BRAF-Mutated Melanoma Journey in Latin America: Expert Recommendations From Diagnosis to Treatment.

OBJECTIVES: • Gather a panel of Latin American experts in testing and treating BRAF-melanoma. • Describe the current landscape of BRAF-mutated melanoma in Latin America. • Outline the current gaps in testing and recommend improvements for testing and treating BRAF-mutated melanoma in the region. INTRODUCTION: Melanoma prevalence in Latin America is lower than in high- and middle-income countries. However, recent data indicate that the region's incidence and mortality are rising, with more stage IV patients being diagnosed. According to international clinical practice guidelines, conducting BRAF-mutation testing in patients with stage III or stage IV melanoma and high-risk resected disease is imperative. Still, BRAF-mutation testing and targeted therapies are inconsistently available in the region. METHODS: Americas Health Foundation convened a meeting of Latin American experts on BRAF-mutated melanoma to develop guidelines and recommendations for diagnosis through treatment. RESULTS AND CONCLUSIONS: Some recommendations for improving diagnostics through improving access and reducing the cost of BRAF-mutation testing, enhancing efficiency in pathology laboratories, and creating country-specific local guidelines. The panel also gave treatment recommendations for neo-adjuvant therapy, adjuvant therapy, and therapy for patients with metastatic disease in Latin America.

Validation of a Nomogram for Non-sentinel Node Positivity in Melanoma Patients, and Its Clinical Implications: A Brazilian-Dutch Study.

BACKGROUND: Non-sentinel node (NSN) positivity impacts the prognosis of melanoma patients; however, the benefits of completion lymph node dissection in patients with positive sentinel nodes (SNs) are limited. OBJECTIVE: We aimed to present a predictive nomogram for NSN positivity in melanoma patients with a positive SN biopsy. METHODS: This retrospective analysis from patients who underwent SN biopsy in a Brazilian institution from 2000 to 2015 was used for the construction and internal validation of the nomogram. This nomogram was then externally validated in a cohort of Dutch patients. RESULTS: The Brazilian cohort comprised 1213 patients, with a mean follow-up of 5.11 years. Breslow thickness (odds ratio [OR] 1.170, 95% confidence interval [CI] 1.043-1.314]; p = 0.008), number of positive SNs (OR 1.092, 95% CI 1.034-1.153; p = 0.001), and largest diameter of the metastatic deposit (OR 3.217, 95% CI 1.551-6.674; p = 0.002) were statistically significant for NSN positivity. Internal validation was performed using a bootstrapping technique. A good performance was observed (Brier score 0.097) and an excellent power of discrimination was achieved (area under the curve [AUC] 0.822). The nomogram was then applied to the Dutch cohort, and its overall performance (Brier score 0.085), calibration (Hosmer-Lemeshow goodness-of-fit test; p = 0.198), and discriminatory power (AUC 0.752, 95% CI 0.615-0.890) were all adequate. CONCLUSIONS: We presented a nomogram for assessing NSN probability that should not only be used for surgical considerations but also for risk stratification and clinical decisions. Internal validation has shown that this is an adequate model, while external validation increases the model's reliability and suggests that it can be globally incorporated.

BAP1 tumor predisposition syndrome case report: pathological and clinical aspects of BAP1-inactivated melanocytic tumors (BIMTs), including dermoscopy and confocal microscopy.

BACKGROUND: BRCA1 associated-protein 1 (BAP1) tumor predisposition syndrome is associated with an increased risk for malignant mesotheliomas, uveal and cutaneous melanomas, renal cell carcinomas, and singular cutaneous lesions. The latter are referred to as BAP1-inactivated melanocytic tumors (BIMTs). When multiple BIMTs manifest, they are considered potential markers of germline BAP1 mutations. CASE PRESENTATION: Here, we report a novel pathogenic BAP1 germline variant in a family with a history of BIMTs, cutaneous melanomas, and mesotheliomas. We also describe singular pathological aspects of the patient's BIMT lesions and their correlation with dermoscopic and reflectance confocal microscopy findings. CONCLUSIONS: This knowledge is crucial for the recognition of BIMTs by dermatologists and pathologists, allowing the determination of appropriate management for high-risk patients, such as genetic investigations and screening for potentially aggressive tumors.

