Prognostic Factors of Long-Term Outcomes after Primary Chemo-Radiotherapy in Non-Metastatic Anal Squamous Cell Carcinoma: An International Bicentric Cohort.

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with human papillomavirus (HPV) infection. The locally advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate the prognostic factors for ASCC after curative CRT. A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at two centers was performed. Complete response (CR), disease-free survival (DFS), and overall survival (OS) were analyzed by Kaplan-Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. The CR rate was 70% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated with shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77-18.81) in a univariate analysis. The median follow-up was 38 months, with a 3-year DFS of 71%. The prognostic factors for DFS were cT1-T2 (p = 0.0002), N0 (p = 0.035), HIV-positive (p = 0.047), HIV-HPV coinfection (p = 0.018), and well-differentiated tumors (p = 0.037). The three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.02) and well-differentiated tumors (p = 0.003) were associated with better OS. The unsupervised analysis demonstrated a clear segregation of patients in three clusters, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.74 95% CI = 1.25-2.42, p = 0.0008) were enriched with the locally advanced disease, anal canal location, HIV-HPV coinfection, and non-CR. In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

Comprehensive Genomic Characterization of Fifteen Early-Onset Lynch-Like Syndrome Colorectal Cancers.

Lynch-like syndrome (LLS) is an increasingly common clinical challenge with an underlying molecular basis mostly unknown. To shed light onto it, we focused on a very young LLS early-onset colorectal cancer (CRC) cohort (diagnosis ≤ 40 y.o.), performing germline and tumor whole-exome sequencing (WES) of 15 patients, and additionally analyzing their corresponding tumor mutational burden (TMB) and mutational signatures. We identified four cases (27%) with double somatic putative variants in mismatch repair (MMR) core genes, as well as three additional cases (20%) with double MSH3 somatic alterations in tumors with unexplained MSH2/MSH6 loss of expression, and two cases (13%) with POLD1 potential biallelic alterations. Average TMB was significantly higher for LLS cases with double somatic alterations. Lastly, nine predicted deleterious variants in genes involved in the DNA repair functions and/or previously associated with CRC were found in nine probands, four of which also showed MMR biallelic somatic inactivation. In conclusion, we contribute new insights into LLS CRC, postulating MSH3 and POLD1 double somatic alterations as an underlying cause of a microsatellite instability (MSI) phenotype, proposing intrinsic biological differences between LLS with and without somatic alterations, and suggesting new predisposing candidate genes in this scenario.

A clinical and molecular portrait of non-metastatic anal squamous cell carcinoma.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk Human papillomavirus (HPV) infection. Despite improved outcomes in non-metastatic ASCC, definitive chemoradiotherapy constitutes the standard treatment for localized disease. Evidences for predictive and prognostic biomarkers are limited. Here, we performed a viral, immune, and mutational characterization of 79 non-metastatic ASCC patients with complete definitive chemoradiotherapy. HPV-16 was detected in 91% of positive cases in single infections (78%) or in coinfections with multiple genotypes (22%). Fifty-four percent of non-metastatic ASCC cases displayed mutations affecting cancer driver genes such as PIK3CA (21% of cases), TP53 (15%), FBXW7 (9%), and APC (6%). PD-L1 expression was detected in 57% of non-metastatic ASCC. Increased PD-L1 positive cases (67%) were detected in patients with complete response compared with non-complete response to treatment (37%) (p = 0.021). Furthermore, patients with PD-L1 positive tumors were significantly associated with better disease-free survival (DFS) and overall survival (OS) compared with patients with PD-L1 negative tumors (p = 0.006 and p = 0.002, respectively). PD-L1 expression strongly impacts CR rate and survival of non-metastatic ASCC patients after standard definitive chemoradiotherapy. PD-L1 expression could be used to stratify good versus poor responders avoiding the associated morbidity with abdominal perineal resection.

Prognostic Impact of An Integrative Landscape of Clinical, Immune, and Molecular Features in Non-Metastatic Rectal Cancer.

