the results of immunohistochemistry of four mismatch repair proteins, the consistency rate between mismatch repair protein deficiency and MSI was 94.23%. There were significant differences in PD-L1, primary tumor site, clinical stage, degree of differentiation, tumor size, lymph node metastasis and the occurrence of multiple primary tumors between the MSI-H group and MSS group (P<0.05 or P<0.001). However, there were no significant differences for sex, age, PD-1, Ki-67 expression and BRAF-V600E. The 24-60-month survival rate of the patients in the MSI-H group was significantly higher than that of those in the MSS group (P<0.05). Furthermore, the number of mitochondrial DNA was significantly amplified in the MSI-H group. In conclusion, the present study demonstrated that the combined detection of PD-L1 and MSI in patients with CRC can provide more accurate and effective guidance for personalized treatment.

Cancer of unknown primary and BRAF V600E meeting the BEACON combination: A case report.

The diagnostic work-up of cancer of unknown primary (CUP) is a challenging task; in addition, only a little data on BRAF targeting in CUP are currently available. Traditionally, the identification of favourable and unfavourable CUP subsets directs the choice of treatment. The present article reports the case of a 50-year-old male patient presenting with a BRAF-mutated CUP, a rare and generally unfavourable subset. Based on imaging, immunohistochemistry and a high value of carbohydrate antigen 19-9, an upper gastrointestinal profile was initially presumed. After disease progression on treatment with a first-line platinum-based doublet chemotherapy, a significant response was documented after treatment with the BEACON combination. The present case report highlighted the paradigm shift in diagnosis and treatment of CUP from a histology-based approach to molecular profiling with the introduction of precision medicine.

Predictive Significance of Combined Plasmatic Detection of BRAF Mutations and S100B Tumor Marker in Early-Stage Malignant Melanoma.

BACKGROUND: Melanoma is the most aggressive skin cancer with ability to recur also after early-stage tumor surgery. The aim was to identify early-stage melanoma patients at high risk of recurrence using liquid biopsy, estimating of mutated BRAF ctDNA and the level of tumor marker S100B in plasma. METHODS: Eighty patients were enrolled in the study. BRAF V600E mutation was determined in FFPE tissue and plasma samples using ultrasensitive ddPCR with pre-amplification. The level of S100B was determined in plasma by immunoassay chemiluminescent method. RESULTS: The best prediction of melanoma recurrence after surgery was observed in patients with combined high level of S100B (S100Bhigh) and ctDNA BRAFV600E (BRAFmut) in preoperative (57.1% vs. 12.5%, p = 0.025) as well as postoperative blood samples (83.3% vs. 14.3%, resp., p = 0.001) in comparison with low S100B and BRAF wild-type. Similarly, patients with preoperative and postoperative S100Bhigh and BRAFmut experienced worse prognosis (DFI p = 0.05, OS p = 0.131 and DFI p = 0.001, OS = 0.001, resp.). CONCLUSION: We observed the benefit of the estimation of combination of S100B and ctDNA BRAFmut in peripheral blood for identification of patients at high risk of recurrence and unfavorable prognosis. SIGNIFICANCE: There is still no general consensus on molecular markers for deciding the appropriateness of adjuvant treatment of early-stage melanoma. We have shown for the first time that the combined determination of the ctDNA BRAFmut oncogene (liquid biopsy) and the high level of tumor marker S100B in pre- and postoperative plasma samples can identify patients with the worst prognosis and the highest risk of tumor recurrence. Therefore, modern adjuvant therapy would be appropriate for these patients with resectable melanoma, regardless of disease stage.

Prediction Model of Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma.

