Enrique Roca - Academia.edu (original) (raw)

Papers by Enrique Roca

Biomedicines

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with ... more 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...

Oncología Clínica, Nov 8, 2022

Translational Oncology, 2021

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-ri... more 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 diseasefree 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.

Frontiers in Oncology, 2022

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Curren... more 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...

World Journal of Surgical Oncology, 2020

BackgroundNonoperative management after neoadjuvant treatment in low rectal cancer enables organ ... more BackgroundNonoperative 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.MethodsPatients 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-Meie...

Annals of Oncology, 2012

Introduction: Recent studies have outlined an increase in the incidence rates of rectal cancer am... more Introduction: Recent studies have outlined an increase in the incidence rates of rectal cancer among adults aged 50 and younger, a group for whom average-risk screening is not a standard of care. Controversies still exist regarding its features and prognosis. Methods: Between February-2007 and December-2011, 578 rectal cancer pts were registered and discussed in our multidisciplinary team "Co-Recto". A retrospective cohort analysis was performed in a subset of adults aged ≤50 years, focusing on clinical and demographic parameters, preoperative assessment, therapeutic approach, tumor response and pattern of disease recurrence. Results: 140/578 (24.2%) pts were aged between 18-50 years, of whom 82 (58%) were identified as being aged ≤40 at presentation. Median age was 37 years, 73/ 140 (52%) were female. Only 35/140 (25%) had medical insurance. The mean time from symptoms onset to diagnosis was 6 months (1-34 months). The most frequent tumor location was lower rectum: 74/140 (53%). Median distance from the anal verge was 50 mm (10-150 mm). Levator muscle-external anal sphincter were involved in 26/140 pts (18%). 26/140 (18%) tumors were single-ring cellsmucinous adenocarcinoma. Regarding colorectal cancer high-risk conditions, 9/140 (6.5%) pts had familial adenomatous polyposis and 8/140 (6%) had inflammatory bowel disease. Lynch syndrome was assessed in 23/140 (16%) pts with microsatellite instability (MSI) analysis and/or immunohistochemistry (IHQ) analysis of mismatch repair (MMR) proteins MLH1, MSH2, MSH6 and PMS2. 22/23 (96%) pts had MMR proficient tumors; in 1/23 pts (4%) a germinal mutation in PMS2 was identified (Lynch syndrome). 10/23 pts were also screened for the two most prevalent MUTYH mutations: G393D and Y176C, identifying biallelic MUTYH mutations in 1 case. 19/140 (13.5%) pts had already undergone elective surgery before discussion in "Co-Recto", and 121/140 (86.5%) were assessed preoperatively in "Co-Recto" to decide the best therapeutic approach. Clinical staging at diagnosis was I: 6(5%), II 18(15%), III 66(54%) and IV: 31 (26%). A curative intent therapeutic approach was done in 90/121 (74%). Neoadjuvant treatment was delivered in 61/90 (68%): induction chemotherapy 49/ 61 (80%), chemoradiotherapy mostly based on capecitabine 58/61 (95%), and chemotherapy alone followed by TME surgery 3/61 (5%). 2/61 pts with clinical complete response by MRI were considered for a watch and wait strategy, pathological complete response rate was 19% (11/59). After a median follow up of 23 months (2-54m), the recurrence rate was: local 2/61 (3.2%), distant 4/61 (6.5%), and both (1/61). Conclusion: In our experience, young-onset rectal cancer frequently presents with locally advanced and/or metastatic disease, requiring more aggressive treatments. Distant relapses often occur. Known hereditary syndromes seem to have a low prevalence. We highlight the challenge of reviewing current screening strategies to warrant a proper and early diagnosis in young patients.