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Currently, there is a lack of reliable markers beyond TNM to deliver a personalized treatment in a cancer setting where the goal is a curative treatment. Here, we performed an integrated characterization of the predictive and prognostic role of clinical features, mismatch-repair deficiency markers, HER2, CDX2, PD-L1 expression, and CD3-CD8+ tumor-infiltrating lymphocytes (TILs) coupled with targeted DNA sequencing of 76 non-metastatic RC patients assigned to total mesorectal excision upfront (TME; n = 15) or neoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed by TME. Eighty-two percent of RC cases displayed mutations affecting cancer driver genes such as TP53, APC, KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observed in approximately 40% of the RC cases, and poor pathological tumor regression was significantly associated with worse disease-free survival (DFS, HR = 3.45; 95%CI = 1.14-10.4; p = 0.028). High neutrophils-platelets score (NPS) (OR = 10.52; 95%CI=1.34-82.6; p = 0.025) and KRAS mutated cases (OR = 5.49; 95%CI = 1.06-28.4; p = 0.042) were identified as independent predictive factors of poor response to nCRT treatment in a multivariate analysis. Furthermore, a Cox proportional-hazard model showed that the KRAS mutational status was an independent prognostic factor associated with higher risk of local recurrence (HR = 9.68; 95%CI = 1.01-93.2; p <0.05) and shorter DFS (HR = 2.55; 95%CI = 1.05-6.21; p <0.05), while high CEA serum levels were associated with poor DFS (HR = 2.63; 95%CI = 1.01-6.85; p <0.05). Integrated clinical and molecular-based unsupervised analysis allowed us to identify two RC prognostic groups (cluster 1 and cluster 2) associated with disease-specific OS (HR = 20.64; 95%CI = 2.63-162.2; p <0.0001), metastasis-free survival (HR = 3.67; 95%CI = 1.22-11; p = 0.012), local recurrence-free survival (HR = 3.34; 95%CI = 0.96-11.6; p = 0.043) and worse DFS (HR = 2.68; 95%CI = 1.18-6.06; p = 0.012). The worst prognosis cluster 2 was enriched by stage III high-risk clinical tumors, poor responders to nCRT, with low TILs density and high frequency of KRAS and TP53 mutated cases compared with the best prognosis cluster 1 (p <0.05). Overall, this study provides a comprehensive and integrated characterization of non-metastatic RC cases as a new insight to deliver a personalized therapeutic approach.

Analysis of long-term oncological results of clinical versus pathological responses after neoadjuvant treatment in locally advanced rectal cancer.

BACKGROUND: Nonoperative management after neoadjuvant treatment in low rectal cancer enables organ preservation and avoids surgical morbidity. Our aim is to compare oncological outcomes in patients with clinical complete response in watch and wait strategy with those who received neoadjuvant therapy followed by surgery with a pathological complete response. METHODS: Patients with non-metastatic rectal cancer after neoadjuvant treatment with clinical complete response in watch and wait approach (group 1, n = 26) and complete pathological responders (ypT0N0) after chemoradiotherapy and surgery (group 2, n = 22), between January 2011 and October 2018, were included retrospectively, and all of them evaluated and followed in a multidisciplinary team. A comparative analysis of local and distant recurrence rates and disease-free and overall survival between both groups was carried out. Statistical analysis was performed using log-rank test, Cox proportional hazards regression model, and Kaplan-Meier curves. RESULTS: No differences were found between patient's demographic characteristics in both groups. Group 1: distance from the anal verge mean 5 cm (r = 1-12), 10 (38%) stage III, and 7 (27%) circumferential resection margin involved. The median follow-up of 47 months (r = 6, a 108). Group 2: distance from the anal verge mean 7 cm (r = 2-12), 16 (72%) stage III, and 13 (59%) circumferential resection margin involved. The median follow-up 49.5 months (r = 3, a 112). Local recurrence: 2 patients in group 1 (8.3%) and 1 in group 2 (4.8%) (p = 0.6235). Distant recurrence: 1 patient in group 1 (3.8%) and 3 in group 2 (19.2%) (p = 0.2237). Disease-free survival: 87.9% in group 1, 80% in group 2 (p = 0.7546). Overall survival: 86% in group 1 and 85% in group 2 (p = 0.5367). CONCLUSION: Oncological results in operated patients with pathological complete response were similar to those in patients under a watch and wait strategy mediating a systematic and personalized evaluation. Surgery can safely be deferred in clinical complete responders.

Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.

Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome.

Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

A Diagnostic Biopsy-Adapted Immunoscore Predicts Response to Neoadjuvant Treatment and Selects Patients with Rectal Cancer Eligible for a Watch-and-Wait Strategy.

PURPOSE: No biomarker to personalize treatment in locally advanced rectal cancer (LARC) is currently available. We assessed in LARC whether a diagnostic biopsy-adapted immunoscore (ISB) could predict response to neoadjuvant treatment (nT) and better define patients eligible to an organ preservation strategy ("Watch-and-Wait"). EXPERIMENTAL DESIGN: Biopsies from two independent cohorts (n 1 = 131, n 2 = 118) of patients with LARC treated with nT followed by radical surgery were immunostained for CD3+ and CD8+ T cells and quantified by digital pathology to determine ISB. The expression of immune-related genes post-nT was investigated (n = 64 patients). Results were correlated with response to nT and disease-free survival (DFS). The ISB prognostic performance was further assessed in a multicentric cohort (n = 73 patients) treated by Watch-and-Wait. RESULTS: ISB positively correlated with the degree of histologic response (P < 0.001) and gene expression levels for Th1 orientation and cytotoxic immune response, post-nT (P = 0.006). ISB high identified patients at lower risk of relapse or death compared with ISB low [HR, 0.21; 95% confidence interval (CI), 0.06-0.78; P = 0.009]. Prognostic performance of ISB for DFS was confirmed in a validation cohort. ISB was an independent parameter, more informative than pre- (P < 0.001) and post-nT (P < 0.05) imaging to predict DFS. ISB combined with imaging post-nT discriminated very good responders that could benefit from organ preservation strategy. In the "Watch-and-Wait" cohort (n = 73), no relapse was observed in patients with ISB high (23.3%). CONCLUSIONS: ISB predicts response to nT and survival in patients with LARC treated by surgery. Its usefulness in the selection of patients eligible for a Watch-and-Wait strategy is strongly suggested.

Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial.

Purpose The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors, and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted.Clinical trial registration www.clinicaltrials.gov NCT01623206.

Lynch-like syndrome is as frequent as Lynch syndrome in early-onset nonfamilial nonpolyposis colorectal cancer.

Early-onset (<50 years-old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed "Lynch-like syndrome" (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003-2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.

Bevacizumab biosimilar BEVZ92 versus reference bevacizumab in combination with FOLFOX or FOLFIRI as first-line treatment for metastatic colorectal cancer: a multicentre, open-label, randomised controlled trial.