BACKGROUND: The objective of this study is to develop a predictive model for the assessment of cervical lymph node metastasis risk in papillary thyroid carcinoma (PTC). METHODS: A retrospective study was conducted on 212 patients with PTC who underwent initial surgical treatment from August 2022 to April 2023 in 2 hospitals. Data were randomly split into 7:3 training-validation sets. Logistic regression was used for feature selection and predictive model creation. Model performance was assessed using receiver operating characteristic (ROC) and calibration curves. Clinical utility was determined using decision curves. RESULTS: Among the 212 patients with PTC, 104 cases (49.1%) exhibited cervical lymph node metastasis, while 108 cases (50.9%) did not. Multivariate logistic regression analysis revealed that age (OR = 0.95), FT3 (OR = 0.41), tumor maximum diameter ≥0.9 cm (OR = 1.85), intratumoral microcalcifications (OR = 1.84), and suspicious lymph node on ultrasound (OR = 2.96) were independent risk factors for lymph node metastasis in PTC patients (P < 0.05). The constructed model for predicting the risk of cervical lymph node metastasis demonstrated a training set ROC curve area under the curve (AUC) of 0.742 (95% CI: 0.664 - 0.821), with a cut-off value of 0.615, specificity of 87.8%, and sensitivity of 51.4%. The validation set exhibited an AUC of 0.648 (95% CI: 0.501 - 0.788), with a cut-off value of 0.644, specificity of 91.2%, and sensitivity of 43.3%. Including the BRAF V600 E mutation did not improve the model's diagnostic performance significantly. Decision curve analysis indicated clinical feasibility of the model. CONCLUSION: The predictive model developed in this study effectively predicts lymph node metastasis risk in PTC patients by incorporating ultrasound features, demographic characteristics, and serum parameters. However, including the BRAF V600 E mutation does not significantly improve the model's diagnostic performance.

BackgroundThe objective of this study is to develop a predictive model for the assessment of cervical lymph node metastasis risk in papillary thyroid carcinoma.MethodsA retrospective study was conducted on 212 patients with papillary thyroid carcinoma who underwent initial surgical treatment at the First Affiliated Hospital of Fujian Medical University from August 2022 to April 2023. Data randomly split into 7:3 training-validation sets. Logistic regression used for feature selection and predictive model creation. Model performance assessed using ROC and calibration curves. Clinical utility determined using decision curves.ResultsAmong the 212 patients with PTC, 104 cases (49.1%) exhibited cervical lymph node metastasis, while 108 cases (50.9%) did not. Multivariate logistic regression analysis revealed that age (OR = 0.95), FT3 (OR = 0.41), tumor maximum diameter ≠¥ 0.9cm(OR = 1.85), intratumoral microcalcifications (OR = 1.84), and suspicious lymph node on ultrasound (OR = 2.96) were independent risk factors for LNM in PTC patients (P < 0.05). The constructed model for predicting the risk of cervical lymph node metastasis demonstrated a training set ROC curve area under the curve (AUC) of 0.742 (95% CI: 0.664 - 0.821), with a cut-off value of 0.615, specificity of 87.8%, and sensitivity of 51.4%. The validation set exhibited an AUC of 0.648 (95% CI: 0.501 - 0.788), with a cut-off value of 0.644, specificity of 91.2%, and sensitivity of 43.3%. Including BRAF V600E gene did not improve model's diagnostic performance significantly. Decision curve analysis indicated clinical feasibility of the model.ConclusionThe predictive model developed in this study effectively predicts lymph node metastasis risk in PTC patients by incorporating ultrasound features, demographic characteristics, and serum parameters.However, Including the BRAF V600E mutation does not significantly improve diagnosis performance.

[Characteristics of long-term complications in Langerhans cell histiocytosis].

About 100 cases of Langerhans cell histiocytosis (LCH) occur annually in Japan. It predominantly occurs in infants, presenting as multisystem disease or multifocal bone involvement. However, LCH can also occur in adults aged 20 to 40. Single-system skin involvement is rare, with most cases presenting with multisystem disease, including bone lesions, which respond to chemotherapy. In adults, lung lesions that improve with smoking cessation are well-known, although multisystem disease is more common and requires aggressive therapeutic intervention similar to that in children. In some infant cases, progression of liver, spleen, and bone marrow lesions can be difficult to control and can become severe. However, targeted molecular therapies are now available as a lifesaving option. More than 30% of cases of multisystem LCH recur at least once, often leading to long-term complications. In particular, the emergence of central diabetes insipidus, anterior pituitary dysfunction, and central nervous system neurodegenerative disorders several years after the diagnosis of LCH is a unique feature not observed in other diseases. New therapeutic strategies are needed to counter these problems.

