Influence of proton pump inhibitors on the pathological response of rectal cancer: a multicentre study.

Background: The standard neoadjuvant therapy for rectal cancer involves fluoropyrimidines and radiotherapy and, most recently, total neoadjuvant therapy (TNT). A drug-drug interaction between fluoropyrimidines and proton-pump inhibitors (PPI) was suggested, with a negative impact on oncological outcomes in breast, colon and gastric cancers. Little is known about such an effect on rectal tumours. We aimed to evaluate the impact of PPI utilisation on the pathological response after chemoradiation for rectal cancer. Materials and methods: Retrospective multicentre study of rectal cancer patients treated with neoadjuvant chemoradiotherapy with capecitabine (cohort 1) or 5-fluororuracil (5-FU) (cohort 2); TNT with oxaliplatin-based regimens was allowed. The pathological response was considered a complete (ypCR) or complete + partial (ypCR + ypPR) according to American Joint Committee on Cancer. PPI use was considered at any time during the neoadjuvant period if concomitant to fluoropyrimidines. Results: From January 2007 to November 2020, 251 patients received capecitabine and 196 5-FU. The rates of PPI use in cohorts 1 and 2 were 20.3% and 26.5%, respectively. TNT was offered to 18.3% in cohort 1. PPI use did not influence ypCR in cohort 1 (yes versus no: 29.4% versus 19.5%; p = 0.13) or 2 (yes versus no: 25.0% versus 26.4%; p = 1.0). Similar ypCR + ypPR were observed in both cohorts 1 (76.5% versus 72.0%; p = 0.60) and 2 (86.5% versus 76.4%; p = 0.16). PPI use was not associated with pathological response in multivariable analysis. PPI users experienced more grade 3 or higher diarrhoea and infections. Conclusion: PPI concomitant to capecitabine/5-FU chemoradiation did not influence the pathological response in rectal cancer but was associated with more treatment-related adverse events.

HORMONET: a phase II trial of tamoxifen for estrogen/progesterone receptor-positive neuroendocrine tumors.

Background: Nearly 30% of neuroendocrine tumors (NETs) have evidence of immunohistochemical (IHC) expression of estrogen (ER) and/or progesterone (PR) receptors. Therefore, targeting ER/PR may offer an effective NET-directed treatment to select patients. Methods: We conducted a multicenter Simon two-stage single-arm phase II trial of tamoxifen in patients with metastatic, progressive NETs. Eligible patients had positive IHC expression of ER and/or PR ⩾ 1%. Prior therapy with somatostatin analogs was required for progressing/functioning cases. Main exclusion criterion was aggressive disease requiring cytotoxic therapy. The primary end point was disease control rate (DCR) at week 24 by Response Evaluation Criteria in Solid Tumors version 1.1. We planned to enroll 23 patients in the first stage, to reach a DCR at week 24 of 70% (versus 50%); if ⩾12 patients reached the primary end point, a total of 37 would be included. Results: From February 2019 to February 2022, 23 out of 59 patients were eligible and enrolled: 15 (65%) were females; the most common sites were pancreas (11; 48%) and small bowel (6; 26%). In all, 13 patients (56.5%) had G2 NETs. At a median follow-up of 27 months, 13 patients (56.5%) had stable disease at week 24 and median progression-free survival (PFS) was 7.9 months [interquartile range (IQR): 3.7-12.1]. The best response was stable disease in 13 patients, with most patients experiencing minor tumor growth. Median PFS times were not significantly different according to ER/PR < or ⩾30% (p = 0.49) or ER versus PR expression (p = 0.19). One patient experienced grade 2 constipation. Conclusion: Tamoxifen for ER-/PR-positive NETs patients is safe but offers modest antitumor effects. Trial registry name: Study of Tamoxifen in Well Differentiated Neuroendocrine Tumors and Hormone Receptor Positive Expression (HORMONET). URL: https://clinicaltrials.gov/ct2/show/NCT03870399?term=03870399&draw=2&rank=1. Registration number: NCT03870399.