A nomogram to identify high-risk melanoma patients with a negative sentinel lymph node biopsy.

BACKGROUND: Melanoma patients with negative nodes after sentinel lymph node biopsy are a heterogeneous group. Current guidelines fail to adequately stratify surveillance and treatment for this group. Also, there is scarce data on adjuvant treatments for these patients. OBJECTIVE: To create a nomogram including clinical and pathologic characteristics capable of evaluating the risk for recurrence of primary melanoma patients with negative sentinel lymph node biopsies (SLNBs). METHODS: We used a retrospective cohort of patients who underwent SLNB during 2000-2015 at a single institution. RESULTS: Our cohort comprised 1213 patients. Among these patients, 967 (79.7%) had a negative SLNB, and mean follow-up was 59.67 months. There were 133 recurrences (13.8%); 45 (33.8%) presented with nodal recurrence, and 35 (26.3%) recurred where a SLNB was performed. Breslow thickness, ulceration, and microsatellitosis were found to be predictive of risk for recurrence at 1, 2, 5, and 10 years. LIMITATION: Single center analysis. CONCLUSION: We created a predictive nomogram for melanoma patients with negative SLNBs. This nomogram is easy to use and identifies high-risk patients who should have more strict surveillance and be considered for adjuvant treatment.

Angiogenesis-related protein expression in bevacizumab-treated metastatic colorectal cancer: NOTCH1 detrimental to overall survival.

BACKGROUND: The development of targeted therapies has undoubtedly broadened therapeutic options for patients with colorectal cancer (CRC). The use of bevacizumab to reduce angiogenesis has been associated with improved clinical outcomes. However, an urgent need for prognostic/predictive biomarkers for anti-angiogenic therapies still exists. METHODS: Clinical data of 105 CRC patients treated with bevacizumab in conjunction with chemotherapy were analyzed. The expression of vascular endothelial growth factor (VEGF) receptors, NOTCH1 receptor and its ligand DLL4 were determined by immunohistochemistry. Tumor samples were arranged on a tissue microarray. The association between protein expression and clinicopathological characteristics and outcomes was determined. RESULTS: Bevacizumab was administered as a first-line of treatment in 70.5 % of our cases. The median progression-free survival (PFS) was 10.2 months. The median overall survival (OS) of the total cohort was 24.4 months. Bevacizumab, as the first-line of treatment, and the presence of liver metastasis were independently associated with objective response rate. Membrane VEGFR1 and VEGFR3 expressions were associated with the presence of lung metastasis; interestingly, VEGFR3 was associated with less liver metastasis. NOTCH1 expression was associated with lymph node metastasis. There was a trend toward association between improved PFS and lower NOTCH1 expression (p = 0.06). Improved OS was significantly associated with lower NOTCH1 expression (p = 0.01). In a multivariate analysis, ECOG (Eastern Cooperative Oncology Group) performance status, liver metastasis, histological grade, and NOTCH1 expression were independently associated with OS. CONCLUSION: Our findings illustrated the expression profile of angiogenesis-related proteins and their association with clinicopathological characteristics and outcomes. NOTCH1 expression is a detrimental prognostic factor in metastatic CRC patients treated with chemotherapy plus bevacizumab.

Popliteal sentinel lymph node involvement in melanoma patients.