BACKGROUND: BEVZ92 is a proposed biosimilar to bevacizumab. The two molecules have similar physicochemical and functional properties in in-vitro and preclinical studies. In this clinical study, we compared the pharmacokinetic profile, efficacy, safety, and immunogenicity of BEVZ92 with reference bevacizumab as a first-line treatment in patients with metastatic colorectal cancer. METHODS: We did a randomised, open-label trial at 15 centres in Argentina, Brazil, India, Spain, and Ukraine. Eligible patients were aged 18 years or older, had metastatic colorectal cancer with at least one measurable non-irradiated lesion for which first-line chemotherapy was indicated and Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, had not received previous treatment for advanced disease, and whose bone marrow, hepatic, renal, and coagulation markers were all within normal ranges. Patients were randomly assigned (1:1) to either BEVZ92 or reference bevacizumab (5 mg/kg on day 1 of each cycle every 2 weeks) in combination with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or fluorouracil, leucovorin, and irinotecan (FOLFIRI). Randomisation was done via a web service based on a stochastic minimisation algorithm and was stratified by chemotherapy regimen (FOLFOX vs FOLFIRI), previous adjuvant therapy (yes vs no), ECOG performance status (0-1 vs 2), and study site. The primary endpoint was the area under the concentration-versus-time curve after a single infusion (AUC0-336h) and at steady state (AUCss)-ie, at cycle 7-in the assessable population, which comprised all treated patients for whom serum concentration measurements were available during the first seven cycles. Bioequivalence was established if the 90% CIs for the ratio of BEVZ92 to reference bevacizumab of the geometric means for AUC0-336h and AUCss were within the acceptance interval of 80-125%. Secondary endpoints included objective response, clinical benefit, and progression-free survival in the intention-to-treat population and immunogenicity and safety profiles in all treated patients. This trial is registered with ClinicalTrials.gov, number NCT02069704, and is closed to new participants, with follow-up completed. FINDINGS: 142 patients were randomly assigned, 71 to the BEVZ92 group and 71 to the reference bevacizumab group. Two participants assigned to BEVZ92 did not receive treatment (one withdrew consent, the other had a serious intestinal obstruction before starting treatment); therefore, the treated population comprised 69 patients in the BEVZ92 group and 71 in the reference bevacizumab group. The geometric mean ratio of AUC0-336h in the BEVZ92 versus the control group was 99·4% (90% CI 90·5-109·0) and of AUCss was 100·0% (90·2-112·0). Objective response (35 [49%] of 71 vs 40 [56%] of 71), clinical benefit (62 [87%] vs 65 [92%]), and progression-free survival (median 10·8 months [95% CI 7·4-11·5] vs 11·1 months [95% CI 8·0-12·8]) were similar in the BEVZ92 and reference bevacizumab groups. No relevant differences were noted between the safety profiles of the two study treatments. Neutropenia was the most common grade 3 or 4 adverse event reported in the BEVZ92 (14 [20%] of 69 patients) and reference bevacizumab (19 [27%] of 71 patients) groups. Serious adverse events occurred in 19 (28%) patients in the BEVZ92 group and 21 (30%) in the reference bevacizumab group. Two patients died because of bevacizumab-related serious adverse events: a sudden death in the BEVZ92 group and a serious large intestinal perforation in the reference bevacizumab group. The occurrence of anti-drug antibodies was low and similar in both treatment groups (two patients in the BEVZ92 group and one in the reference bevacizumab group). INTERPRETATION: Our results suggest that BEVZ92 and reference bevacizumab are pharmacokinetically bioequivalent and have no appreciable differences in efficacy, immunogenicity, and safety profiles as first-line treatment in combination with FOLFOX or FOLFIRI in patients with metastatic colorectal cancer. FUNDING: mAbxience Research SL.

Recomendaciones sobre el manejo del cáncer de páncreas tipo adenocarcinoma en Latinoamérica: Reunión del Consenso del Simposio Latinoamericano de Gastroenterología Oncológica (SLAGO) y de la Asociación Ibero Latinoamericana de Terapia Radiante (ALATRO), Viña del Mar, Chile 2015 / Recommendations for the management of pancreatic cancer type adenocarcinoma: A consensus statement reached during the 2015 Latin American Symposium on Gastroenterological Oncology

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Viña del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

Non-surgical management of rectal cancer. Series of 68 cases, long follow up in two leading centres in Argentina.

BACKGROUND: The non-surgical management in a selected group of rectal cancer patients has shown promising results with adequate follow up. AIMS: describing the results of the non-surgical management in patients with complete clinical response, with a close follow up. METHODS: Between 2006 and 2015, patients with rectal cancer, stages I-III, without metastasis, treated with neoadjuvant CRT/CT, who had clinical complete response were included. CCR was defined through digital palpation, endoscopy-based criteria and MRI. Follow up was set according to institutional guidelines. RESULTS: 68 patients were included. Initial stage was assessed with MRI in 55/68 pts and EUS 11/68. Considering the recurrence risk factors 57.6% (29/68) were T2-3ab N0, 3.3% (2/68) were T4N0, 29% (20/68) were T3-4 N1-2, with 39.7% with positive MRC. Mean distance to the anal margin was 3cm. Chemoradiation included radiotherapy at 50.4cGy, and concurrent capecitabine. In 22% a fluoropirimidine and oxaliplatin-based schema was used as induction therapy. Median follow up was 37.5 months and response assessment time 9 weeks (5-19). Eleven patients recurred, 6 endoluminally, 3 developed mesorectal recurrence, and two distant failure. Five years DFS and OS were 76.3% and 93.8%. CONCLUSIONS: conservative management was feasible with close follow up in leading cancer centres. In this series, DFS and OS were comparable to the data already reported in the literature.