Does the Addition of Mutations of CTNNB1 S45F to Clinical Factors Allow Prediction of Local Recurrence in Patients With a Desmoid Tumor? A Local Recurrence Risk Model.

BACKGROUND: The initial approach to the treatment of desmoid tumors has changed from surgical resection to watchful waiting. However, surgery is still sometimes considered for some patients, and it is likely that a few patients would benefit from tumor removal if the likelihood of local recurrence could be predicted. However, to our knowledge, there is no tool that can provide guidance on this for clinicians at the point of care. QUESTION/PURPOSE: We sought to explore whether a combined molecular and clinical prognostic model for relapse in patients with desmoid tumors treated with surgery would allow us to identify patients who might do well with surgical excision. METHODS: This was a retrospective, single-center study of 107 patients with desmoid tumors who were surgically treated between January 1980 and December 2015, with a median follow-up of 106 months (range 7 to 337 months). We correlated clinical variables (age, tumor size, and localization) and CTNNB1 gene mutations with recurrence-free survival. Recurrence-free survival was estimated using a Kaplan-Meier curve. Univariate and multivariable analyses of time to local recurrence were performed using Cox regression models. A final nomogram model was constructed according to the final fitted Cox model. The predictive performance of the model was evaluated using measures of calibration and discrimination: calibration plot and the Harrell C-statistic, also known as the concordance index, in which values near 0.5 represent a random prediction and values near 1 represent the best model predictions. RESULTS: The multivariable analysis showed that S45F mutations (hazard ratio 5.25 [95% confidence interval 2.27 to 12.15]; p < 0.001) and tumor in the extremities (HR 3.15 [95% CI 1.35 to 7.33]; p = 0.008) were associated with a higher risk of local recurrence. Based on these risk factors, we created a model; we observed that patients considered to be at high risk of local recurrence as defined by having one or two factors associated with recurrence (extremity tumors and S45F mutation) had an HR of 8.4 compared with patients who had no such factors (95% CI 2.84 to 24.6; p < 0.001). From these data and based on the multivariable Cox models, we also developed a nomogram to estimate the individual risk of relapse after surgical resection. The model had a concordance index of 0.75, or moderate discrimination. CONCLUSION: CTNNB1 S45F mutations combined with other clinical variables are a potential prognostic biomarker associated with the risk of relapse in patients with desmoid tumors. The developed nomogram is simple to use and, if validated, could be incorporated into clinical practice to identify patients at high risk of relapse among patients opting for surgical excision and thus help clinicians and patients in decision-making. A large multicenter study is necessary to validate our model and explore its applicability. LEVEL OF EVIDENCE: Level III, therapeutic study.

PD-L1 expression in gastric and gastroesophageal junction cancer patients treated with perioperative chemotherapy.

BACKGROUND AND OBJECTIVES: The incidence, predictive, and prognostic impact of programmed cell death (PD-L1) expression in gastric (GC) and gastroesophageal junction tumors (GEJC) treated with perioperative chemotherapy is poorly understood. We aimed to assess PD-L1 expression by immunohistochemistry (IHC) in both pre and posttreatment specimens evaluating its impact on pathological response and survival outcomes. METHODS: Retrospective cohort of patients with GC and GEJ tumors treated in a single western cancer center between 2007 and 2017. PD-L1 expression was assessed by IHC before and after neoadjuvant chemotherapy, in surgical samples, and reported as combined positive score (CPS). CPS > 1% was tested for its association with pathological response and overall survival (OS). RESULTS: We were able to assess PD-L1 expression in at least one tissue sample from 155 subjects. PD-L1 positivity rate was 20%. In 74 paired samples, a 21% discordance between PD-L1 expression in biopsy sample and surgical specimen was observed. With a median follow-up period of 60.3 months, 5-years disease-free survival was 60.5% with a median OS not reached. PD-L1 expression was neither associated with pathological response or survival outcomes. CONCLUSIONS: PD-L1 expression in the setting of locally advanced GC tumors was relatively low and can vary considering the tissue sample analyzed. This expression had no association with survival or pathological response in this population.