Frequency of KRAS and BRAF mutations in colorectal carcinoma and their association with clinical-pathological characteristics in a tertiary hospital in Kenya.

Introduction: Colorectal carcinoma is a leading cause of cancer morbidity and mortality globally. Its management includes the use of targeted therapy which require assessment for biomarkers to choose eligible patients. KRAS and BRAF mutations are biomarkers predictive of response to anti-EGFR therapy. This study aimed at determining the frequency of BRAF V600E and KRAS exon 2,3,4 mutations in colorectal carcinoma patients at the Aga Khan University Hospital Nairobi, Kenya. Methods: Study participants were patients who had colectomy for colorectal carcinoma. They were identified from the laboratory information system. The patients age, gender and tumor location were determined from the medical records. The histological diagnosis, pathological tumor and nodal stage were confirmed by examining hematoxylin and eosin-stained slides prepared from the colectomy specimen. DNA was extracted from the specimens using Qiagen QIAamp DNA FFPE Tissue Kit and PCR performed using EntroGen KRAS/BRAF mutation analysis kit following manufacturer's protocol. Results: One hundred fourteen patients were enrolled. Colorectal carcinoma was significantly more common in males than females. The mean age at diagnosis was 58 years. Majority of the tumors were in the right colon, were of pathological tumor stage T3 and had nodal involvement. Forty six percent (46%) of the cases had KRAS mutations while 5.3% had BRAF V600E mutation. KRAS mutation was associated with a high pathological tumor stage and nodal involvement. Conclusion: Colorectal carcinoma in our patients is more common in males and tend to occur at a younger age. The patients tend to have a high tumor pathological stage and nodal involvement at diagnosis. The high frequency of KRAS exon 2,3,4 mutation and low frequency of BRAF V600E mutations is similar to what has been reported in literature.

Complete response to encorafenib plus binimetinib in a BRAF V600E-mutant metastasic malignant glomus tumor.

Glomus tumors (GT) are very rare mesenchymal neoplasms arising from glomus bodies, arteriovenous structures located in the dermis and involved in thermoregulation. Although most are benign, they may occasionally present malignant histological features associated with aggressive clinical behavior, metastatic spread, and poor response to conventional chemotherapy. The BRAF V600E mutation has been identified in a subset of malignant GT, highlighting a promising therapeutic target. Here, we report the impressive clinical and morpho-metabolic response of a metastatic BRAF V600E-mutated glomangiosarcoma after treatment with encorafenib and binimetinib.

Development and validation of a clinical prognostic model for BRAF V600E-mutated colorectal cancer patients based on pathological stage, microsatellite status, and primary tumor site.

Objective: To develop and validate a prognostic model for patients with BRAF V600E-mutated colorectal cancer. Methods: The clinical and pathological information of 206 patients with BRAF V600E-mutated colorectal cancer diagnosed in Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College from 2014 to 2021 was retrospectively collected. Least absolute shrinkage and selection operator (LASSO) regression, Cox regression, and nomograms were used to develop clinical prognostic models. The differentiation was measured using C-statistic, and the predicted variability was evaluated using the calibration curve. The prognostic model was externally validated using validation set data from 164 patients pooled from five studies. Results: Our clinical prognostic model included three variables: pathological stage, microsatellite status, and primary tumor site. In internal validation, the model had a concordant index of 0.785 (95% CI [0.732-0.839]) and a concordant index of 0.754 (95% CI [0.698-0.810]) using pathological staging. External validation confirmed the robustness of the model with a consistency index of 0.670 (95% CI [0.617-0.724]) and a consistency index of 0.584 (95% CI [0.546-0.622]) using pathological staging. Likelihood ratio test results show that our model is better (internal validation, p = 5.141e-03; external validation, p = 2.728e-05). The calibration graph drawn based on the prediction and the actual situation is close to the 45° diagonal. Conclusion: By adding microsatellite status and primary tumor site on the basis of pathological stage, we improved the discriminability and prediction accuracy of the model and successfully established a prognosis model for patients with BRAF V600E mutation of colorectal cancer.

Sarcomatoid Morphology in Pediatric Langerhans Cell Neoplasm Does Not Always Predict Aggressive Clinical Course.