BACKGROUND: Sentinel lymph nodes (SLN) in popliteal basins are rare, and there is controversy in literature regarding their origin, management, and outcomes. OBJECTIVES: To correlate clinical and pathological features of popliteal basin drainage and analyze the impact of popliteal lymph node drainage on survival. MATERIALS AND METHODS: Retrospective analysis of SLN biopsies performed at a single institution between 2000 and 2010. RESULTS: SLN biopsies were performed in 254 patients with melanoma in lower limbs, 247 of which were evaluated. In this group, there were 59 patients (24%) with a positive SLN. Twenty-seven cases (11%) presented with popliteal drainage, one of which lacked concurrent groin drainage. Among these 27 patients, three (11%) had popliteal metastasis, one of which had exclusive involvement of this basin. Popliteal drainage was associated with worse 5-year disease-free survival (DFS) (P = 0.028) but not 5-year overall survival (OS) (P = 0.219) in univariate analysis. In multivariate analysis, Breslow thickness, mitotic index, and positive SLN were prognostic factors for DFS. Only mitotic index correlated significantly with OS (P = 0.044). CONCLUSIONS: Popliteal drainage seems to be associated with worse prognostic features of the primary tumor.

KRAS gene mutation in a series of unselected colorectal carcinoma patients with prognostic morphological correlations: a pyrosequencing method improved by nested PCR.

INTRODUCTION: Inhibition of EGFR is a strategy for treating metastatic colorectal cancer (CRC) patients. KRAS sequencing is mandatory for selecting wild-type tumor patients who might benefit from this treatment. DNA from formalin-fixed paraffin-embedded (FFPE) tissues is commonly used for routine clinical detection of mutations, and its amplification succeeds only when all preanalytical histological processes have been controlled. In cases that are not properly processed, the DNA results can be poor, with low peak pyrosequencing findings. We designed and tested a pair of forward and reverse primers for a nested PCR method, followed by pyrosequencing, in a single Latin American institution series of 422 unselected CRC patients, correlating KRAS mutations with pathological and clinical data. MATERIALS AND METHODS: Patient DNA samples from tumors were obtained by scraping or laser microdissection of cells from FFPE tissue and extracted using a commercial kit. DNA was first amplified by PCR using 2 primers that we designed; then, nested PCR was performed with the amplicon from the preamplification PCR using the KRAS PyroMark™ Q96 V2.0 kit (Qiagen). Pathological data were retrieved from pathology reports. RESULTS: KRAS mutation was observed in 33% of 421 cases. Codon 12 was mutated in 76% of cases versus codon 13 in 24%. Right-sided CRCs harbored more KRAS mutations than left-sided tumors, as did tumors that presented with perineural invasion. CONCLUSION: Our findings in this Latin American population are consistent with the literature regarding the frequency of KRAS mutations in CRC, their distribution between codons 12 and 13, and type of nucleotide substitution. By combining nested PCR and pyrosequencing, we achieved a high rate of conclusive results in testing KRAS mutations in CRC samples - a method that can be used as an ancillary test for failed assays by conventional PCR.

KRAS insertions in colorectal cancer: what do we know about unusual KRAS mutations?

INTRODUCTION: KRAS mutations are negative predictors of the response to anti-EGFR therapy in colorectal carcinomas (CRCs). Point mutations in codons 12, 13, and 61 are the most common KRAS mutations in CRC. There are few reports on insertions in KRAS, and little is known about its ability to activate the RAS pathway. The scarcity of data regarding insertion frequencies and nucleotide additions in KRAS impedes the management of patients with such mutations. We present data on KRAS insertions in CRC and discuss a case. MATERIALS AND METHODS: Pyrosequencing and Sanger sequencing were performed to identify KRAS and BRAF mutations in paraffin-embedded samples of CRC. Expression of mismatch repair proteins was examined by immunohistochemistry. RESULTS: We detected a GGT insertion between codons 12 and 13 (c.36_37insGGT;p.G12_G13insG) in a CRC patient. We found that insertions in KRAS is very rare in CRC and that the most frequent type of insertion is c.36_37insGGT. CONCLUSIONS: KRAS gene insertions represent a diagnostic and clinical challenge due to the difficult and unusual pyrosequencing findings and the lack of information regarding its clinical impact.

Dermatofibrosarcoma protuberans of the vulva: margins assessment and reconstructive options - a report of two cases.