Annals of Oncology, 2012

NETs and capecitabine (cap) has been effectively substituted for 5FU in many tumours. The NET01 t... more NETs and capecitabine (cap) has been effectively substituted for 5FU in many tumours. The NET01 trial was designed to investigate whether cap + strep ± cisplatin warrant further evaluation. Methods: Patients (pts) with histologically confirmed, unresectable, advanced and/or metastatic NETs of foregut, pancreatic or unknown primary site were randomised (1:1) to 6 cycles of 3-weekly cap 625 mg/m 2 po bd daily (D1-21), strep 1.0g/m 2 IV (D1), with cisplatin 70mg/m 2 IV (D1) (Cap-strep-cist) or without (Cap-strep). The primary outcome measure was RR using RECIST criteria. 84 pts were required to test a RR of <40% vs >60% with a significance level of 5% and 80% power in each arm. Central pathology review and 10% of central radiology review were performed. Results: 86 pts (58% male, median age 59 years) were randomised (44 Cap-strep, 42 Cap-strep-cist) with primary siteforegut 20%, pancreatic 48% and unknown 33%. The grade was low 12 (17%), intermediate 43 (62%) and high 14 (20%). Baseline characteristics were balanced between the 2 arms. 59% Cap-strep and 33% Cap-strep-cist pts received ≥6 cycles. 18 Cap-strep and 26 Cap-strep-cist pts experienced grade ≥3 toxicities. Outcome results are summarised in the table.

Journal of Clinical Oncology, 2015

3561 Background: Controversies exist about the proper management of pts with clinical complete tu... more 3561 Background: Controversies exist about the proper management of pts with clinical complete tumor regression after preoperative therapy. A non-operative management (NOM) of selected patients has achieved promising long-term outcomes in some Watch and Wait (W&W) series. Regardless of encouraging results, and in spite of being a readily accepted strategy by patients, reluctance to recommend this strategy as an affordable option still exists in rectal cancer guidelines. Our aim is to evaluate the NOM for pts with clinical complete response discussed in Co-Recto( interdisciplinary and cooperative team for the Management of rectal cancer) Argentina Methods: Pts with resectable rectal cancer (stage I-III) selected for neoadjuvant therapy in Co-Recto between 2008-2014 were retrospectively reviewed to determine pts with clinical complete response(cCR) selected for Non operative management. cCR was defined between digital exam, endoscopic criteria, MRI and CEA. F-up for W&W policy was performed during the first...

Journal of Clinical Oncology, 2004

9065 Background: GIST are the most common non-epitelial tumour of the gastrointestinal tract with... more 9065 Background: GIST are the most common non-epitelial tumour of the gastrointestinal tract with an increasing incidence after molecular discovery ( KIT gene) and clinical- pathological diagnostic...

Journal of Clinical Oncology, 2004

3769 Background: OXA and infused FU plus LV (FOLFOX) has proved to be one of the most active regi... more 3769 Background: OXA and infused FU plus LV (FOLFOX) has proved to be one of the most active regimens in ACRC. On going trials, adjuvant and metastatic setting, have hypothesized that OXA given with bolus FU plus LV would be equally active and safe as OXA combined with infusional FU regimens. Since OXA registration in our country, constrains related to cost and convenience prompt to develop schedules of OXA/bolus FU/ld-LV. PATIENTS AND METHODS We assessed retrospectively a cohort of pts with ACRC treated with OXA 85 mg/m2 days 1 and 15 plus LV 20 mg/m2 followed by a 500 mg/m2 bolus dose of FU on days 1, 8, and 15 every 28 days. Data of safety and efficacy are presented. RESULTS Between 1996 and 2002, 273 pts were treated in two centers. Pts characteristics: median age 56 (22-79), male/female: 151/122, colon/rectum 199/74, median metastatic sites 1 (1-4), first line/second / third (%): 68/ 13/ 3 and 16% received after metastasis resection (R0). 1146 cycles (cy) were administered, median per patient 4 (1-11). SAFETY the main grade 3-4 toxicities were (pts): gastrointestinal 28, hematological 18, allergies 2, sepsis 3 pts and severe neurotoxicity 12 pts (4,3%). Toxic deaths occurred in 3 pts (1%) Efficacy: objective response rate (ORR) and time related parameters are summarized as follows: 17 pts initially unresectable ACRC pts were rendered resectable after a 6 (2-11) median cy of treatment. CONCLUSIONS OXA combined with bolus FU and ld-LV seems to be safe and effective. Next multicentre randomized trials will show the comparative value between OXA combined with bolus or infusional FU. [Figure: see text] No significant financial relationships to disclose.