Exome and Tissue-Associated Microbiota as Predictive Markers of Response to Neoadjuvant Treatment in Locally Advanced Rectal Cancer.

The clinical and pathological responses to multimodal neoadjuvant therapy in locally advanced rectal cancers (LARCs) remain unpredictable, and robust biomarkers are still lacking. Recent studies have shown that tumors present somatic molecular alterations related to better treatment response, and it is also clear that tumor-associated bacteria are modulators of chemotherapy and immunotherapy efficacy, therefore having implications for long-term survivorship and a good potential as the biomarkers of outcome. Here, we performed whole exome sequencing and 16S ribosomal RNA (rRNA) amplicon sequencing from 44 pre-treatment LARC biopsies from Argentinian and Brazilian patients, treated with neoadjuvant chemoradiotherapy or total neoadjuvant treatment, searching for predictive biomarkers of response (responders, n = 17; non-responders, n = 27). In general, the somatic landscape of LARC was not capable to predict a response; however, a significant enrichment in mutational signature SBS5 was observed in non-responders (p = 0.0021), as well as the co-occurrence of APC and FAT4 mutations (p < 0.05). Microbiota studies revealed a similar alpha and beta diversity of bacteria between response groups. Yet, the linear discriminant analysis (LDA) of effect size indicated an enrichment of Hungatella, Flavonifractor, and Methanosphaera (LDA score ≥3) in the pre-treatment biopsies of responders, while non-responders had a higher abundance of Enhydrobacter, Paraprevotella (LDA score ≥3) and Finegoldia (LDA score ≥4). Altogether, the evaluation of these biomarkers in pre-treatment biopsies could eventually predict a neoadjuvant treatment response, while in post-treatment samples, it could help in guiding non-operative treatment strategies.

The Current and Evolving Role of Immunotherapy in Metastatic Colorectal Cancer.

Immunotherapy can be considered a therapeutic revolution in oncology, with great impact on many tumor types, such as melanoma and non-small cell lung cancer. However, in metastatic colorectal cancer, the benefits in terms of prolonged tumor control and high response rate are limited to the rare subgroup of tumors with high mutation burden - mostly tumors that harbor microsatellite instability (MSI) or a deficient mismatch repair system (dMMR), or tumor microsatellite stability and damaging mutations in the exonuclease domains of POLE or POLD. The KEYNOTE-028 uncontrolled phase II trial demonstrated an impressive antitumor activity of pembrolizumab in patients with treatmentrefractory Lynch-associated tumors, including colorectal cancer. Nivolumab with or without ipilimumab confirmed the efficacy of immune checkpoint inhibitors in patients with previously treated dMMR / MSI metastatic colorectal cancer. The recent KEYNOTE-177 phase III trial demonstrated that pembrolizumab significantly reduced the relative risk of disease progression or death and improved progression-free survival in patients with treatment-naive dMMR / MSI metastatic colorectal cancer in comparison with first-line chemotherapy with or without biologics. Unfortunately, current pharmacological strategies with immunotherapy have not been successful for most patients with microsatellite stable metastatic colorectal cancer. In this review, we critically appraise the applicability of immune checkpoint inhibitors in dMMR/MSI metastatic colorectal cancer. We also discuss the recent negative trials of immunotherapy combinations in microsatellite stabl.

Circulating Tumor Cells in Desmoid Tumors: New Perspectives.