BACKGROUND: Dermatofibrosarcoma Protuberans (DFSP) of the vulva is rare and oncologic surgery with free margins may lead to severe functional damage, requiring multidisciplinary approach regarding resection, margin assessment and reconstruction.Case Report: Two cases of DFSP in vulva were treated in a single institution. A 28-year-old patient with an incisional biopsy in the vulvar region revealing DFSP underwent a partial vulvectomy with clitoris preservation. Pathological studies revealed free margins and reconstructive surgery was performed. This patient is disease free in a 40 months follow up. The other, a 57-year-old patient was also referred after an incomplete resection of a DFSP in the vulvar region. A 1-cm margim resection followed by Complete Circumferential and Peripheral Deep Margin Assessment (CCPDMA) was performed. Although the upper lateral margin was positive, it was possible to perform another wide local excision with preservation of the clitoris and primary closure. CONCLUSION: DFSP of the vulva requires an accurate evaluation of margins, resections following oncological principles and reconstruction. Although being a very challenging lesion that usually implies difficult surgical management, if treated in a multidisciplinary environment, with surgical oncologists, experienced dermatopathologists and reconstructive surgeons can achieve good results. Even in difficult cases that presents with large lesions and compromising challenging areas, a complete oncologic resection can be performed minimizing functional damage for the patient.

Intraoperative assessment of surgical margins using "en face" frozen sections in the management of cutaneous carcinomas.

BACKGROUND: Basal cell and squamous cell carcinomas (BCC and SCC) are the most common types of cancer worldwide. Intraoperative assessment of surgical margins by frozen section has been widely used to ensure disease-free margins. The intraoperative "en face" freezing technique evaluates all peripheral and deep margins. OBJECTIVE: To report the results of the "en face" freezing technique in relation to tumor recurrence and agreement with paraffin-embedded tissue examination. METHODS: Retrospective analysis of patients undergoing surgical excision of BCC and SCC at the A. C. Camargo Cancer Center, Brazil. RESULTS: This study included 542 skin carcinomas, which were excised from 397 patients. A total of 201 male patients (50.6%), and 196 female patients (49.4%) were assessed, whose mean age was 64 years. The tumors were mostly located on the head and neck region (87.8%). BCC corresponded to 79.7% of the cases. The mean follow-up was 38 months. Tumor relapse occurred in 0.86% of the primary tumors and 3.7% of recurrent tumors. The result of the intraoperative "en face" frozen section evaluation was in agreement with the final result of the anatomopathological examination (paraffin test) in 98% of the lesions. STUDY LIMITATIONS: Not having a minimum follow-up time of 5 years for all patients. CONCLUSION: The "en face" freezing technique shows low tumor relapse, being reliable and safe to guarantee negative surgical margins of the tumor.

Pigmented lesion on the face: which is the chance of being melanoma using reflectance confocal microscopy features?

Facial melanoma presents itself as a brownish macula, being difficult to differentiate it from benign pigmented lesions of the face on clinical examination. Reflectance confocal microscopy (RCM) assists in diagnosing facial lesions in which dermoscopy has limitations, allowing to increase the diagnostic accuracy. The study aimed to analyze the RCM features of pigmented isolated lesions of the face for diagnosing melanoma. Also, we sought to establish the chance of a pigmented lesion on the face being a melanoma using RCM criteria. In this retrospective and prospective study, 105 clinical pigmented lesions on the face underwent RCM, and cytoarchitectural features in the epidermis, the dermo-epidermal junction (DEJ), and dermis were described. For statistical analysis, the exact chi-square test was applied to the RCM criteria. The odds ratio was estimated using univariate logistic regression. Finally, we used the multiple logistic regression method for creating a nomogram to predict the chance of a lesion being a melanoma. After univariate and multivariate logistic regression, atypical round nucleated cells within the epidermis, pagetoid spread, and follicular dendritic cells presented as statistically significant features. Then, a complex nomogram was created to give the chance of a pigmented lesion on the face being a melanoma. The presence of these three features resulted in a 98% probability for melanoma. This study allowed to estimate the diagnosis of melanoma on the face, using RCM, practicable and feasible in the daily routine, through the presence of some RCM nomogram criteria.