Langerhans cell sarcoma (LCS), a rare malignant neoplasm in the general category of myeloid neoplasms characterized by overtly malignant Langerhans cells (LC) with conspicuous mitotic activity including atypical forms. Although most cases occur in adults, rare examples of LCS have been reported in children with variable clinical outcome. We present 2 childhood cases of Langerhans cell neoplasm with high grade sarcomatous features and OSBPL9::BRAF fusion and BRAF V600E mutation.

Efficacy and safety of the combination of encorafenib/cetuximab with or without binimetinib in patients with BRAF V600E-mutated metastatic colorectal cancer: an AGEO real-world multicenter study.

BACKGROUND: The combination of encorafenib with cetuximab has become the standard of care in patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC) after a prior systemic therapy. This study aims to describe the efficacy and safety of encorafenib/cetuximab +/- binimetinib in patients with BRAF V600E-mutated mCRC in a real-world setting. PATIENTS AND METHODS: This retrospective study included patients with BRAF V600E-mutated mCRC who received this combination from January 2020 to June 2022 in 30 centers. RESULTS: A total of 201 patients were included, with 55% of women, a median age of 62 years, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) >1 in 20% of cases. The main tumor characteristics were 60% of right-sided primary tumor, 11% of microsatellite instability/mismatch repair deficient phenotype, and liver and peritoneum being the two main metastatic sites (57% and 51%). Encorafenib/cetuximab +/- binimetinib was prescribed in the first, second, third, and beyond third line in 4%, 56%, 29%, and 11%, respectively, of cases, with the encorafenib/cetuximab/binimetinib combination for 21 patients (10%). With encorafenib/cetuximab treatment, 21% of patients experienced grade ≥3 adverse events (AEs), with each type of grade ≥3 AE observed in <5% of patients. The objective response rate was 32.2% and the disease control rate (DCR) was 71.2%. The median progression-free survival (PFS) was 4.5 months [95% confidence interval (CI) 3.9-5.4 months] and the median overall survival (OS) was 9.2 months (95% CI 7.8-10.8 months). In multivariable analysis, factors associated with a shorter PFS were synchronous metastases [hazard ratio (HR) 1.66, P = 0.04] and ECOG-PS >1 (HR 1.88, P = 0.007), and those associated with a shorter OS were the same factors (HR 1.71, P = 0.03 and HR 2.36, P < 0.001, respectively) in addition to treatment beyond the second line (HR 1.74, P = 0.003) and high carcinoembryonic antigen level (HR 1.72, P = 0.003). CONCLUSION: This real-world study showed that in patients with BRAF V600E-mutated mCRC treated with encorafenib/cetuximab +/- binimetinib, efficacy and safety data confirm those reported in the BEACON registration trial. The main poor prognostic factors for this treatment are synchronous metastases and ECOG-PS >1.

Confined copper depletion via a hydrogel platform for reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant colorectal cancer.

BRAFV600E-mutant colorectal cancer (CRC) is resistant to most first-line therapeutics, including the BRAF inhibitor dabrafenib and epidermal growth factor receptor (EGFR) inhibitor cetuximab. Although copper depletion shows promise in reversing dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC, its application is limited by the potential for excessive copper depletion in non-tumor objects. In this study, we have developed a hydrogel platform for confined copper depletion in BRAFV600E-mutant CRC cells, which effectively reverses dabrafenib/cetuximab resistance and enhancing therapeutic efficiency. The hydrogel platform enables precise intracellular copper depletion through localized administration, acidity-triggered drug release, and oxidized activation of a copper prochelator. The dosage of this prochelator is 37.5 µg/kg in mouse models, which is significantly lower than the commonly used tetrathiomolybdate. Furthermore, both dabrafenib and the prochelator are preloaded into acid-responsive nanoparticles before being embedded in the hydrogel matrix to facilitate efficient endocytosis and acid-activatable drug release. Confined copper depletion inhibits MEK1 signaling and suppresses the MAPK signaling pathway when combined with BRAF and EGFR inhibitors. Moreover, the hydrogel platform inhibits tumor growth and prolongs survival in subcutaneous and postsurgical models of BRAFV600E-mutant CRC. This study provides an innovative strategy for overcoming dabrafenib/cetuximab resistance in BRAFV600E-mutant CRC through precise intracellular copper depletion.