INTRODUCTION: Desmoid tumor (DT) is a rare neoplasm with high local recurrence rates, composed of fibroblastic cells that are characterized by the expression of key molecules, including the intermediate filament vimentin, cyclooxygenase-2 (COX-2), and nuclear ß-catenin, and lack of epithelial markers. Circulating tumor cells (CTCs) isolated from the peripheral blood of patients with sarcomas and other neoplasms can be used as early biomarkers of tumor invasion and dissemination. Moreover, CTCs can also re-colonize their tumors of origin through a process of "tumor self-seeding." OBJECTIVES: We aimed to identify CTCs in the peripheral blood of patients with DT and evaluate their expression of ß-catenin, transforming growth factor receptor I (TGF-ßRI), COX-2, and vimentin proteins. MATERIAL AND METHODS: We conducted a prospective study of patients with initial diagnosis or relapsed DT with measurable disease. Blood samples from each patient were processed and filtered by ISET® (Rarecells, France) for CTC isolation and quantification. The CTC expression of ß-catenin, COX-2, TGF-ßRI, and vimentin was analyzed by immunocytochemistry (ICC). RESULTS: A total of 18 patients were included, and all had detectable CTCs. We found a concordance of ß-catenin expression in both CTCs and primary tumors in 42.8% (6/14) of cases by using ICC and immunohistochemistry, respectively. CONCLUSIONS: Our study identified a high prevalence of CTCs in DT patients. Concordance of ß-catenin expression between primary tumor and CTCs brings new perspectives to assess the dynamics of CTCs in the blood compartment, opening new avenues for studying the biology and behavior of DT. In addition, these results open the possibility of using CTCs to predict DT dynamics at the time of disease progression and treatment. Further studies with larger sample sizes are needed to validate our findings.

Outcomes of Patients With Metastatic Anal Cancer According to HIV Infection: A Multicenter Study by the Latin American Gastrointestinal Oncology Group (SLAGO).

BACKGROUND: HIV-positive patients are underrepresented in clinical trials of metastatic squamous cell carcinoma of the anal canal (mSCCA). We aimed to compare the clinical outcomes of mSCCA patients according to HIV infection. METHODS: This was a retrospective multicenter cohort study of consecutive patients with mSCCA. All HIV-positive patients received antiretroviral therapy. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and response rate (RR). RESULTS: From January 2005 to December 2019, 113 patients were included: 20 (17.6%) had HIV infection. HIV-positive patients were younger at diagnosis and more frequently male, and 20% (n = 8) received exclusively best supportive care in comparison with 8.6% of HIV-negative patients (P = .13). Both groups were similar in terms of Eastern Cooperative Oncology Group (ECOG) performance status, pattern of metastatic disease, and type of first-line chemotherapy. Five (25%) HIV-positive and 36 (38.7%) HIV-negative patients received second-line therapies (P = .24). RR and median PFS in first-line were similar between the groups: 35% and 30.1% (P = .78) and 4.9 and 5.3 months (P = .85) for patients with and without HIV infection, respectively. At a median follow-up of 26 months, median OS was 11.3 months (95% confidence interval [CI] 10.1 to 26.4) for HIV-infected patients versus 14.6 months (95% CI 11.1 to 18.1) for HIV-negative patients (P = .92). In the univariate analysis for OS, only ECOG performance status was significant. CONCLUSION: HIV-positive mSCCA patients under antiretroviral therapy have oncological outcomes similar to those of HIV-negative patients. These patients should be included in trials of mSCCA.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of oesophageal cancer.

Oesophageal cancer is among the ten most common types of cancer worldwide. More than 80% of the cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of oesophageal and oesophagogastric junction (OGJ) carcinomas. The Brazilian Group of Gastrointestinal Tumours invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy (including checkpoint inhibitors) and follow-up, which was followed by presentation, discussion and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of oesophageal and OGJ carcinomas in several scenarios and clinical settings.

Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of gastric cancer.

Gastric cancer is among the ten most common types of cancer worldwide. Most cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of gastric carcinomas. The Brazilian Group of Gastrointestinal Tumors (GTG) invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy and follow-up, which was followed by presentation, discussion, and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of gastric carcinomas in several scenarios and clinical settings.

Disease-Free Survival and Time to Complete Response After Definitive Chemoradiotherapy for Squamous-Cell Carcinoma of the Anus According to HIV Infection.

