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

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

Estudio prospectivo acerca de la precisión diagnóstica del test inmunológico de sangre oculta en materia fecal en una única ronda para la realización de pesquisa del cáncer colorrectal en pacientes de riesgo promedio en la Argentina / Prospective study on the diagnostic accuracy of the immunochemical fecal occult blood test in a single round for colorectal cancer screening in average risk patients in Argentina

Introducción: El cáncer colorrectal (CCR) es la segunda causa de muerte por cáncer en Argentina. Debido a su alta prevalencia es fundamental normatizar un programa de pesquisa para la prevención y detección temprana. La precisión del test de sangre oculta en materia fecal inmunológico (SOMFi) para pesquisa de CCR en población de riesgo promedio ha demostrado ser adecuada según la bibliografía internacional, no habiendo, sin embargo, información a nivel local. El objetivo es evaluar en nuestro medio la precisión diagnóstica del test de SOMFi en una única ronda para la pesquisa de CCR en pacientes de riesgo promedio. Diseño: Prospectivo de precisión diagnóstica. Material y Método: Se incluyeron pacientes con riesgo promedio que consultaron para realizar una videocolonoscopía (VCC) por pesquisa de CCR en el Hospital Alemán de Buenos Aires, entre el 1 de junio del 2015 y 31 diciembre de 2017. Se excluyeron todos los pacientes con riesgo incrementado para CCR. Todos los pacientes realizaron el test de SOMFi y posteriormente la VCC. Los endoscopistas estaban ciegos para el resultado del test al momento de realizar la VCC. Se evaluó la precisión diagnóstica del test SOMFi para detectar lesiones neoplásicas avanzadas (LNA) calculando la sensibilidad (S), especificidad (E), valor predictivo positivo (VVP) y negativo (VVN), coeficiente de probabilidad positivo (CP+) y negativo (CP-). Se evaluó también la precisión para la detección de adenomas de bajo riesgo, pólipos aserrados y CCR. Resultados: Se incluyeron un total de 300 pacientes; 273 (91%) entregaron la muestra de materia fecal para realizar el test de SOMFi y completaron la VCC. La edad media de los pacientes fue de 56.9 (40-85) años y 54% fueron hombres. Del total de pacientes que realizaron ambos estudios (273), 53 pacientes (19%) presentaron al menos un adenoma de bajo riesgo, en 18 pacientes (6,59%) observamos al menos un adenoma aserrado sésil y en 21 pacientes (7,7%) al menos una lesión neoplásica avanzada (LNA). Solo 4 pacientes (1.5%) presentaron CCR. En cuanto a la precisión diagnóstica del test de SOMFi en una única ronda para detectar LNA observamos una S de 30%, E de 84%, VPP de 13% y un VPN de 94%. Para adenomas de bajo riesgo observamos una S de 13%, E de 84%, VPP de 17%, VPN de 79%. Para adenomas aserrados sésiles observamos una S de 16.7%, E de 87%, VPP de 11% y de VPN 91%. La precisión para el CCR fue la siguiente, S de 75%, E de 83%, VPP 6%, VPN 99%. No se observaron complicaciones post procedimientos. Conclusiones: La precisión diagnóstica del test de SOMFi en nuestro medio es comparable a los resultados internacionales. Sin embargo, la baja precisión observada en una única ronda realza la necesidad de realizarlo de forma anual o bianual para poder optimizar su precisión y lograr programas de pesquisa efectivos.(AU)