Journal of Clinical Oncology, 2015

255 Background: Grade 2 (G2) Neuroendocrine tumors (NETs), of the digestive tract is a heterogene... more 255 Background: Grade 2 (G2) Neuroendocrine tumors (NETs), of the digestive tract is a heterogeneous group of tumors. Several treatment options including chemotherapy and target therapy are available, but there is a lack of prospective trials assessing the role of pronostic factors in this population. Aim(s): to analyze prognostic factors and clinical characteristics in a population of patients with G2 GEP-NETs. To determine the role of ki 67 in the stratification of G2 population. Methods: Study population was obtained from our prospective database (Argentum Group). Survival was estimated using the Kaplan-Meier method and compared between Ki-67 quartiles using the log-rank test. Value of Ki-67 to discriminate mortality was assesed with a ROC curve analysis Results: 144 pts were evaluated. Mean age 54.9, 46.7% male. 102 (70.8%) with metastatic disease, mainly hepatic in 97 pts. (67.4%). 67.9 % underwent surgery. 34% received chemotherapy, and 10.9% target therapy. Median Ki-67 value...

Future Oncology, 2015

Introduction: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal t... more Introduction: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. 18F-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.

Acta gastroenterologica Latinoamericana, 2009

Elevated circulating levels of chromogranin A (CgA) are found in the neuroendocrine tumors (NETs)... more Elevated circulating levels of chromogranin A (CgA) are found in the neuroendocrine tumors (NETs), but diagnostic usefulness of this marker is still debatable. To assess the role of CgA for the identification and follow up of gastroenteropancreatic neuroendocrine tumors (GEP-NET), a multicenter prospective longitudinal study has been carried out in Argentina. CgA was measured by RIA in 119 histologically proven GEP-NET patients and in 39 healthy controls. A cutoff value of 2.8 nmol/L was established from a receiver-operating characteristic (ROC) curve, as discriminating between controls and patients with active disease (specificity 100% and sensitivity 92.3%). CgA levels were higher in functioning than in no functioning tumors (median 55 nmol/L vs 5 nmol/L, p < 0.05). Metastases were present in 83 patients and their CgA levels were significantly higher than levels in the 36 patients without metastases (median 44 nmol/L vs 64 nmol/L, p < 0.0001). CgA levels are strongly correla...

Molecular and Clinical Oncology, 2014

Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells ... more 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.

PLoS ONE, 2012

Objective: Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that ... more 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 (6SD) 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.