BACKGROUND: The standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our group showed significantly lower rates of disease-free survival (DFS) and overall survival at 3 years among HIV-positive patients. We aimed to compare detailed treatment outcomes between the groups of HIV-positive and -negative patients. PATIENTS AND METHODS: We performed a retrospective multicenter study of a comparative cohort of consecutive patients with histologic diagnosis of localized squamous-cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients' characteristics and outcomes were compared according to HIV status. The primary end points were time to complete response (CR) and DFS time. RESULTS: From June 2001 to September 2018, a total of 185 patients were included; 43 (30.2%) were HIV positive and 142 (69.8%) were HIV negative. The overall CR rates were 67.4% and 91.5% for HIV-positive and -negative patients, respectively (P < .001). The median follow-up was 47.8 months and the median time to experience CR was 7.8 months (95% confidence interval [CI], 5.7-10.5) for HIV-positive versus 4.89 months (95% CI, 4.54-5.25) for HIV-negative (P < .001) patients. The median DFS times were 79.7 months (95% CI, 56.8-102.6) and 127.9 months (95% CI, 112.6-143.2) for HIV-positive and -negative patients, respectively (P = .02). There was a trend toward greater grade 3/4 toxicity in the HIV-positive group. CONCLUSION: HIV-positive patients take longer to experience CR and present worse DFS. These findings have clinical implications because waiting longer to define CR among these patients may prevent unnecessary anorectal amputations.

Brazilian consensus on the diagnosis and treatment of extremities soft tissue sarcomas.

INTRODUCTION: Soft tissue sarcomas (STSs) are rare tumors and constitute only 1% of all tumors in adults. Indeed, due to their rarity, most cases in Brazil are not treated according to primary international guidelines. METHODS: This consensus addresses the treatment of STSs in the extremities. It was made by workgroups from Brazilian Societies of Surgical Oncology, Orthopaedics, Clinical Oncology, Pathology, Radiology and Diagnostic Imaging, and Radiation Oncology. The workgroups based their arguments on the best level of evidence in the literature and recommendations were made according to diagnosis, staging, and treatment of STSs. A meeting was held with all the invited experts and the topics were presented individually with the definition of the degree of recommendation, based on the levels of evidence in the literature. RESULTS: Risk factors and epidemiology were described as well as the pathological aspects and imaging. All recommendations are described with the degree of recommendation and levels of evidence. CONCLUSION: Recommendations based on the best literature regional aspects were made to guide professionals who treat STS. Separate consensus on specific treatments for retroperitoneal, visceral, trunk, head and neck sarcomas, and gastrointestinal stromal tumor, are not contemplated into this consensus.

Molecular and Kinetic Analyses of Circulating Tumor Cells as Predictive Markers of Treatment Response in Locally Advanced Rectal Cancer Patients.

Neoadjuvant chemoradiation (NCRT) followed by total mesorectal excision is the standard treatment for locally advanced rectal cancer (LARC). To justify a non-surgical approach, identification of pathologic complete response (pCR) is required. Analysis of circulating tumor cells (CTCs) can be used to evaluate pCR. We hypothesize that monitoring of thymidylate synthase (TYMS) and excision repair protein, RAD23 homolog B (RAD23B), can be used to predict resistance to chemotherapy/radiotherapy. Therefore, the aims of this study were to analyze CTCs from patients with LARC who underwent NCRT plus surgery for expression of TYMS/RAD23B and to evaluate their predictive value. Blood samples from 30 patients were collected prior to NCRT (S1) and prior to surgery (S2). CTCs were isolated and quantified by ISET®, proteins were analyzed by immunocytochemistry, and TYMS mRNA was detected by chromogenic in situ hybridization. CTC counts decreased between S1 and S2 in patients exhibiting pCR (p = 0.02) or partial response (p = 0.01). Regarding protein expression, TYMS was absent in 100% of CTCs from patients with pCR (p = 0.001) yet was expressed in 83% of non-responders at S2 (p < 0.001). Meanwhile, RAD23B was expressed in CTCs from 75% of non-responders at S1 (p = 0.01) and in 100% of non-responders at S2 (p = 0.001). Surprisingly, 100% of non-responders expressed TYMS mRNA at both timepoints (p = 0.001). In addition, TYMS/RAD23B was not detected in the CTCs of patients exhibiting pCR (p = 0.001). We found 83.3% of sensitivity for TYMS mRNA at S1 (p = 0.001) and 100% for TYMS (p = 0.064) and RAD23B (p = 0.01) protein expression at S2. Thus, TYMS mRNA and/or TYMS/RAD23B expression in CTCs, as well as CTC kinetics, have the potential to predict non-response to NCRT and avoid unnecessary radical surgery for LARC patients with pCR.

