Genomic Landscape of Lynch Syndrome Colorectal Neoplasia Identifies Shared Mutated Neoantigens for Immunoprevention.

BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.

Watch-and-Wait policy versus robotic surgery for locally advanced rectal cancer: A cost-effectiveness study (RECCOSTE).

INTRODUCTION: Complete surgical resection for locally advanced rectal cancer is the standard treatment after a clinical complete response following chemoradiotherapy. However, some novel clinical approaches could achieve better functional results, such as Robotic Resection, or avoiding surgical procedure and incrementing surveillance intensity, called Watch-and-Wait policy. We use computational techniques to compare these clinical approaches using quality adjusted life years (QALYs). METHODS: A Markov decision analytic model was used in order to perform a cost-utility analysis, comparing standard resection (SR), Robotic Rectal Resection (RRR) and Watch-and-Wait (WW) strategies, estimating the incremental cost-effectiveness ratio per QALY to be gained from patients reaching a clinical complete response to chemoradiotherapy. Model parameter estimates were informed by previously published studies comparing WW to SR and from our database of RRR versus SR. Lifetime incremental cost-utility ratio was calculated among approaches, and a sensitivity analysis were performed in order to estimate the model uncertainty. A willingness-to-pay of per one additional QALY gained was measured to determine which strategies would be most cost-effective. RESULTS: WW is a dominating option over SR ( -75,486. 75 € and +2.04 QALYs) and RRR ( -75,486. 75 € and +0.41 QALYs). The cost-effectiveness plane shows that WW does not always dominate over RRR or SR. WW saves costs in 99.98% of the simulations when compared with either SR or RRR but only 86.9% and 55.38% (respectively) of these fall within the SR quadrant. WW is only more effective than SR 55% of the time which implies a significant uncertainty due to the high utility value assigned to cCR after chemoradiotherapy in the RRR alternative. CONCLUSION: This study provides data of cost-effectiveness differences among Standard Surgery, Watch-and-Wait and Robotic Resection approaches in clinical complete response in locally advanced rectal cancer patients after neoadjuvant chemoradiotherapy, showing a benefit for Watch-and-Wait policy.

Hemogram-derived ratios as prognostic markers of ICU admission in COVID-19.

BACKGROUND: The vast impact of COVID-19 call for the identification of clinical parameter that can help predict a torpid evolution. Among these, endothelial injury has been proposed as one of the main pathophysiological mechanisms underlying the disease, promoting a hyperinflammatory and prothrombotic state leading to worse clinical outcomes. Leukocytes and platelets play a key role in inflammation and thrombogenesis, hence the objective of the current study was to study whether neutrophil-to-lymphocyte ratio (NLR), platelets-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII) as well as the new parameter neutrophil-to-platelet ratio (NPR), could help identify patients who at risk of admission at Intensive Care Units. METHODS: A retrospective observational study was performed at HM Hospitales including electronic health records from 2245 patients admitted due to COVID-19 from March 1 to June 10, 2020. Patients were divided into two groups, admitted at ICU or not. RESULTS: Patients who were admitted at the ICU had significantly higher values in all hemogram-derived ratios at the moment of hospital admission compared to those who did not need ICU admission. Specifically, we found significant differences in NLR (6.9 [4-11.7] vs 4.1 [2.6-7.6], p <  0.0001), PLR (2 [1.4-3.3] vs 1.9 [1.3-2.9], p = 0.023), NPR (3 [2.1-4.2] vs 2.3 [1.6-3.2], p <  0.0001) and SII (13 [6.5-25.7] vs 9 [4.9-17.5], p <  0.0001) compared to those who did not require ICU admission. After multivariable logistic regression models, NPR was the hemogram-derived ratio with the highest predictive value of ICU admission, (OR 1.11 (95% CI: 0.98-1.22, p = 0.055). CONCLUSIONS: Simple, hemogram-derived ratios obtained from early hemogram at hospital admission, especially the novelty NPR, have shown to be useful predictors of risk of ICU admission in patients hospitalized due to COVID-19.

The impact of submucosal fatty tissue during colon endoscopic submucosal dissection in a western center.