Journal of Clinical Oncology, 2005

International Journal of Radiation Oncology*Biology*Physics, 2002

Purpose: Oxaliplatin (OXA)/5-fluorouracil (5-FU) have confirmed their preclinical synergy in adva... more Purpose: Oxaliplatin (OXA)/5-fluorouracil (5-FU) have confirmed their preclinical synergy in advanced colorectal cancer patients. Chemoradiotherapy with 5-FU ؉ leucovorin (LV) is considered the standard treatment in unresectable rectal cancer patients. The objective was to evaluate OXA with 5-FU ؉ LV and concurrent radiotherapy in unresectable rectal cancer patients. Patients and Methods: Treatment: OXA 25 mg/m 2 /day in 30-min infusions, followed by bolus LV 20 mg/m 2 /day and bolus 5-FU 375 mg/m 2 /day. All drugs were given on 4 days during Weeks 1 and 5 of a standard radiotherapy cycle (50.4 Gy). A single OXA dose (50 mg/m 2) was also given on the third week of radiotherapy. A cycle of OXA with 5-FU ؉ LV was administered 4 weeks after chemoradiotherapy, with surgery planned 4 weeks later. Results: Between March 1998 and April 2000, 22 patients with T3-T4 unresectable rectal cancer were accrued. Patient characteristics included the following: 11 females, 11 males, median age 58 (range: 18-76). Performance status ECOG (PS) 0: 2 patients, PS 1: 7 patients, and PS 2: 13 patients. The following RTOG Grade 3-4 toxicities were reported: diarrhea, 6 patients; cutaneous, 3 patients; neutropenia-leukopenia, 2 patients; and thrombocytopenia, 1 patient; 1 treatment-related death resulted (febrile neutropenia-sepsis after chemoradiotherapy). Only 1 patient had neurosensory Grade 2 (OXA-specific Levi's scale) toxicity. Nine patients had PS worsening during treatment. Five patients had chemoradiotherapy delay (median: 6 days). Of 22 patients, 16 underwent surgery (without serious surgical complications); 12/16 had a complete resection (5/12 had sphincter preservation). Pathologic examination revealed 3/12 complete remissions, 2/12 minimal microscopic residual disease, 2/12 T2N0, 1/12 T3N0, and 4/12 positive nodes; 4/16 had unresectable disease. Median follow-up was 15 months (range: 3.0-43.4 months), median time to progression was 15.7 months (CI 95%, 0, 31.7), and median overall survival was 19.5 months (CI 95%, 18.0, 21). Conclusions: Outpatient treatment with low-dose, 30-min daily OXA infusion was feasible and very active, with acceptable toxicity.

International Congress Series, 2004

Microsatellite analysis is emerging as an important tool in the study of cancer. The addition of ... more Microsatellite analysis is emerging as an important tool in the study of cancer. The addition of novel microsatellite alleles is referred as microsatellite instability (MSI) indicating possible mutations in cellular DNA repair mechanism. The detection of these genetic changes demonstrates the presence of a clonal population of cells that share altered genetic information, which is characteristic of cancer cells. In this study, we analyzed the five MSI markers: D2S123, D5S346, D17S250, BAT 25, BAT 26 recommended at the 1997 National Cancer Institute in a patient with suspicious familiar history of Non-Polyposic Hereditary Colorectal Cancer (NHPCC), Lynch syndrome, and high instability MSI-H was confirmed.

Biomedicines

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with ... more 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...

Oncología Clínica, Nov 8, 2022

Translational Oncology, 2021

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-ri... more 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 diseasefree 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.

Frontiers in Oncology, 2022

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Curren... more 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...

World Journal of Surgical Oncology, 2020

BackgroundNonoperative management after neoadjuvant treatment in low rectal cancer enables organ ... more BackgroundNonoperative 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.MethodsPatients 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-Meie...