Case report: Metastatic BRAF V600E-mutated adult Wilms' tumor with robust response to BRAF/MEK inhibitor therapy.

Nephroblastoma or Wilms' tumor (WT) is the most common pediatric renal malignancy but rare in adults. Treatment protocols for adults are typically extrapolated from pediatric guidelines, but there are no standard guidelines for adults due to the rarity of the disease. However, next-generation sequencing has led to new therapeutic options for adult WT patients. We present the first case to our knowledge of a recurrent adult WT treated with dual BRAF/MEK-targeted therapy, which showed initial robust clinical response and was well tolerated.

BRAF V600E mutation in thyroid carcinoma: a large-scale study in Han Chinese population.

BACKGROUND: The prevalence of genetic mutations in thyroid cancer varies significantly among different ethnic backgrounds. The present study aimed to investigate the clinical potential of BRAF V600E in a large group of homogenous Han Chinese patients. METHODS: From 2018 to 2021, 6232 thyroid disease patients who underwent thyroidectomy at our hospital were enrolled. We measured the diagnostic value of BRAF and plotted ROC curves. Patients with full clinical-pathological data were selected and divided into the BRAF mutation and wild type groups. We conducted univariate and multivariate analyses to quantify the differences in potential predictive factors of papillary thyroid carcinoma (PTC) patients between the groups. Kaplan-Meier survival analysis was used to estimate overall recurrence and recurrence rate. RESULTS: The prevalence of BRAF V600E mutation was 86.0% in PTCs. The sensitivity and specificity of BRAF mutation for diagnosing PTC from suspicious lesions were 85.5% and 100%, respectively. The sensitivity and specificity of BRAF analysis in the indeterminate cytology group were 72.5% and 100%, respectively. BRAF mutation showed an independent association with older age, negative HT, larger tumor size, extrathyroidal extension, and multifocality in PTCs. In micro-PTCs (tumor size ≤ 1), the mutation was also positively correlated with progressive phenotypes of extrathyroidal extension and multifocality. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analysis. CONCLUSIONS: This large single-center study reveals that BRAF V600E is highly prevalent in the Han Chinese population and demonstrates BRAF V600E mutation testing has high diagnostic accuracy and its strong association with the progress of aggressiveness in PTCs and a higher probability of recurrence. BRAF mutation can serve as an accurate marker for diagnosis and decision-making with great value.

The Expression and Clinicopathological Significance of BRAF V600E and Mucin 6 in Intrahepatic Cholangiocarcinoma: A Retrospective Study.

Aim. The study aims to explore the expression levels and clinicopathological significance of BRAF V600E and mucin 6 in intrahepatic cholangiocarcinoma. Method. Immunohistochemistry for BRAF V600E and mucin 6 was performed in 110 patients with intrahepatic cholangiocarcinoma. Subsequently, a comprehensive review of medical records and clinicopathological analysis was undertaken. Results. BRAF V600E expression was detected in 11 patients (10%); mucin 6 expression was observed in 19 intrahepatic cholangiocarcinoma specimens (17%). Thereafter, Cox regression models indicated that positive expression of either MUC6 positive (hazard ratio = 0.091, 95% confidence interval = 0.034-0.247, P < .001) and BRAF V600E positive (hazard ratio =0.150, 95% confidence interval = 0.058-0.388, P < .001) was significantly linked with longer overall survival for intrahepatic cholangiocarcinoma patients. Conclusion. The study concludes that positive expression of BRAF V600E and mucin 6 could potentially implied significant survival benefits for patients diagnosed with intrahepatic cholangiocarcinoma.

Real-world outcomes of stage II and III colorectal cancers treated by postoperative adjuvant chemotherapy based on the mismatch repair status.

