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.

Short-course radiotherapy for rectal cancer: real-world evidence in Argentina.

Background: Short-course radiotherapy (SCRT) of 25 Gy in five daily fractions is a recommended strategy in the neoadjuvant setting for resectable locally advanced rectal cancer (LARC), as well as in cases of metastatic disease for local control. There is scarce information regarding the use of SCRT for patients who have received nonoperative management. Objectives: To describe the characteristics of patients who received treatment with SCRT for LARC and metastatic rectal cancer, toxicity, and the approach after radiation treatment. Methods: This is a retrospective analysis of all patients who underwent SCRT for rectal cancer at the Alexander Fleming Institute from March 2014 to June 2022. Results: In total, 44 patients were treated with SCRT. The majority were male (29, 66%), with a median age of 59 years (interquartile range 46-73). Most patients had stage IV disease (26, 59.1%), followed by LARC (18, 40.9%). Most lesions were located in the middle rectum (30, 68%). The majority of LARC patients underwent SCRT followed by consolidation chemotherapy (ChT) (16/18, 89%), while most patients with metastatic disease underwent SCRT followed by consolidation ChT (14/26, 53.8%). A clinical complete response (cCR) was documented in 8/44, 18.2% of patients. Most patients with LARC and cCR were managed by a watch and wait approach (5/18, 27.7%). Local recurrence was observed in LARC cases (2/18, 11.1%). Patients who underwent SCRT following consolidation ChT were more likely to have adverse events (AEs) than those undergoing induction ChT following SCRT (11/30, 36.7% versus 3/12, 25%, p = 0.02). Conclusion: In a subgroup of patients diagnosed with LARC and treated with SCRT followed by ChT, surgical treatment could be omitted after they achieved a cCR. Local recurrence was similar to that reported in a previous study. SCRT is a reasonable option for local disease control in stage IV disease, yielding low toxicity rates. Therefore, decisions must be made by a multidisciplinary team. Prospective studies are necessary to reach further conclusions.

Atypical pattern of response in rectal cancer after neoadjuvant pembrolizumab treatment: a case report, literature review, and proposed management model.

Background: Immunotherapy is the first-line treatment in patients with advanced microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) colorectal cancer (CRC). Although immune checkpoint inhibitors (ICIs) for locally advanced rectal cancer (LARC) are not yet a standard, the results are very encouraging and raise the question of whether patients with clinical complete response (cCR) could receive nonoperative management (NOM). However, different patterns of response have challenged management strategies. Case Description: A 34-year-old woman diagnosed with dMMR LARC started treatment with capecitabine 2,000 mg/m2 on day 1 to 14 and oxaliplatin 130 mg/m2 on day 1 and every 21 days. Magnetic resonance imaging (MRI), performed three cycles later, showed local progression of the primary rectal lesion, which at that time had new peritoneal reflex involvement. A new hepatic lesion in segment V was observed. Due to disease progression, she was administered pembrolizumab 200 mg every 21 days. After three cycles, a discordant radiological response was observed on a new MRI scan that showed a complete response of the liver lesion and magnetic resonance tumor regression grade (mrTRG) 1 in the rectum. However, new involvement of the mesentery and enlargement of the regional lymph nodes (LNs) were also evident. A new colonoscopic biopsy was performed, showing no cancerous cells. She underwent surgery on the rectum and liver lesion. Pathology showed a complete response of the rectal wall and liver lesion, but 1 of 22 LNs was positive for adenocarcinoma (ypT0 N1 M0). The patient continued on pembrolizumab, and 14 months after surgery, she had not relapsed. Conclusions: Neoadjuvant immunotherapy for rectal cancer requires new recommendations for the assessment of clinical response. Pseudoprogression should be ruled out as an atypical response before deciding on surgical treatment. We propose an algorithm to address pseudoprogression in this setting.

Implementation of a virtual multicenter gastrointestinal tumor board to reduce cancer disparities in Argentina.

Given the increasing complexity of cancer care, multidisciplinary tumor boards have become essential in daily clinical oncology practice. The Project Extension for Community Healthcare Outcomes (ECHO) initiative developed an innovative telementoring model using a "hub and spoke" design consisting of a team of experts (hub) that offers a full service to multiple participants (the spokes) during regularly scheduled sessions discussing patients' clinical cases. The Alexander Fleming Cancer Institute in Buenos Aires was the first hub in Latin America to implement Project ECHO for gastrointestinal tumors. In our 3-year experience, 80 patients from 37 centers were evaluated within Project ECHO and a range of three to five cases were discussed in each meeting. From our perspective, the impact of this novel approach was a remarkable strategy to reduce care disparities by equalizing access to high-quality medical knowledge in a multidisciplinary environment for medical discussions. Additionally, it was shown to have a cost-effective impact directly on the patients and the local health system, since relevant costs were saved after unnecessary treatments, studies and travel expenses were avoided.