[Recommendations for the management of pancreatic cancer type adenocarcinoma: A consensus statement reached during the 2015 Latin American Symposium on Gastroenterological Oncology]. / Recomendaciones sobre el manejo del cáncer de páncreas tipo adenocarcinoma en Latinoamérica: Reunión del Consenso del Simposio Latinoamericano de Gastroenterología Oncológica (SLAGO) y de la Asociación Ibero Latinoamericana de Terapia Radiante (ALATRO), Viña del Mar, Chile 2015.

Pancreatic cancer is a malignancy of great impact in developed countries and is having an increasing impact in Latin America. Incidence and mortality rates are similar for this cancer. This is an important reason to offer to the patients the best treatments available. During the Latin American Symposium of Gastroenterology Oncology (SLAGO) held in Viña del Mar, Chile, in April 2015, a multidisciplinary group of specialists in the field met to discuss about this disease. The main conclusions of this meeting, where practitioners from most of Latin American countries participated, are listed in this consensus that seek to serve as a guide for better decision making for patients with pancreatic cancer in Latin America.

Pitfalls in the diagnosis of biallelic PMS2 mutations.

Constitutional Mismatch Repair Deficiency (CMMR-D) syndrome is an inherited childhood cancer syndrome due to bi-allelic mutations in one of the four DNA mismatch repair genes involved in Lynch syndrome. The tumor spectrum of this syndrome includes hematological, brain and Lynch syndrome associated malignancies, with an increased risk of synchronous and metachronous cancers, and signs of Neurofibromatosis type-1 syndrome such as café-au-lait macules during the first three decades of life. Here, we report the first Argentinian patient with CMMR-D syndrome, focusing on her history of cancer and gastrointestinal manifestations, and the challenging molecular algorithm to finally reach her diagnosis.

Assessment of early response to imatinib 800 mg after 400 mg progression by ¹8F-fluorodeoxyglucose PET in patients with metastatic gastrointestinal stromal tumors.

INTRODUCTION: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. (18)F-fluorodeoxyglucose PET computed tomography (FDG PET/CT) shows a faster response than computed tomography in nonpretreated patients. PATIENTS & METHODS: After disease progression on imatinib 400 mg, 16 patients were exposed to 800 mg. Tumor response was evaluated by FDG PET/CT on days 7 and 37. Primary objective was to correlate early metabolic response (EMR) with progression-free survival (PFS). RESULTS: EMR by FDG PET/CT scan was not predictive of PFS. Median PFS in these patients was 3 months. Overall survival was influenced by gastric primary site (p = 0.05). CONCLUSION: The assessment of EMR by FDG PET/CT in patients with advanced gastrointestinal stromal tumor exposed to imatinib 800 mg was not predictive of PFS or overall survival.

Observational study of patients with gastroenteropancreatic and bronchial neuroendocrine tumors in Argentina: Results from the large database of a multidisciplinary group clinical multicenter study.

Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells throughout the body. The objective of this clinical investigation of retrospectively and prospectively collected data was to describe the prevalence, demographic data, clinical symptoms and methods of diagnosis of NET and the treatment and long-term follow-up of patients with NET. Data were provided by the participating centers and assessed for consistency by internal reviewers. All the cases were centrally evaluated (when necessary) by the pathologists in our group. The tissue samples were reviewed by hematoxylin and eosin and immunohistochemical staining techniques to confirm the diagnosis of NET. In total, 532 cases were documented: 461 gastroenteropancreatic-NET (GEP-NET) and 71 bronchial NET (BNET). All the tumors were immunohistochemically defined according to the World Health Organization (WHO) and European Neuroendocrine Tumor Society criteria. The most common initial symptoms in GEP-NET were abdominal pain, diarrhea, bowel obstruction, flushing, gastrointestinal bleeding and weight loss. The most common tumor types were carcinoid (58.0%), non-functional pancreatic tumor (23.0%), metastatic NET of unknown primary (16.0%) and functional pancreatic tumor (3.0%). Of the BNET, 89.0% were typical and 11.0% atypical carcinoids. Of the patients with GEP-NET, 59.2% had distant metastasis at diagnosis. The locations of the primary tumors in GEP-NET were the small bowel (26.9%), pancreas (25.2%), colon-rectum (12.4%), appendix (7.6%), stomach (6.9%), esophagus (2.8%), duodenum (2.0%) and unknown primary (16.3%). The histological subtypes based on the WHO classification were well-differentiated NET (20.1%), well-differentiated neuroendocrine carcinomas (66.5%) and poorly differentiated neuroendocrine carcinomas (10.3%). Overall, 67.3% of the patients underwent surgery, 41.2% with curative intent and 26.1% for palliative purposes. The 5-year survival rates were 65.1% (95% confidence interval, 58.0-71.4%) in GEP-NET and 100.0% in typical carcinoid of the lung. This observational, non-interventional, longitudinal study aimed to accumulate relevant information regarding the epidemiology, clinical presentation and current practices in the treatment of NET patients in Argentina, providing insight into regional differences and patterns of care in this heterogeneous disease.

Reducing the Anaerobic Digestion Model No. 1 for its application to an industrial wastewater treatment plant treating winery effluent wastewater.

The Anaerobic Digestion Model No. 1 (ADM1) is a complex model which is widely accepted as a common platform for anaerobic process modeling and simulation. However, it has a large number of parameters and states that hinder its calibration and use in control applications. A principal component analysis (PCA) technique was extended and applied to simplify the ADM1 using data of an industrial wastewater treatment plant processing winery effluent. The method shows that the main model features could be obtained with a minimum of two reactions. A reduced stoichiometric matrix was identified and the kinetic parameters were estimated on the basis of representative known biochemical kinetics (Monod and Haldane). The obtained reduced model takes into account the measured states in the anaerobic wastewater treatment (AWT) plant and reproduces the dynamics of the process fairly accurately. The reduced model can support on-line control, optimization and supervision strategies for AWT plants.

Hazardous organic chemicals in rubber recycled tire playgrounds and pavers.

In this study, the presence of hazardous organic chemicals in surfaces containing recycled rubber tires is investigated. Direct material analyses using solvent extraction, as well as SPME analysis of the vapour phase above the sample, were carried out. Twenty-one rubber mulch samples were collected from nine different playgrounds. In addition, seven commercial samples of recycled rubber pavers were acquired in a local store of a multinational company. All samples were extracted by ultrasound energy, followed by analysis of the extract by GC-MS. The analysis confirmed the presence of a large number of hazardous substances including PAHs, phthalates, antioxidants (e.g. BHT, phenols), benzothiazole and derivatives, among other chemicals. The study evidences the high content of toxic chemicals in these recycled materials. The concentration of PAHs in the commercial pavers was extremely high, reaching values up to 1%. In addition, SPME studies of the vapour phase above the samples confirm the volatilisation of many of those organic compounds. Uses of recycled rubber tires, especially those targeting play areas and other facilities for children, should be a matter of regulatory concern.

A high degree of LINE-1 hypomethylation is a unique feature of early-onset colorectal cancer.

OBJECTIVE: Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously. DESIGN: We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤ 50 years old (n=188), a group of sporadic CRC >50 years (MSS n=89; MSI n=46), and a group of Lynch syndrome CRCs (n=20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated. RESULTS: Mean LINE-1 methylation levels (± SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥ 65% LINE-1 methylation had significantly better overall survival (p=0.026, log rank test). CONCLUSIONS: LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.