Impact of ypT, ypN, and Adjuvant Therapy on Survival in Gastric Cancer Patients Treated with Perioperative Chemotherapy and Radical Surgery.

BACKGROUND: Perioperative chemotherapy and surgery is the standard of care in advanced gastroesophageal cancer patients, but its impact among those treated with radical surgery still needs further assessment. We present the results of this multimodality treatment approach in a gastric cancer patients cohort treated with D2 lymphadenectomy. We aimed to identify prognostic factors associated with improved survival. PATIENTS AND METHODS: This retrospective cohort study enrolled patients treated with perioperative chemotherapy and resection in a single cancer center in Brazil between 2006 and 2016. Subjects presenting tumors of the gastric stump, esophageal tumors, or treated with intraperitoneal chemotherapy were excluded. Intention-to-treat survival analysis was performed for all subjects who started neoadjuvant chemotherapy, and prognostic factors were determined among those who had R0 resection. RESULTS: This study included 239 patients, of whom 198 had R0 resection. The mean age was 59.9 years, and most had clinical stage IIB or III disease (88%). Among the 239 patients who started neoadjuvant chemotherapy, 207 (86.6%) completed all neoadjuvant treatment cycles, and surgical resection was performed in 225 subjects (94.1%). Overall 60-day morbidity and mortality rates were 35.6% and 4.4%, respectively. For the entire cohort, median survival was 78 months and the 5-year survival rate was 55.3%. Factors associated with worse survival were ypT3-4 stage, ypN + stage, extended resection, and no adjuvant chemotherapy. CONCLUSIONS: Perioperative chemotherapy resulted in very good outcomes for patients treated with radical surgery, and downstaging after chemotherapy was shown to be a major determinant of prognosis.

Genomics and epidemiology for gastric adenocarcinomas (GE4GAC): a Brazilian initiative to study gastric cancer

Gastric cancer (GC) is the fifth most common type of cancer worldwide with high incidences in Asia, Central, and South American countries. This patchy distribution means that GC studies are neglected by large research centers from developed countries. The need for further understanding of this complex disease, including the local importance of epidemiological factors and the rich ancestral admixture found in Brazil, stimulated the implementation of the GE4GAC project. GE4GAC aims to embrace epidemiological, clinical, molecular and microbiological data from Brazilian controls and patients with malignant and pre-malignant gastric disease. In this letter, we summarize the main goals of the project, including subject and sample accrual and current findings

Mutation Detection in Tumor-Derived Cell Free DNA Anticipates Progression in a Patient With Metastatic Colorectal Cancer.

Background: The observation of tumor-derived cell-free DNA (ctDNA) in plasma brought new expectations to monitor treatment response in cancer patients. Case presentation: In an exploratory case of a 57-year-old man diagnosed with metastatic sigmoid adenocarcinoma, we used a hotspot panel of cancer-associated gene mutations to identify tumor-specific mutations in the primary tumor and metastasis. RESULTS: Five mutations were detected (KRAS, p.Gly12Val; TP53, p.Arg175His; RB1, p.Ile680Thr; ALK, p.Gly1184Glu; and ERBB2, p.Lys860Lys), of which three were detected in both tissue types (primary tumor and metastasis). All five mutations were monitored in the ctDNA of six serial plasma samples. Only KRAS and TP53 mutations were detected at a high frequency in the first plasma sample. After 1 month of chemotherapy the allele frequencies of both mutations fell below the detection limit. From the third month of systemic treatment onward, the allele frequencies of both mutations were detectable in plasma, displaying a continual increase thereafter. The remaining three mutations were not detected in plasma samples. Signs of disease progression in ctDNA during the treatment period were evident while computed tomography (CT) measurements suggested stable metastatic lesions throughout the treatment. Conclusions: Liquid biopsies revealed tumor heterogeneity and predicted tumor progression, demonstrating the potential of ctDNA analysis to be a sensitive and specific tool for monitoring treatment responsivity and for early identification of treatment resistance.