Annals of Oncology, 2012

Introduction: Recent studies have outlined an increase in the incidence rates of rectal cancer am... more Introduction: Recent studies have outlined an increase in the incidence rates of rectal cancer among adults aged 50 and younger, a group for whom average-risk screening is not a standard of care. Controversies still exist regarding its features and prognosis. Methods: Between February-2007 and December-2011, 578 rectal cancer pts were registered and discussed in our multidisciplinary team "Co-Recto". A retrospective cohort analysis was performed in a subset of adults aged ≤50 years, focusing on clinical and demographic parameters, preoperative assessment, therapeutic approach, tumor response and pattern of disease recurrence. Results: 140/578 (24.2%) pts were aged between 18-50 years, of whom 82 (58%) were identified as being aged ≤40 at presentation. Median age was 37 years, 73/ 140 (52%) were female. Only 35/140 (25%) had medical insurance. The mean time from symptoms onset to diagnosis was 6 months (1-34 months). The most frequent tumor location was lower rectum: 74/140 (53%). Median distance from the anal verge was 50 mm (10-150 mm). Levator muscle-external anal sphincter were involved in 26/140 pts (18%). 26/140 (18%) tumors were single-ring cellsmucinous adenocarcinoma. Regarding colorectal cancer high-risk conditions, 9/140 (6.5%) pts had familial adenomatous polyposis and 8/140 (6%) had inflammatory bowel disease. Lynch syndrome was assessed in 23/140 (16%) pts with microsatellite instability (MSI) analysis and/or immunohistochemistry (IHQ) analysis of mismatch repair (MMR) proteins MLH1, MSH2, MSH6 and PMS2. 22/23 (96%) pts had MMR proficient tumors; in 1/23 pts (4%) a germinal mutation in PMS2 was identified (Lynch syndrome). 10/23 pts were also screened for the two most prevalent MUTYH mutations: G393D and Y176C, identifying biallelic MUTYH mutations in 1 case. 19/140 (13.5%) pts had already undergone elective surgery before discussion in "Co-Recto", and 121/140 (86.5%) were assessed preoperatively in "Co-Recto" to decide the best therapeutic approach. Clinical staging at diagnosis was I: 6(5%), II 18(15%), III 66(54%) and IV: 31 (26%). A curative intent therapeutic approach was done in 90/121 (74%). Neoadjuvant treatment was delivered in 61/90 (68%): induction chemotherapy 49/ 61 (80%), chemoradiotherapy mostly based on capecitabine 58/61 (95%), and chemotherapy alone followed by TME surgery 3/61 (5%). 2/61 pts with clinical complete response by MRI were considered for a watch and wait strategy, pathological complete response rate was 19% (11/59). After a median follow up of 23 months (2-54m), the recurrence rate was: local 2/61 (3.2%), distant 4/61 (6.5%), and both (1/61). Conclusion: In our experience, young-onset rectal cancer frequently presents with locally advanced and/or metastatic disease, requiring more aggressive treatments. Distant relapses often occur. Known hereditary syndromes seem to have a low prevalence. We highlight the challenge of reviewing current screening strategies to warrant a proper and early diagnosis in young patients.

Annals of Oncology, 2012

NETs and capecitabine (cap) has been effectively substituted for 5FU in many tumours. The NET01 t... more NETs and capecitabine (cap) has been effectively substituted for 5FU in many tumours. The NET01 trial was designed to investigate whether cap + strep ± cisplatin warrant further evaluation. Methods: Patients (pts) with histologically confirmed, unresectable, advanced and/or metastatic NETs of foregut, pancreatic or unknown primary site were randomised (1:1) to 6 cycles of 3-weekly cap 625 mg/m 2 po bd daily (D1-21), strep 1.0g/m 2 IV (D1), with cisplatin 70mg/m 2 IV (D1) (Cap-strep-cist) or without (Cap-strep). The primary outcome measure was RR using RECIST criteria. 84 pts were required to test a RR of <40% vs >60% with a significance level of 5% and 80% power in each arm. Central pathology review and 10% of central radiology review were performed. Results: 86 pts (58% male, median age 59 years) were randomised (44 Cap-strep, 42 Cap-strep-cist) with primary siteforegut 20%, pancreatic 48% and unknown 33%. The grade was low 12 (17%), intermediate 43 (62%) and high 14 (20%). Baseline characteristics were balanced between the 2 arms. 59% Cap-strep and 33% Cap-strep-cist pts received ≥6 cycles. 18 Cap-strep and 26 Cap-strep-cist pts experienced grade ≥3 toxicities. Outcome results are summarised in the table.

Journal of Clinical Oncology, 2015

3561 Background: Controversies exist about the proper management of pts with clinical complete tu... more 3561 Background: Controversies exist about the proper management of pts with clinical complete tumor regression after preoperative therapy. A non-operative management (NOM) of selected patients has achieved promising long-term outcomes in some Watch and Wait (W&W) series. Regardless of encouraging results, and in spite of being a readily accepted strategy by patients, reluctance to recommend this strategy as an affordable option still exists in rectal cancer guidelines. Our aim is to evaluate the NOM for pts with clinical complete response discussed in Co-Recto( interdisciplinary and cooperative team for the Management of rectal cancer) Argentina Methods: Pts with resectable rectal cancer (stage I-III) selected for neoadjuvant therapy in Co-Recto between 2008-2014 were retrospectively reviewed to determine pts with clinical complete response(cCR) selected for Non operative management. cCR was defined between digital exam, endoscopic criteria, MRI and CEA. F-up for W&W policy was performed during the first...