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.

Appraising the quality of meta-analysis for breast cancer treatment in the adjuvant setting: A systematic review.

INTRODUCTION: Breast cancer is the tumor with highest incidence in women worldwide and adjuvant treatment is extremely important to achieve disease control. Given the relevance of systematic reviews, their rigor should be warranted to avoid biased conclusions. Our objective was to investigate the methodological quality of meta-analysis of early breast cancer adjuvant treatment. MATERIAL AND METHODS: Comprehensive searches were performed using electronic databases from 1/1/2007 to 11/12/2018. All studies identified as a systematic review with meta-analysis investigating the efficacy of breast cancer adjuvant treatments were included. Two reviewers independently assessed titles and abstracts, then full-texts for eligibility. Quality was assessed using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) version 2 tool. RESULTS: Of 950 citations retrieved, 66 studies (7.0%) were deemed eligible. Methodological quality was highly variable, median AMSTAR score 8.5 (IQR 7-9.5) and range 0-16. There was a weak positive correlation between journal impact factor and AMSTAR score (r = 0.17) and citation rate and AMSTAR score (r = 0.16). Cochrane Systematic Reviews were of higher quality than reviews from other journals. Overall confidence was critically low for 61 (92.4%) studies, and the least well-reported domains were the statement of conflict of interest and funding source for the included studies (4.6%), the report of a pre-defined study protocol (15.2%), and the description of details of excluded studies (6.1%). CONCLUSIONS: Our findings reinforce concerns about the design, conduction and interpretation of meta-analysis in current literature. Methodological quality should be carefully considered and journal editors, decision makers and readers in general, must follow a critical approach to this studies.

Implementation of a molecular tumour board in LATAM: the impact on treatment decisions for patients evaluated at Instituto Alexander Fleming, Argentina.

BACKGROUND: The role of the molecular tumour board (MTB) is to recommend personalised therapy for patients with cancer beyond standard-of-care treatment. A comprehensive molecular analysis of the tumour in a molecular pathology laboratory is important for all targeted therapies approaches. Here we report the 1-year experience of the Instituto Alexander Fleming Molecular Tumour Board. PATIENTS AND METHODS: The MTB of the Instituto Alexander Fleming was launched in December 2019 in a monthly meeting. In each interactive monthly session, five cases were presented and discussed by the members. These cases were referred by the treating oncologists. The MTB recommendations were sent to each physician individually, and to the rest of the meeting participants. This was discussed with the patients/families by the treating oncologist. The final decision to choose therapy was left to the treating physicians. Of the 32 patients presented at MTB, 28 (87.5%) had potentially actionable alterations and only 4 (12.5%) had no actionable mutation. Six (19%) patients received a local regulatory agency approved drug recommendation, nine (28%) patients received an off-label approval treatment recommendation and three (9%) patients did not receive the treatment due to access and reimbursement of the drug. CONCLUSION: In most of the cases evaluated, the MTB was able to provide treatment recommendations based on targetable genetic alterations. Molecular-guided extended personalised patient care is effective for a small but clinically significant proportion of patients in challenging clinical situations. We believe that the implementation of a MTB is feasible in the Latin America (LATAM) region.

Opportunistic and Serious Infections in Patients with Neuroendocrine Tumors Treated with Everolimus: A Multicenter Study of Real-World Patients.

INTRODUCTION: The incidence of infections is poorly studied in patients with neuroendocrine tumors (NET) treated with everolimus outside of clinical trials. We aimed to evaluate the frequency of and risk factors for opportunistic infections (Opl) or any serious infection in eligible patients. METHODS: This was a retrospective multicenter study of a Latin American cohort of consecutive patients with advanced NET treated with everolimus. Duration of everolimus, comorbidities, Charlson comorbidity score, type of prior treatment, institution, and concurrent immunosuppressive conditions were tested for possible associations with serious (grade 3-5) infections in univariate and multivariable logistic regression models. RESULTS: One hundred eleven patients from 5 centers were included. The median duration of everolimus was 8.9 months. After a median follow-up of 32.9 months, 34 patients (30.6%; 95% CI 22.2-40.1) experienced infections of any grade, with 24 (21.6%; 95% CI 14.8-30.4) having a serious infection and 7 (6.3%; 95% CI 2.6-12.6) having at least 1 OpI (Candida sp., Toxoplasma gondi, Pneumocystis sp., Herpes sp., and Cryptococcus sp.). Four patients (3.6%) died from infections, but only 2 deaths (1.8%) were deemed to be related to everolimus. The multivariable analysis identified everolimus duration (every 6-month increase; OR = 1.28; 95% CI 1.02-1.60; p = 0.03) as an independent risk factor for serious infection. CONCLUSION: Infections are more frequent in NET patients using everolimus than previously reported in clinical trials. Patients on everolimus should be closely monitored for infections, especially those receiving it for several months.