Background: Colorectal cancer (CRC) is the second leading cause of cancer death in Argentina. Due to its high prevalence, it is essential to standardize a screening program for prevention and early detection. According to international literature, the accuracy of the immunochemical fecal occult blood test (FIT) for CRC screening in an average-risk population has proven to be adequate, but there is no information at the local level. Objective: To evaluate the diagnostic accuracy of the FIT test in a single round for CRC screening in average-risk patients in our setting. Design: Diagnostic accuracy prospective study. Material and Methods: Average-risk patients who consulted for a CRC screening video colonoscopy (VCC) at the Hospital Alemán of Buenos Aires, between June 1, 2015 and December 31, 2017 were included. All patients with increased risk for CRC were excluded. All patients performed FIT and subsequently VCC. The endoscopists were blind to FIT result at the time of VCC. The diagnostic accuracy of FIT to detect advanced neoplastic lesions (ANL) was evaluated by calculating sensitivity (S), specificity (Sp), positive predictive value (PPV), negative (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-). The accuracy for the detection of low-risk adenomas, serrated polyps and CRC was also evaluated. Results: A total of 300 patients were included; 273 (91%) submitted the stool sample to perform FIT and completed VCC. The mean age of patients was 56.9 (40-85) years and 54% were men. Of the total number of patients who carried out both studies (273), 53 (19%) patients had at least one low-risk adenoma, 18 (6.59%) patients had at least one sessile serrated adenoma and 21 (7.7%) patients had at least one ANL. Only 4 (1.5%) patients presented CRC. The diagnostic accuracy of FIT in a single round to detect ANL was: S 30%, Sp 84%, PPV 13%, NPV 94%; for low-risk adenomas: S 13%, Sp 84%, PPV 17%, NPV 79%; for sessile serrated adenomas: S 16.7%, Sp 87%, PPV 11%, NPV 91% and for CRC: S 75%, Sp 83%, PPV 6%, NPV 99%. No post-procedure complications were observed. Conclusions: The diagnostic accuracy of FIT in our setting is comparable to international results. However, the low precision observed in a single round highlights the need to do it annually or biannually in order to optimize its accuracy and achieve effective screening programs. (AU)

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

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

Proctitis infecciosa por Chlamydia Trachomatis / Infectious proctitis by Chlamydia Trachomatis

Introducción: Las infecciones transmisibles sexualmente (ITS) son motivo de consulta frecuente, encontrándose Chlamydia trachomatis (CT) entre las prevalentes. Este germen provoca proctitis de diversa gravedad según el biovar involucrado. Los casos más floridos suelen ser ocasionados por el biovar LGV, responsable de la entidad linfogranuloma venéreo. Se desconocen la prevalencia de CT como causa de proctitis en Argentina y los biovares implicados. Con el objetivo de estudiar estas variables, se diseñó un protocolo para detectar y genotipificar CT en pacientes con proctitis infecciosa. Pacientes y métodos: Se incluyeron pacientes mayores de 18 años con cuadro de proctitis infecciosa atendidos en un centro público y otro privado. Se excluyeron pacientes con enfermedad inflamatoria intestinal y radioterapia pelviana. El estudio fue aprobado por un Comité de Ética y los pacientes firmaron un consentimiento informado. En las muestras de hisopado anal se realizó detección y tipificación molecular de CT. Resultados: Entre 31de agosto de 2017 y 31 de mayo de 2018, se incluyeron 56 pacientes (1 mujer, 53 hombres, 2 mujeres trans), 79% HIV+. En 29 casos (52%) se detectó CT. Todos eran hombres que tienen sexo con hombres (HSH) y refirieron practicar sexo anal u oral receptivo no protegido. La mediana de edad de este subgrupo fue de 31 años; 83% HIV+ en tratamiento antirretroviral y mediana de CD4 637 cel/mm3. La coinfección con otras ITS fue del 41% (siendo las más frecuentes HPV, gonococia y sífilis). Los motivos de consulta más frecuentes fueron proctorragia, pujo y tenesmo, proctalgia y secreción. Las manifestaciones clínicas fueron variadas: proctitis, úlcera perianal, tumor endoanal/rectal y absceso/fístula. El 86% de las proctitis correspondió al biovar LGV, siendo 62% moderadas a graves. La mediana de tiempo de evolución hasta el diagnóstico fue 21 días. Los casos más prolongados correspondieron a cuadros clínicos y endoscópicos más graves. La duración del tratamiento se adecuó al biovar involucrado. Todos los pacientes respondieron favorablemente; sin embargo, las dos fístulas perianales requirieron resolución quirúrgica. Conclusiones: Proctitis, úlceras y fístulas son manifestaciones inespecíficas; el hallazgo clínico y endoscópico per se no son suficientes para definir la etiología; sólo una anamnesis minuciosa permite presumir una ITS como agente causal. La tipificación logra definir el biovar, dato fundamental para adecuar el tratamiento, cortar la cadena de transmisión y contar con datos epidemiológicos a nivel local. Como resultado de esta investigación, el Ministerio de Salud de Nación proyectó la emisión de una alerta sobre la presencia de LGV en nuestro medio. Tipo de estudio: Observacional, transversal, analítico, multicéntrico.