Journal of Clinical Oncology, 2004

9065 Background: GIST are the most common non-epitelial tumour of the gastrointestinal tract with... more 9065 Background: GIST are the most common non-epitelial tumour of the gastrointestinal tract with an increasing incidence after molecular discovery ( KIT gene) and clinical- pathological diagnostic...

Journal of Clinical Oncology, 2004

3769 Background: OXA and infused FU plus LV (FOLFOX) has proved to be one of the most active regi... more 3769 Background: OXA and infused FU plus LV (FOLFOX) has proved to be one of the most active regimens in ACRC. On going trials, adjuvant and metastatic setting, have hypothesized that OXA given with bolus FU plus LV would be equally active and safe as OXA combined with infusional FU regimens. Since OXA registration in our country, constrains related to cost and convenience prompt to develop schedules of OXA/bolus FU/ld-LV. PATIENTS AND METHODS We assessed retrospectively a cohort of pts with ACRC treated with OXA 85 mg/m2 days 1 and 15 plus LV 20 mg/m2 followed by a 500 mg/m2 bolus dose of FU on days 1, 8, and 15 every 28 days. Data of safety and efficacy are presented. RESULTS Between 1996 and 2002, 273 pts were treated in two centers. Pts characteristics: median age 56 (22-79), male/female: 151/122, colon/rectum 199/74, median metastatic sites 1 (1-4), first line/second / third (%): 68/ 13/ 3 and 16% received after metastasis resection (R0). 1146 cycles (cy) were administered, median per patient 4 (1-11). SAFETY the main grade 3-4 toxicities were (pts): gastrointestinal 28, hematological 18, allergies 2, sepsis 3 pts and severe neurotoxicity 12 pts (4,3%). Toxic deaths occurred in 3 pts (1%) Efficacy: objective response rate (ORR) and time related parameters are summarized as follows: 17 pts initially unresectable ACRC pts were rendered resectable after a 6 (2-11) median cy of treatment. CONCLUSIONS OXA combined with bolus FU and ld-LV seems to be safe and effective. Next multicentre randomized trials will show the comparative value between OXA combined with bolus or infusional FU. [Figure: see text] No significant financial relationships to disclose.

Journal of Clinical Oncology, 2015

255 Background: Grade 2 (G2) Neuroendocrine tumors (NETs), of the digestive tract is a heterogene... more 255 Background: Grade 2 (G2) Neuroendocrine tumors (NETs), of the digestive tract is a heterogeneous group of tumors. Several treatment options including chemotherapy and target therapy are available, but there is a lack of prospective trials assessing the role of pronostic factors in this population. Aim(s): to analyze prognostic factors and clinical characteristics in a population of patients with G2 GEP-NETs. To determine the role of ki 67 in the stratification of G2 population. Methods: Study population was obtained from our prospective database (Argentum Group). Survival was estimated using the Kaplan-Meier method and compared between Ki-67 quartiles using the log-rank test. Value of Ki-67 to discriminate mortality was assesed with a ROC curve analysis Results: 144 pts were evaluated. Mean age 54.9, 46.7% male. 102 (70.8%) with metastatic disease, mainly hepatic in 97 pts. (67.4%). 67.9 % underwent surgery. 34% received chemotherapy, and 10.9% target therapy. Median Ki-67 value...

Future Oncology, 2015

Introduction: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal t... more Introduction: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. 18F-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.

Acta gastroenterologica Latinoamericana, 2009

Elevated circulating levels of chromogranin A (CgA) are found in the neuroendocrine tumors (NETs)... more Elevated circulating levels of chromogranin A (CgA) are found in the neuroendocrine tumors (NETs), but diagnostic usefulness of this marker is still debatable. To assess the role of CgA for the identification and follow up of gastroenteropancreatic neuroendocrine tumors (GEP-NET), a multicenter prospective longitudinal study has been carried out in Argentina. CgA was measured by RIA in 119 histologically proven GEP-NET patients and in 39 healthy controls. A cutoff value of 2.8 nmol/L was established from a receiver-operating characteristic (ROC) curve, as discriminating between controls and patients with active disease (specificity 100% and sensitivity 92.3%). CgA levels were higher in functioning than in no functioning tumors (median 55 nmol/L vs 5 nmol/L, p < 0.05). Metastases were present in 83 patients and their CgA levels were significantly higher than levels in the 36 patients without metastases (median 44 nmol/L vs 64 nmol/L, p < 0.0001). CgA levels are strongly correla...