PURPOSE: In Japan, immunohistochemistry for mismatch repair (MMR) proteins targeted at stage II and III colorectal cancers (CRCs) has been covered by national insurance since October, 2022. This study aimed to clarify the long-term outcomes of patients with stage II and III CRCs receiving postoperative adjuvant chemotherapy based on their MMR status. METHODS: The outcomes of 640 patients who underwent radical surgery for stage II and III CRCs were analyzed retrospectively. RESULTS: Deficient MMR (dMMR) was diagnosed in 41 (13.3%) patients with stage II and 28 (9.1%) patients with stage III CRC. The overall survival and recurrence rates were not significantly different between the patients with stage II and those with stage III CRC. The risk factors for recurrence among those with stage II CRC were tumors on the left side, T4 disease, and the presence of BRAF wild type. The recurrence rates were lower in the stage II CRC patients with sporadic dMMR than in those with suspected Lynch syndrome (LS). The first site of recurrence was more frequently the peritoneum or distant lymph node in patients with dMMR. CONCLUSIONS: Stage II CRC patients with sporadic dMMR were found to have a very good prognosis. On the other hand, peritoneal dissemination or distant lymph node metastasis tended to develop in patients with dMMR.

Colorectal cancer with BRAF V600E mutation: Trends in immune checkpoint inhibitor treatment.

Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.

Central nervous system involvement in Erdheim-Chester disease: a magnetic resonance imaging study.

PURPOSE: To characterize brain MR imaging findings in a cohort of 58 patients with ECD and to evaluate relationship between these findings and the BRAFV600E pathogenic variant. METHODS: ECD patients of any gender and ethnicity, aged 2-80 years, with biopsy-confirmed ECD were eligible to enroll in this study. Two radiologists experienced in evaluating ECD CNS disease activity reviewed MRI studies. Any disagreements were resolved by a third reader. Frequencies of observed lesions were reported. The association between the distribution of CNS lesions and the BRAFV600Epathogenic variant was evaluated using Fisher's exact test and odd ratio. RESULTS: The brain MRI of all 58 patients with ECD revealed some form of CNS lesions, most likely due to ECD. Cortical lesions were noted in 27/58 (46.6 %) patients, cerebellar lesions in 15/58 (25.9 %) patients, brain stem lesions in 17/58 cases (29.3 %), and pituitary lesions in 10/58 (17.2 %) patients. Premature cortical atrophy was observed in 8/58 (13.8 %) patients. BRAFV600E pathogenic variant was significantly associated with cerebellar lesions (p = 0.016) and bilateral brain stem lesions (p = 0.043). A trend toward significance was noted for cerebral atrophy (p = 0.053). CONCLUSION: The study provides valuable insights into the brain MRI findings in ECD and their association with the BRAFV600E pathogenic variant, particularly its association in cases with bilateral lesions. We are expanding our understanding of how ECD affects cerebral structures. Knowledge of MRI CNS lesion patterns and their association with mutations such as the BRAF variant is helpful for both prognosis and clinical management.

No drug holidays in BRAFV600E glioma patients: An argument for dose reduction of targeted therapies.

Background: Combined BRAF and MEK inhibition is effective for some BRAFV600E-altered gliomas, a cancer for which there are few effective therapies. While recent clinical trials demonstrate objective response rates of 30%-40%, tolerable adverse event rates are 70%-90%, and 12%-15% of patients stop therapy for toxicity. There are no clear guidelines regarding the timing and reinitiation of BRAF-targeted therapies following drug holidays. Here, we describe 4 patients with rapid disease progression during periods of treatment interruption. All patients experienced a response upon resumption of targeted therapy. Methods: This is a multi-institutional, retrospective review of 4 patients. Results: Three patients were diagnosed with BRAFV600E mutated anaplastic pleomorphic xanthoastrocytoma (aPXA) and 1 with epithelioid glioblastoma. The age range was 32 to 46; 3 patients were female and one patient was male. All patients were initially treated with radiation and were subsequently treated with BRAF/MEK inhibitors after disease progression. All patients with aPXA required the targeted therapy to be held due to toxicity and 1 patient held the therapy prior to transitioning to a novel BRAF-targeted agent. All patients were restarted on BRAF/MEK inhibitors after a drug holiday. Three patients required a dose reduction and all improved clinically following reinitiation. Conclusions: Clinical and radiographic progression may occur rapidly upon holding BRAF-targeted therapy, warranting judicious dose reductions and minimization of drug holidays.