Introduction: Sexually transmitted infections (STI) are a frequent reason for consultation, being Chlamydia trachomatis (CT) among the most prevalent ones. It causes proctitis of varying severity depending on the biovar involved. The most severe cases are usually caused by the LGV biovar, responsible for the entity called lymphogranuloma venereum. The prevalence of CT as a cause of proctitis in Argentina and the biovars involved are unknown. In order to study these variables, a protocol was designed to detect and genotype CT in patients with infectious proctitis. Patients and methods: Patients over 18 years old with infectious proctitis were attended in a public and private center. Patients with inflammatory bowel disease and pelvic radiation therapy were excluded. The study was approved by an Ethics Committee and the patients signed an informed consent. The detection and molecular typing of CT was performed in anal swab samples. Results: Between 31-08-2017 and 31-05-2018, 56 patients were included (1 woman, 53 men, 2 trans women), 79% HIV +. In 29 cases (52%) CT was detected. All were MSM and reported to practice unprotected receptive oral or anal sex. The median age of this subgroup was 31 years; 83% HIV + on antiretroviral treatment and median CD4 637 cel / mm3. The coinfection with other STIs was present 41% (the most frequent were HPV, gonococcal and syphilis). The most frequent symptoms were bleeding, tenesmus, proctalgia and secretion. The clinical manifestations were varied: proctitis, perianal ulcer, endoanal / rectal tumor and abscess / anal fistula. 86% of the proctitis corresponded to the LGV biovar, being 62% moderate to severe. The median time of evolution until the diagnosis was 21 days. The most prolonged cases corresponded to more severe clinical and endoscopic symptoms. The duration of the treatment was adapted to the biovar involved. All patients responded favorably; however, the two perianal fistulas required surgical resolution. Conclusions: Proctitis, ulcers and fistulas are nonspecific manifestations; the clinical and endoscopic findings per se are not sufficient to define the etiology; only a meticulous anamnesis allows us to presume an STI as a causative agent. The typification allows to define the biovar, a fundamental data to adapt the treatment, stop chain of transmission and provides local epidemiological data. As a result of this investigation, the Ministry of Health of the Argentina issued an alert about the presence of LGV in our country. Type of study: Observational, cross-sectional, analytical, multicenter study.

[Sacral neuromodulation. Long-term results]. / Neuromodulación. sacra. Resultados a largo plazo.

Sacral neuromodulation involves electrical stimulation of af­ferent nerve roots to restore the balance between inhibitory and excitatory reflexes who improve the functional activity of the pelvic floor. With benefits in patients with fecal inconti­nence, constipation and chronic anorectal pain. Objective. The aim of this study is present the results obtained with sacral neuromodulation for the treatment of patients with fecal incontinence, severe and intractable chronic constipa­tion and chronic anorectal pain. Patients and methods. 33 patients had indication for transitory electrical sacral stimu­lation, 25 patients performed transitory electrical stimula­tion for fecal incontinence, 5 with refractary constipation and 3 with chronic anorectal pain. In cases of fecal inconti­nence, the patients performed previous anorectal manometry and ultrasonography examination of anal sphincters. When the constipation is the indication, we performed stimulation in patients with severe and refractary constipation like step before total colectomy. In cases of chronic anorectal pain, the electrical transitory test was performed according to our treatment algorithm for management of functional anorectal pain. In all cases, if the patients had satisfactory results after 2 weeks period the definitive implant was placed. Results. Mean follow-up was 69 months (range 6-130). Definitve implant was placed for treatment of fecal incontinence in 23 patients with a decrease in fecal incontinence scores in 98%, with an average success rate of 66% (range: 45-92). In cases of constipation, 3 definitive implants were placed, the mean follow-up was 77 months (range: 51-96) with a success rate between 50%-80% as measured by bowel frequency. We performed definitive electrical stimulation in 3 patients wit chronic and intractable anorectal pain. Response rates as measured by visual analog scale were between 40%-70%. Conclusions. Sacral neuromodulation is an area in constant growth, with more indications. The success depends on the correct indication and the patients need to be treated with other therapeutic options before sacral neuromodulation.