Molecular and Clinical Oncology, 2014

Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells ... more 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.

PLoS ONE, 2012

Objective: Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that ... more 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 (6SD) 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.

Journal of Clinical Oncology, 2005

International Journal of Radiation Oncology*Biology*Physics, 2002

Purpose: Oxaliplatin (OXA)/5-fluorouracil (5-FU) have confirmed their preclinical synergy in adva... more Purpose: Oxaliplatin (OXA)/5-fluorouracil (5-FU) have confirmed their preclinical synergy in advanced colorectal cancer patients. Chemoradiotherapy with 5-FU ؉ leucovorin (LV) is considered the standard treatment in unresectable rectal cancer patients. The objective was to evaluate OXA with 5-FU ؉ LV and concurrent radiotherapy in unresectable rectal cancer patients. Patients and Methods: Treatment: OXA 25 mg/m 2 /day in 30-min infusions, followed by bolus LV 20 mg/m 2 /day and bolus 5-FU 375 mg/m 2 /day. All drugs were given on 4 days during Weeks 1 and 5 of a standard radiotherapy cycle (50.4 Gy). A single OXA dose (50 mg/m 2) was also given on the third week of radiotherapy. A cycle of OXA with 5-FU ؉ LV was administered 4 weeks after chemoradiotherapy, with surgery planned 4 weeks later. Results: Between March 1998 and April 2000, 22 patients with T3-T4 unresectable rectal cancer were accrued. Patient characteristics included the following: 11 females, 11 males, median age 58 (range: 18-76). Performance status ECOG (PS) 0: 2 patients, PS 1: 7 patients, and PS 2: 13 patients. The following RTOG Grade 3-4 toxicities were reported: diarrhea, 6 patients; cutaneous, 3 patients; neutropenia-leukopenia, 2 patients; and thrombocytopenia, 1 patient; 1 treatment-related death resulted (febrile neutropenia-sepsis after chemoradiotherapy). Only 1 patient had neurosensory Grade 2 (OXA-specific Levi's scale) toxicity. Nine patients had PS worsening during treatment. Five patients had chemoradiotherapy delay (median: 6 days). Of 22 patients, 16 underwent surgery (without serious surgical complications); 12/16 had a complete resection (5/12 had sphincter preservation). Pathologic examination revealed 3/12 complete remissions, 2/12 minimal microscopic residual disease, 2/12 T2N0, 1/12 T3N0, and 4/12 positive nodes; 4/16 had unresectable disease. Median follow-up was 15 months (range: 3.0-43.4 months), median time to progression was 15.7 months (CI 95%, 0, 31.7), and median overall survival was 19.5 months (CI 95%, 18.0, 21). Conclusions: Outpatient treatment with low-dose, 30-min daily OXA infusion was feasible and very active, with acceptable toxicity.

International Congress Series, 2004

Microsatellite analysis is emerging as an important tool in the study of cancer. The addition of ... more Microsatellite analysis is emerging as an important tool in the study of cancer. The addition of novel microsatellite alleles is referred as microsatellite instability (MSI) indicating possible mutations in cellular DNA repair mechanism. The detection of these genetic changes demonstrates the presence of a clonal population of cells that share altered genetic information, which is characteristic of cancer cells. In this study, we analyzed the five MSI markers: D2S123, D5S346, D17S250, BAT 25, BAT 26 recommended at the 1997 National Cancer Institute in a patient with suspicious familiar history of Non-Polyposic Hereditary Colorectal Cancer (NHPCC), Lynch syndrome, and high instability MSI-H was confirmed.