Health resource utilisation by patients with neuroendocrine tumours with or without carcinoid heart disease: a multinational study.

BACKGROUND: Carcinoid heart disease (CHD) is a rare and severe complication from carcinoid syndrome which may be associated with high health resource utilisation (HRU). We aimed to compare HRU between patients with and without CHD. METHODS: Multicentre retrospective study of 137 consecutive patients with neuroendocrine tumours (NET) and elevated urinary 5-hydroxyindoleacetic acid treated in seven large hospitals in Latin America. We used the chi-squared test for binary variables and the Mann-Whitney test for quantitative correlations. Variables were entered into a multivariable linear regression model for higher HRU. RESULTS: One-third of the patients had (45) had CHD. Patients with CHD had significantly more emergency visits and echocardiograms as compared to patients without CHD. In the bivariate models, CHD (R2 = 0.61, p = 0.01), private health system (R 2 = 0.63, p = 0.02) and simultaneous cardiovascular comorbidities (R 2 = 0.61, p = 0.04) were associated with a higher HRU. The multivariate model pointed out the accumulated effect of variables on HRU (R 2 = 0.2, p < 0.01). CONCLUSIONS: NET patients with CHD present higher HRU independently of other clinical factors or health system. Effectively treating carcinoid syndrome, and likely delaying the onset of CHD, may potentially reduce the amount of HRU by these patients.

Peripheral changes in immune cell populations and soluble mediators after anti-PD-1 therapy in non-small cell lung cancer and renal cell carcinoma patients.

Patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline samples, discriminant analysis revealed a combination of four variables that helped differentiate stable disease-response (SD-R) from progressive disease (PD) patients: augmented frequency of central memory CD4+ T cells and leukocyte count was associated with response while increased percentage of PD-L1+ natural killer cells and naïve CD4+ T cells was associated with lack of response. After therapy, differential changes between responders and non-responders were found in leukocytes, T cells and TIM-3+ T cells. Patients with progressive disease showed an increase in the frequency of TIM-3 expressing CD4+ and CD8+ T cells, whereas SD-R patients showed a decrease in these subsets. Our findings indicate that a combination of immune variables from peripheral blood (PB) could be useful to distinguish response groups in NSCLC and RCC patients treated with anti-PD-1 therapy. Frequency of TIM-3+ T cells showed differential changes after treatment in PD vs SD-R patients, suggesting that it may be an interesting marker for monitoring progression during therapy.

Uso de inhibidores de tirosina quinasa en carcinoma medular de tiroides. Experiencia Institucional / Use of tyrosine kinase inhibitors in medullary thyroid carcinoma. Institutional Experience

El cáncer medular de tiroides (CMT) correspondeal 5% de los tumores de la glándula tiroides. El único tratamiento curativo es la cirugía. En pacientes con compromiso locorregional o a distancia, la enfermedad puede evolucionar en forma indolente o bien con una rápida progresión de síntomas, requiriendo tratamiento sistémico. Si bien el CMT se caracteriza por tener escasa respuesta a la quimioterapia (QT), la evidencia actual en estudios aleatorizados demostró que los inhibidores de tirosina quinasa (ITQ) han demostrado beneficio en supervivencia libre de progresión (SLP). Se analizaron 6 pacientes con un seguimiento mediano de 29 meses. Todos presentaron más de dos sitios metastásicos. Dos requirieron tratamientos locorregionales (quimioembolización y RT). Los ITQ más utilizados fueron: vandetanib (3), sorafenib (2) y sunitinib (1). Un 50% inició tratamiento con dosis plenas y 3 requirieron reducción de dosis debido a toxicidad G3-G4. El intervalo libre de progresión (ILP) mediano, luego del inicio con ITQ, fue de 4.1 meses (AU)

Medullary thyroid cancer (CMT) accounts for 5% of thyroid tumors. The only curative treatment is surgery. In patients with locally or distal involvement, the disease may evolve indolently or with rapid progression of symptoms, requiring systemic treatment. Although CMT is characterized by a poor response to chemotherapy, current evidence in randomized trials has shown that tyrosine kinase inhibitors (ITKs) have demonstrated benefit in progressionfree survival. Six patients with a median follow-up of 29 months were analyzed. All had more than two metastatic sites. Two patients required locoregional treatments (chemoembolization and radio therapy). The most commonly used ITKs were: vandetanib (3), sorafenib (2) and sunitinib (1). The 50% initiated treatment with full dose and 3 required reduction of the dose due to G3- G4 toxicity. The median progression-free interval after initiation with ITK was 4.1 months (AU)