Neoadjuvant Hypofractionated Radiotherapy and Chemotherapy in High-Grade Extremity Soft Tissue Sarcomas: Phase 2 Clinical Trial Protocol.

BACKGROUND: Neoadjuvant radiotherapy (RT) and chemotherapy are applied to large, high-grade extremity soft tissue sarcomas to treat metastatic disease earlier and sterilize margins to perform R0 surgery. However, preoperative RT increases wound complication rates (rWC), delaying adjuvant chemotherapy or preventing it from being administered altogether. Hypofractionated neoadjuvant RT can be offered in this situation, concomitant to chemotherapy, allowing patients to receive chemotherapy as a preoperative treatment in less time with an acceptable rWC. OBJECTIVE: The objectives of this protocol are to maintain low rates of morbidity and mortality compared to literature data, improving survival rates and avoiding poor responders from receiving unnecessary adjuvant chemotherapy. METHODS: This noncontrolled, single-arm, phase 2 clinical trial recruited patients aged over 18 years with high-grade soft tissue sarcomas in the girdles or extremities. Three neoadjuvant chemotherapy (ifosfamide and doxorubicin) cycles were administered with 5 days of hypofractionated RT (25 Gy in 5 fractions) in the second cycle of doxorubicin only. Viable cell counts in the surgical specimen were measured, and patients in whom this value was less than 30% continued to receive an additional 3 full chemotherapy cycles as adjuvant treatment. RESULTS: Primary endpoint will be disease-specific survival measured by the evaluation of local and distant recurrence after neoadjuvant treatment. The secondary endpoints will be wound complication and amputation rates and chemotherapy toxicity. We also will record the viable cell rates after the schema and correlate this with survival. CONCLUSIONS: As seems with other solid tumors, hypofractionated RT has comparable efficacy and safety as conventional fractionation. This modality of treatment combined with chemotherapy could increase the pathological response rates and improve the outcomes of select patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02812654; https://clinicaltrials.gov/ct2/show/NCT02812654 (Archived by WebCite at http://www.webcitation.org/6qC3puBOy).

Isolation, detection, and immunomorphological characterization of circulating tumor cells (CTCs) from patients with different types of sarcoma using isolation by size of tumor cells: a window on sarcoma-cell invasion.

BACKGROUND: Sarcomas are rare and heterogeneous neoplasms with poor prognosis that are thought to spread to distant organs mainly by hematogenous dissemination. However, circulating tumor cells (CTCs) have never been visualized in sarcomas. OBJECTIVES: To investigate the feasibility of using isolation by size of tumor cells (ISET) for isolation, identification, and characterization of CTCs derived from patients with high-grade and metastatic sarcomas. PATIENTS AND METHODS: We studied eleven patients with metastatic/recurrent or locally advanced soft-tissue sarcomas (STSs), six of whom had synovial sarcomas. Blood samples (8 mL) were collected from patients with advanced STS and treated by ISET, a marker- independent approach that isolates intact CTCs from blood, based on their larger size compared with leukocytes. CTCs were identified by cytomorphology and characterized by dual-color immunocytochemistry using antivimentin or anti-Pan CK, and anti-CD45. RESULTS: All patients with STS included in this study showed CTCs, with numbers ranging from two to 48 per 8 mL of blood. CONCLUSION: This study shows the feasibility of isolating, identifying, and characterizing CTCs from patients with different types of sarcomas and the presence of circulating sarcoma cells in all the tested patients. Our results set the basis for further studies aimed at exploring the presence, number, and immunomolecular characteristics of CTCs in different types of sarcoma, and bring more light to the mechanisms of tumor invasion for these tumors.