OBJECTIVES: Obesity is associated with submucosal fatty tissue. The main aim of this study was to assess the impact of submucosal fatty tissue on the success of colonic endoscopic submucosal dissection (C-ESD) in a western population. METHODS: This was a retrospective analysis of 125 consecutive C-ESDs performed between October 2015 and July 2017. Fatty tissue sign was defined as positive when the submucosal layer was covered with fatty tissue. The complexity of performing an ESD was assessed by the performing endoscopist, defined by the occurrence of intraprocedural perforation, inability to complete an en-bloc resection or a procedure time exceeding 180 min. RESULTS: Fatty tissue sign positive was present in 44.8% of the procedures. There were 28 (22.4%) c-ESD defined as complex. Factors associated with complex ESD included; fatty tissue sign [odds ratio (OR) 12.5; 95% confidence interval (CI), 1.9-81.9; P = 0.008], severe fibrosis (OR 148.6; 95% CI, 6.6-3358.0; P = 0.002), poor maneuverability (OR 267.4; 95% CI, 11.5-6212.5; P < 0.001) and polyp size ≥35 mm (OR 17.2; 95% CI, 2.6-113.8; P = 0.003). In patients demonstrating the fatty tissue sign, BMI and waist-to-height ratio (WHtR) were higher (27.8 vs. 24.7; P < 0.001 and 0.56 vs. 0.49; P < 0.001, respectively) and en-bloc resection was achieved less frequently (76.8 vs. 97.1%, P = 0.001). Multivariate analysis revealed higher risk of fatty tissue sign positive associated with WHtR ≥0.52 (OR 26.10, 95% CI, 7.63-89.35, P < 0.001). CONCLUSION: This study demonstrates that the fatty tissue sign contributes to procedural complexity during C-ESD. Central obesity correlates with the likelihood of submucosal fatty tissue and as such should be taken into account when planning procedures.

Feasibility and learning curve of unsupervised colorectal endoscopic submucosal hydrodissection at a Western Center.

OBJECTIVES: Colorectal endoscopic submucosal dissection (CR-ESD) is an evolving technique in Western countries. We aimed to determine the results of the untutored implementation of endoscopic submucosal hydrodissection for the treatment of complex colorectal polyps and establish the learning curve for this technique. METHODS: This study included data from 80 consecutive CR-ESDs performed by a single unsupervised western therapeutic endoscopist. To assess the learning curve, procedures were divided into four groups of 20 each. RESULTS: En bloc resection was achieved in 55, 75, 75 and 95% cases in the consecutive time periods (period 1 vs. 4, P = 0.003). Curative resection was achieved in 55, 75, 70 and 95%, respectively (P = 0.037). Overall, series results demonstrated R0 resection in 75% of cases, with 23.7% requiring conversion to endoscopic piecemeal mucosal resection, and 1.25% incomplete resections. Complications included perforations (7.5%) and bleeding (3.7%). Multivariate analysis revealed factors more likely to result in association with non en bloc vs. En bloc resection, where polyp size ≥35 mm [70 vs. 23.4%; odds ratio (OR) 13.2 (1.7-100.9); P = 0. 013], severe fibrosis [40 vs. 11.7%; OR 10.2 (1.2-86.3); P = 0.033] and where carbon dioxide for insufflation was not used [65 vs. 30%; OR 0.09 (0.01-0.53); P = 0.008]. CONCLUSION: CR-ESD by hydrodissection has good safety and efficacy profile and offers well tolerated and effective treatment for complex polyps. As such, this technique may be useful in the West, in centers, where previous gastric ESD is not frequent or Japanese mentoring is not possible.

Drug resistance in cancer immunotherapy: new strategies to improve checkpoint inhibitor therapies.

Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment. Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation. Nevertheless, some patients are primary unresponsive or develop ulterior resistance to these family of drugs. This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.

Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. RESULTS: A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P<0.001). The median PFS of AS patients was 11.4 months (95% confidence interval, 8.6-15.8) versus 8.3 months for patients without AS (95% confidence interval, 5.6-16.4; P=0.04). CONCLUSIONS: Chemotherapy plus Bevacizumab combination in mCRC patients results in dynamic changes in plasma cytokines, which is associated with better disease control and longer PFS. These new findings support continuing studying AS as a potential marker of angiogenesis inhibitor effectiveness.

Osteosarcoma en gota tofácea: descripción de un caso clínico y revisión de la literatura / Osteosarcoma in tophaceous gout: a case report and literature review

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Dynamic Biomarkers of Response to Antiangiogenic Therapies in Colorectal Cancer: A Review.

BACKGROUND: Identification of clinical and molecular biomarkers to predict dynamic response or monitor in real-time the efficacy of antiangiogenic therapy represents a major point in the treatment of patients with advanced colorectal cancer. Several stu-dies have been conduced to identify some predictive biomarkers to select patients who will benefit from bevacizumab, the most widely used antiangiogenic monoclonal anti-body. CONCLUSION: After a decade since the introduction of bevacizumab, no effective predictive biomarkers are available in routine clinical practice. In this review, we summarized the potential candidate dynamic biomarkers that may play a role in this setting.

Massive Intrabile Duct Invasion Caused by a Fatal Progression of Colonic Adenocarcinoma: Abdominal Computed Tomography Findings and Cholangiography Correlation.

In this report, we present an unusual case of jaundice in a patient with advanced colorectal cancer due to intraductal tumour invasion of the intra- and extrahepatic biliary tree. This complication proved to be fatal despite aggressive therapeutic management. A correct diagnosis of this type of involvement was achieved by a combination of diagnostic and therapeutic cholangiography. Despite adequate biliary decompression, the patient died from liver failure and biliary sepsis.

Phase II Trial of Target-guided Personalized Chemotherapy in First-line Metastatic Colorectal Cancer.