[Perianal Kaposi's sarcoma. A case report and a review of the literature]. / Sarcoma de Kaposi perianal. Presentación de un caso y revisión de la literatura.

Kaposi's sarcoma is the most common cancer in men who have sex with men with AIDS. The estimated prevalence in the United States is 25% in patients with positive serology for the human immunodeficiency virus (HIV). The commitment of the gastrointestinal tract is seen in 40% of patients with Kaposi's sarcoma related to AIDS but lesions can occur anywhere in the body and evolve rapidly. We present a 33-year-old patient who kept sex with men, with epidemiological history of hepatitis B and syphilis, who consulted the service of Coloproctology for perianal ulcer. He was studied according to the protocols of sexually transmitted diseases, was diagnosed HIV and an excision biopsy of the lesion was performed. The diagnosis of perianal Kaposi's sarcoma was reached. Kaposi's sarcoma-HIV was staged, no other lesions were found and the patient started antiretrovirals with poor response to therapy. He evolved with rapid progression of the disease and died with the presumptive diagnosis of Fournier's syndrome at three months after the excision biopsy. We conclude that perianal ulcers are a relatively common pathology in the office of Coloproctology and differential diagnosis are different according to the positivity for HIV or not and the patient's sexual practices. We consider that is important to publish and spread these cases.

Sarcoma de Kaposi perianal. Presentación de un caso y revisión de la literatura / [Perianal Kaposi’s sarcoma. A case report and a review of the literature].

Kaposi’s sarcoma is the most common cancer in men who have sex with men with AIDS. The estimated prevalence in the United States is 25

in patients with positive serology for the human immunodeficiency virus (HIV). The commitment of the gastrointestinal tract is seen in 40

of patients with Kaposi’s sarcoma related to AIDS but lesions can occur anywhere in the body and evolve rapidly. We present a 33-year-old patient who kept sex with men, with epidemiological history of hepatitis B and syphilis, who consulted the service of Coloproctology for perianal ulcer. He was studied according to the protocols of sexually transmitted diseases, was diagnosed HIV and an excision biopsy of the lesion was performed. The diagnosis of perianal Kaposi’s sarcoma was reached. Kaposi’s sarcoma-HIV was staged, no other lesions were found and the patient started antiretrovirals with poor response to therapy. He evolved with rapid progression of the disease and died with the presumptive diagnosis of Fournier’s syndrome at three months after the excision biopsy. We conclude that perianal ulcers are a relatively common pathology in the office of Coloproctology and differential diagnosis are different according to the positivity for HIV or not and the patient’s sexual practices. We consider that is important to publish and spread these cases.

Sarcoma de Kaposi perianal. Presentación de un caso y revisión de la literatura. / [Perianal Kaposis sarcoma. A case report and a review of the literature].

Kaposis sarcoma is the most common cancer in men who have sex with men with AIDS. The estimated prevalence in the United States is 25

in patients with positive serology for the human immunodeficiency virus (HIV). The commitment of the gastrointestinal tract is seen in 40

of patients with Kaposis sarcoma related to AIDS but lesions can occur anywhere in the body and evolve rapidly. We present a 33-year-old patient who kept sex with men, with epidemiological history of hepatitis B and syphilis, who consulted the service of Coloproctology for perianal ulcer. He was studied according to the protocols of sexually transmitted diseases, was diagnosed HIV and an excision biopsy of the lesion was performed. The diagnosis of perianal Kaposis sarcoma was reached. Kaposis sarcoma-HIV was staged, no other lesions were found and the patient started antiretrovirals with poor response to therapy. He evolved with rapid progression of the disease and died with the presumptive diagnosis of Fourniers syndrome at three months after the excision biopsy. We conclude that perianal ulcers are a relatively common pathology in the office of Coloproctology and differential diagnosis are different according to the positivity for HIV or not and the patients sexual practices. We consider that is important to publish and spread these cases.