Unique SLC12A2-ROS1 fusion is associated with marked response to crizotinib in lung adenocarcinoma.

Chromosomal rearrangements involving the c-ros oncogene 1 (ROS1) gene define a subset of non-small cell lung cancers highly sensitive to small-molecule tyrosine kinase inhibitors. However, little is known about the impact of different fusion partners on tyrosine kinase inhibitor efficacy. We herein describe a case of a 26-year-old never-smoker patient from southern Africa with metastatic lung adenocarcinoma driven by SLC12A2-ROS1 fusion, who had a pronounced and durable response to crizotinib. The present case underscores the importance of pursuing actionable alterations in patients with similar clinical and epidemiological characteristics. In addition, provides the second report of crizotinib activity against lung malignancies harboring the unique SLC12A2-ROS1 fusion and highlights the importance of a deeper understanding of molecular alterations in underrepresented subgroups of patients to tailor the decision-making in daily practice.

Tumor glycolytic profiling through 18F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC.

Background: A significant proportion of patients with non-small-cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICIs). Since metabolic reprogramming with increased glycolysis is a hallmark of cancer and is involved in immune evasion, we used 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) to evaluate the baseline glycolytic parameters of patients with advanced NSCLC submitted to ICIs, and assessed their predictive value. Methods: 18F-FDG PET/CT results in the 3 months before ICIs treatment were included. Maximum standardized uptake values, whole metabolic tumor volume (wMTV), and whole-body total lesion glycolysis (wTLG) were evaluated. Cutoff values for high or low glycolytic categories were determined using receiver-operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were evaluated. Patients with a complete response and a matching group with resistance to ICIs underwent immunohistochemistry analysis. An unsupervised k-means clustering model integrating programmed cell death ligand 1 (PD-L1) expression, glycolytic parameters, and ICIs therapy was performed. Results: In all, 98 patients were included. Lower baseline 18F-FDG PET/CT parameters were associated with responses to ICIs. Patients with low wMTV or wTLG had improved PFS and OS. High wTLG, strong tumor expression of glucose transporter-1, and lack of responses were significantly associated. Patients with low glycolytic parameters benefited from ICIs, regardless of chemotherapy. Conversely, those with high parameters benefited from the addition of chemotherapy. Patients with higher wTLG and lower PD-L1 were associated with progression and worse survival to ICIs monotherapy. Conclusions: Glycolytic metabolic profiles established through baseline 18F-FDG PET/CT are useful biomarkers for evaluating ICI therapy in advanced NSCLC.

Surgical implications of mesenteric lymph node metastasis from advanced ovarian cancer after bowel resection.

BACKGROUND: Studies addressing mesenteric and mesocolic lymph node metastasis in patients with advanced ovarian cancer that have undergone bowel resection are lacking. METHODS: A retrospective analysis was performed in a series of 50 individuals who underwent surgical cytoreduction for epithelial ovarian cancer that included bowel resection from April 2004 to September 2010. RESULTS: Forty-one patients had bowel resection with mesenteric lymph nodes that were suitable for analysis. Twenty-four (58.5%) patients underwent retosigmoidectomies, 14 (34.1%) received other types of colectomies, and three (7.3%) underwent small bowel resection. There was serosal involvement in 14 cases (34.1%), muscularis propria invasion in 13 cases (31.7%), submucosa invasion in six cases (14.6%), and mucosa in eight cases (19.5%). Lymphatic invasion was observed in 24 patients (58.5%). A median of 14 mesenteric lymph nodes were analyzed. Metastatic lymph nodes were observed in 29 (70.7%) cases. Invasion into the muscularis propria (P = 0.036), lymphatic invasion (P = 0.045), and retroperitoneal lymph node metastasis (P = 0.002) correlated significantly with mesenteric lymph node involvement. CONCLUSIONS: Resection of regional lymph nodes of affected organs that is similar to surgical procedures that are performed for colorectal carcinoma is an appropriate, optimal debulking surgery for patients with ovarian carcinoma.