PURPOSE: The aim of this study was to investigate the feasibility and efficacy of personalizing treatment of patients with advanced untreated colorectal cancer (CRC). PATIENTS AND METHODS: Patients with untreated metastatic CRC, performance status 0-1, and candidates for systemic chemotherapy were eligible. Tumor tissues were analyzed for KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), excision repair cross-complementing gene 1 (ERCC1), thymidylate synthase (TS), and thymidine phosphorylase (TP). Patients with Topo-1 expression received irinotecan, whereas patients with negative Topo-1 and ERCC1 expression received oxaliplatin. Otherwise, patients received physician's choice of treatment. If TS was positive, no fluoropyrimidine was administered and if negative, 5-flurorouracil if TP was negative, or capecitabine if TP was positive. KRAS-mutated patients were treated with bevacizumab, whereas KRAS-native received cetuximab. The primary endpoint of the study was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled and 67 received personalized treatment including irinotecan (n=27), oxaliplatin (n=16), FOLFIRI (n=12), and FOLFOX (n=12). Thirty-eight patients received cetuximab and 29 bevacizumab. With a median follow-up time of 18.3 months (95% confidence interval [CI], 4-36), the overall median PFS was 8.3 months (95% CI, 6.9-9.7), representing a 12-month PFS rate of 36.5% (95% CI, 25-48). Overall clinical benefit, including response rate and disease stabilization, was 86% (95% CI, 73%-97%). The overall median survival was 21 months (95% CI, 11-40). CONCLUSIONS: Real-time target-guided personalized first-line treatment of patients with advanced CRC is feasible but, with the approached used, did not result in a clear improvement in PFS to warrant phase III testing.

A prospective pilot study of target-guided personalized chemotherapy with intensity-modulated radiotherapy in patients with early rectal cancer.

PURPOSE: To investigate the feasibility of personalizing chemotherapy in patients with rectal cancer. METHODS: Patients with cT3 or cN1 and cM0 rectal cancer were eligible. A set of 6 molecular markers including KRAS, BRAF, and PI3K mutations and expression of topoisomerase-1 (Topo-1), ERCC-1, and thymidylate synthase (TS) using immunohistochemistry were performed in a tumor biopsy. All patients were treated with capecitabine 625 to 825 mg/m/12 h M-F in combination with either irinotecan or oxaliplatin based on Topo-1 and ERCC-1 expression plus either bevacizumab or cetuximab based on the mutation status. All patients received intensity-modulated radiation therapy. A surgery was performed 6 to 8 weeks after the treatment. RESULTS: Fifteen patients (94%) had T3 tumor and 10 (62%) N+ disease of 16 patients enrolled. In all patients, the full set of markers was analyzed within 10 days. Seven patients had K-ras mutation, and 4, 5, and 10 expressed Topo-1, ERRC-1 and TS, respectively. All patients had wild-type BRAF and PI3K tumors. The median time from obtaining informed consent to the treatment period was 18 days and all patients completed the chemoradiation treatment. Fifty percent achieved a complete pathologic response to treatment. Four patients (25%) developed grade 3 proctitis or diarrhea. There were no relevant surgical complications. Sixty-nine percent of the patients received adjuvant XELOX. CONCLUSIONS: The individualization of neoadjuvant chemotherapy in patients with rectal cancer is feasible and leads to a high rate of pathologic response.

Emergent toxicities associated with the use of mTOR inhibitors in patients with advanced renal carcinoma.

The inhibitors of the mammalian target of rapamycin (mTOR) improve outcomes in patients with advanced renal cell carcinoma. These agents are associated with unusual class-adverse events that represent a challenge to the clinician, making it critical to recognize and treat them appropriately. This study aims to highlight the clinical management of these toxicities by presenting evidence from the literature and suggesting treatment recommendations. A critical review of the literature is performed and a summary of the most relevant emergent toxicities and their management is presented. Treatment recommendations of metabolic disturbances induced by mTOR inhibitors, such as hypophosphatemia, hyperglycemia, and hyperlipidemia along with the management of drug-induced pneumonitis and possible pharmacological interactions are presented. Most of these toxicities, if recognized and treated accordingly, should resolve with minimal impact on patients' quality of life and in the efficacy of this anticancer therapy. Oncologists should be familiar with the recognition and appropriate medical management of these clinical scenarios.

Isolated recurrence of distal adenocarcinoma of the extrahepatic bile duct on a draining sinus scar after curative resection: case report and review of the literature.

BACKGROUND: Surgical resection remains the gold standard for the treatment of localized adenocarcinoma of the extrahepatic bile ducts. Yet, treatment of loco-regional recurrences is not well defined. CASE PRESENTATION: We present an unusual case of distal adenocarcinoma of the extrahepatic bile ducts that was treated with surgery and relapsed two years later with a solitary recurrence on the tract of a previous Redon drain. In addition, a review of the literature on management of loco regional relapses is presented. CONCLUSIONS: The ideal management of these patients still remains undefined. Decisions are made based on clinical parameters from retrospective series, such as tumor grade, surgical margins or lymph node involvement. Prospective studies, that include molecular and genetic markers, are needed to improve patient selection and outcomes on this population.