Adjuvant chemoradiotherapy after d2-lymphadenectomy for gastric cancer: the role of n-ratio in patient selection. results of a single cancer center.

BACKGROUND: Adjuvant chemoradiotherapy is part of a multimodality treatment approach in order to improve survival outcomes after surgery for gastric cancer. The aims of this study are to describe the results of gastrectomy and adjuvant chemoradiotherapy in patients treated in a single institution, and to identify prognostic factors that could determine which individuals would benefit from this treatment. METHODS: This retrospective study included patients with pathologically confirmed gastric adenocarcinoma who underwent surgical treatment with curative intent in a single cancer center in Brazil, between 1998 and 2008. Among 327 patients treated in this period, 142 were selected. Exclusion criteria were distant metastatic disease (M1), T1N0 tumors, different multimodality treatments and tumors of the gastric stump. Another 10 individuals were lost to follow-up and there were 3 postoperative deaths. The role of several clinical and pathological variables as prognostic factors was determined. RESULTS: D2-lymphadenectomy was performed in 90.8% of the patients, who had 5-year overall and disease-free survival of 58.9% and 55.7%. The interaction of N-category and N-ratio, extended resection and perineural invasion were independent prognostic factors for overall and disease-free survival. Adjuvant chemoradiotherapy was not associated with a significant improvement in survival. Patients with node-positive disease had improved survival with adjuvant chemoradiotherapy, especially when we grouped patients with N1 and N2 tumors and a higher N-ratio. These individuals had worse disease-free (30.3% vs. 48.9%) and overall survival (30.9% vs. 71.4%). CONCLUSION: N-category and N-ratio interaction, perineural invasion and extended resections were prognostic factors for survival in gastric cancer patients treated with D2-lymphadenectomy, but adjuvant chemoradiotherapy was not. There may be some benefit with this treatment in patients with node-positive disease and higher N-ratio.

Safety and preliminary results of perioperative chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for high-risk gastric cancer patients.

BACKGROUND: Gastric cancer relapse occurs in about 30% of the patients treated with gastrectomy and D2-lymphadenectomy, mainly as distant or peritoneal metastases. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been associated with an improvement in survival and lower peritoneal recurrence, albeit with increased morbidity. The aim of this study is to report the preliminary results of the association of perioperative chemotherapy, radical surgery and HIPEC in high-risk gastric patients in a single institution. METHODS: Treatment protocol was started in 2007 and included patients younger than 65 years old, with good performance status and gastric adenocarcinoma with serosa involvement and lymph node metastases, located in the body or antrum. Patients should receive three preoperative cycles of DCF (Docetaxel 75 mg/m2, Cisplatin 75 mg/m2 and continuous intravenous infusion of 5-Fluorouracil 750 mg/m2 for 5 days), followed by gastric resection with D2-lymphadenectomy, hyperthermic intraperitoneal chemotherapy with Mytomicin C 34 mg/m2 and three more postoperative cycles of DCF. RESULTS: Ten patients were included between 2007 and 2011. Their median age was 47 years old and six were male. Nine were staged with cT4 cN + tumors and one as cT3 cN+. Nine patients completed all three preoperative chemotherapy cycles. Eight individuals were treated with a total gastrectomy and the other two had a distal gastrectomy, all having HIPEC. Postoperative morbidity was 50%, with no deaths. Regarding postoperative chemotherapy, only 5 patients completed three cycles. With a median follow-up of 25 months, three relapses were identified and 7 patients remain disease-free, two with more than 4 years of follow-up. CONCLUSION: The association of perioperative systemic and intraperitoneal chemotherapy plus radical surgery is a feasible multimodality treatment, with acceptable morbidity. With a longer follow-up and a larger group of patients, we hope to be able to determine if it also influences survival outcomes and patterns of recurrence. MINI-ABSTRACT: The association of perioperative chemotherapy, gastric resection and D2-lymphadenectomy and hyperthermic intraperitoneal chemotherapy proved to be associated with acceptable morbidity. For survival analysis, a longer follow-up is needed.