Multiple mutations in the Kras gene in colorectal cancer: review of the literature with two case reports.

PURPOSE: Kras mutations are negative predictors of anti-EGFR therapy, occurring in 40% of colorectal carcinomas (CRCs). Point substitutions in codon 12 or 13 are the most frequent mutations in Kras, but multiple mutations (MMs) in other codons can also develop. Few data exist on MMs with regard to their frequency and the codons and amino acids that are affected. We report two cases of Kras double mutations in codons 12 and 13 and review Kras MMs in primary CRC in PubMed databases. CASE REPORT: A 53-year-old woman and a 70-year-old man presented with deep, invasive, moderately differentiated CRC at an advanced clinical stage. The former had regional lymph node involvement and vaginal wall neoplastic implantation, and the latter had liver metastasis. Primary tumors were examined for Kras mutations by pyrosequencing, which were confirmed by direct sequencing. Both tumors had a mutation in codons 12 and 13, wherein codon 12 was mutated to GAT, and codon 13 became GAC. CONCLUSIONS: We identified 69 reported cases of Kras MMs and reported two other cases, representing 2.1% of all mutated tumors; the incidence of such mutations is 1.0% in CRC patients. In most cases (59%), MMs develop in a single codon, usually codon 12. Codons 12 and 13 are affected simultaneously in only 27% of cases. These findings add information about the impact of specific amino acid changes in the Kras gene.

Emerging biomarkers in metastatic urothelial carcinoma: tumour mutational burden, PD-L1 expression and APOBEC polypeptide-like signature in a patient with complete response to anti-programmed cell death protein-1 inhibitor.

Immunotherapy has recently been incorporated into the treatment guidelines for metastatic urothelial carcinoma. Nevertheless, the role of prognostic and predictive biomarkers in this setting is not completely defined. To date, PD-L1 expression and a high tumour mutational burden (TMB) seem to predict better responses to immune checkpoint inhibitors, but patients without these biomarkers may still respond to immunotherapy. There are some caveats regarding these biomarkers, such as lack of standardisation of techniques, tumour heterogeneity and other factors influencing the tumour microenvironment. Genomic signatures are other promising emerging strategies. We hereby discuss the management of a 70-year-old man with a metastatic recurrence of urothelial carcinoma within 1 year after neoadjuvant chemotherapy and radical cystectomy. Tumour next-generation sequencing showed a high TMB and a CD274 (PD-L1) amplification. The patient was treated with pembrolizumab and achieved a complete response.

Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome.

PURPOSE: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer. MATERIALS AND METHODS: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil. RESULTS: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria. CONCLUSION: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

How does the mitotic index impact patients with T1 melanoma? Comparison between the 7th and 8th edition of the American Joint Committee on Cancer melanoma staging system.

BACKGROUND: The mitotic index is no longer used to classify T1 melanoma patients into T1a and T1b, so it should not be used to indicate sentinel node biopsy in these patients. OBJECTIVES: To evaluate patients with T1 melanoma who underwent sentinel lymph node biopsy and to compare those who were classified as T1a with those classified T1b, according to the 7th and 8th Edition of the melanoma staging system, regarding a positive biopsy result. The authors also aimed to assess whether there is any difference in the results in both staging systems. MATERIAL AND METHODS: This was a retrospective analysis of 1213 patients who underwent sentinel lymph node biopsy for melanoma, from 2000 to 2015, in a single institution. RESULTS: Of 399 patients with thin melanomas, 27 (6.7%) presented positive sentinel lymph nodes; there was no difference in positivity for sentinel node biopsy when comparing T1a vs. T1b in both staging systems. Furthermore, the clinical results were also similar between the two groups. However, in the complete cohort analysis, the mitotic index was associated with positivity for sentinel lymph node biopsy (p < 0.0001), positivity for non-sentinel lymph node (p < 0.0001), recurrence-free survival (p < 0.0001), and specific melanoma survival (p = 0.023). STUDY LIMITATION: Unicentric study. CONCLUSION: The mitotic index was shown to be a very important prognostic factor in the present study, but it was not observed in patients classified as T1. The mitotic index should no longer be used as the only reason to refer sentinel lymph node biopsy in patients with thin melanoma.

Is there a role for rechallenge and reintroduction of anti-EGFR plus chemotherapy in later lines of therapy for metastatic colorectal carcinoma? A retrospective analysis.

BACKGROUND: Mechanisms of resistance have been described during disease progression (PD) for patients under treatment with anti-EGFR plus chemotherapy (CT). The aim of our study was to evaluate efficacy of anti-EGFR rechallenge (ReCH) and reintroduction (ReIn) in metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: This is a retrospective analysis of patients with mCRC that previously received anti-EGFR + CT and interrupted therapy due to PD in the ReCH group and other reasons in the ReIn group. We aimed to describe progression-free survival (PFS), overall survival (OS) and response rate (RR) after re-exposure and to evaluate prognostic factors associated with PFS. RESULTS: Sixty-eight patients met the inclusion criteria. The median follow-up after re-exposure was 39.3 months. ReCH was adopted in 25% and ReIn in 75%. The median anti-EGFR free interval was at 10.5 months. At re-exposure, the main CT regimen was FOLFIRI in 58.8%. Cetuximab and Panitumumab were used in 59 and 9 patients, respectively. mPFS for ReCH and ReIn was 3.3 × 8.4 months, respectively (p 0.001). The objective response rate for ReCH and ReIn was 18% and 52%, respectively. In univariate analysis, adverse prognostic factors related to PFS were: stable disease or PD at first anti-EGFR exposure (HR: 2.12, CI:1.20-3.74; p = 0.009); ReCH (HR: 3.44, CI:1.88-6.29, p < 0.0001); rechallenge at fourth or later lines (HR: 2.51, CI:1.49-4.23, p = 0.001); panitumumab use (HR: 2.26 CI:1.18-5.54, p = 0.017). In the multivariate model, only ReCH remained statistically significant (HR = 2.63, CI: 1.14-6.03, p = 0.022). CONCLUSION: In our analysis, ReCH resulted in short PFS and low RR. However, reintroduction of anti-EGFR plus CT before complete resistance arose resulted in prolonged PFS. These data could be clinically useful to guide a treatment break due to side effects or patient decisions. Our data should be confirmed by larger and prospective trials.

The prognostic influence of tumour budding in Western patients with stage II colorectal cancer.

BACKGROUND: Tumour budding (TB) refers to loss of tumour cohesiveness and is defined as isolated cells or a cell cluster of up to four tumour cells at the microscopic analysis. The International Tumour Budding Consensus Conference (ITBCC) in 2016 proposed a scoring system to standardise the pathology evaluation of TB in colorectal cancer (CRC) as high (H), intermediate (I) and low (L) TB. OBJECTIVE: To evaluate the recurrence-free survival (RFS) of stage II CRC patients as per the ITBCC 2016 classification and associations between TB and clinical pathological features. METHODS: Cases of stage II CRC undergoing surgery with available tumour tissue underwent central pathology review for TB. Prognostic factors, retrospectively retrieved from electronic medical charts, were evaluated in univariate and multivariate Cox regression analyses for RFS (primary end point). RESULTS: Among 137 patients included, L-TB was observed in 107 (78.1%), I-TB in 21 (15.3%) and H-TB in 9 (6.6%). In a median follow-up of 69 months, the median RFS was 134 months, with 14 patients (10.2%) presenting with tumour recurrence: 10 (9.3%) with L-TB, 2 (9.5%) with I-TB and 2 (22.2%) with H-TB. Perineural invasion was more commonly seen in the H-TB group. In multivariate analysis, TB (H and I versus L; HR = 2.6; p = 0.059) and not receiving adjuvant chemotherapy (HR 3.7; p = 0.020) were independently associated with RFS. Adjuvant chemotherapy was associated longer RFS (HR = 3.7; p = 0.022). CONCLUSION: In this series of Western patients, TB grade was associated with perineural invasion and increased risk of disease relapse.