Socioeconomic Disparities in Anal Cancer: Effect on Treatment Delay and Survival.

BACKGROUND: Socioeconomic inequities have implications for access to health care and may be associated with disparities in treatment and survival. OBJECTIVE: To investigate the impact of socioeconomic inequities on time to treatment and survival of anal squamous-cell carcinoma. DESIGN: This is a retrospective study using a nationwide data set. SETTINGS: The patients were selected from the National Cancer Database and enrolled from 2004 to 2016. PATIENTS: We identified patients with stage I to III squamous-cell carcinoma of the anus who were treated with chemoradiation therapy. MAIN OUTCOMES MEASURES: Socioeconomic factors, including race, insurance status, median household income, and percentage of the population with no high school degrees, were included. The association of these factors with treatment delay and overall survival was investigated. RESULTS: A total of 24,143 patients who underwent treatment for grade I to III squamous-cell carcinoma of the anus were identified. The median age was 60 years, and 70% of patients were women. The median time to initiation of treatment was 33 days. Patients from zip codes with lower median income, patients with a higher percentage of no high school degree, and patients with other government insurance followed by Medicaid insurance had treatment initiated after 60 days from diagnosis. Kaplan-Meier survival analysis showed that the late-treatment group had worse overall survival compared to the early treatment group (98 vs 125 months; p < 0.001). LIMITATIONS: No detailed information is available about the chemoradiotherapy regimen, completion of treatment, recurrence, disease-free survival, and individual-level socioeconomic condition and risk factors. CONCLUSION: Patients from communities with lower median income, level of education, and enrolled in public insurance had longer time to treatment. Lower socioeconomic status was also associated with poorer overall survival. These results warrant further analysis and measures to improve access to care to address this disparity. See Video Abstract . DESIGUALDADES SOCIOECONMICAS EN CASOS DE CNCER ANAL EFECTOS EN EL RETRASO DEL TRATAMIENTO Y LA SOBREVIDA: ANTECEDENTES:Las desigualdades socio-económicas tienen implicaciones en el acceso a la atención médica y pueden estar asociadas con disparidades en el tratamiento y la sobrevida.OBJETIVO:Indagar el impacto de las desigualdades socio-económicas sobre el tiempo de retraso en el tratamiento y la sobrevida en casos de carcinoma a células escamosas del ano (CCEA).DISEÑO:Estudio retrospectivo utilizando un conjunto de datos a nivel nacional.AJUSTES:Todos aquellos pacientes inscritos entre 2004 a 2016 y que fueron seleccionados de la Base Nacional de Datos sobre el Cáncer.PACIENTES:Identificamos pacientes con CCEA en estadíos I-III y que fueron tratados con radio-quimioterápia.PRINCIPALES MEDIDAS DE RESULTADOS:Se incluyeron factores socio-económicos tales como la raza, el tipo de seguro de salud, el ingreso familiar medio y el porcentaje de personas sin bachillerato de secundaria (SBS). Se investigó la asociación entre estos factores con el retraso en iniciar el tratamiento y la sobrevida global.RESULTADOS:Se identificaron un total de 24.143 pacientes que recibieron tratamiento para CCEA estadíos I-III. La mediana de edad fue de 60 años donde 70% eran de sexo femenino. La mediana del tiempo transcurrido desde el diagnóstico hasta el inicio del tratamiento fue de 33 días. Los pacientes residentes en zonas de código postal con ingresos medios más bajos, con un mayor porcentaje de individuos SBS y los pacientes con otro tipo de seguro gubernamental de salud, seguidos del seguro tipo Medicaid iniciaron el tratamiento solamente después de 60 días al diagnóstico inicial de CCEA. El análisis de Kaplan-Meier de la sobrevida mostró que el grupo de tratamiento tardío tuvo una peor supervivencia general comparada con el grupo de tratamiento precoz o temprano (98 frente a 125 meses; p <0,001).LIMITACIONES:No se dispone de información detallada sobre el tipo de radio-quimioterapia utilizada, ni sobre la finalización del tratamiento o la recurrencia, tampoco acerca de la sobrevida libre de enfermedad ni sobre las condiciones socio-económicas o aquellos factores de riesgo a nivel individual.CONCLUSIÓN:Los pacientes de comunidades con ingresos medios más bajos, con un nivel de educación limitado e inscritos en un seguro público tardaron mucho más tiempo en recibir el tratamiento prescrito. El nivel socio-económico más bajo también se asoció con una sobrevida global más baja. Los presentes resultados justifican mayor análisis y medidas mas importantes para mejorar el acceso a la atención en salud y poder afrontar esta disparidad. (Traducción-Dr. Xavier Delgadillo ).

Serum Depletion of Complement Component 5a Is Associated With Increased Inflammation and Poor Clinical Outcomes in Patients With Perianal Fistulas.

BACKGROUND: Persistent disease is a significant issue in the management of perianal fistulas, with up to 50% of patients requiring additional treatment after surgery. OBJECTIVE: This study aimed to identify a novel prognostic modality in hopes of risk-stratifying patients for persistent disease following corrective surgery. DESIGN: This was a retrospective study based on prospectively collected data using a combination of histopathology, high-throughput proteomic arrays, and ELISA-based methods. SETTINGS: This study used data obtained from patients who underwent corrective surgery for perianal fistulas at the University of Illinois Hospital between June 2019 and July 2020. PATIENTS: A cohort of 22 consecutive patients who had corrective surgery for perianal fistulas were included in this study. The patients were divided into 2 groups: those with resolving fistulas (N = 13) and those with persisting fistulas (N = 9). MAIN OUTCOME MEASURES: Nonresolving fistulas were determined by disease representation within 2 months of corrective surgery. RESULTS: Serum samples from patients with persistent perianal fistulas displayed a consistent decrease in the expression of complement pathway component C5a compared with either healthy controls or patients with resolving forms of disease. This was paralleled by an increase in the fistula expression of C5a and an associated increase in tissue infiltrating leukocytes and interleukin-1ß expression. LIMITATIONS: This study was limited by its retrospective design, relatively small sample size, and single-center data analysis. CONCLUSIONS: These results suggest that C5a is modestly depleted in patients with nonresolving forms of disease and traffics to the site of tissue damage and inflammation. Accordingly, serum C5a warrants continued investigation as a prognostic biomarker and predictor of recurrence in patients presenting with perianal fistulas. See Video Abstract at http://links.lww.com/DCR/B982 . LA DEPLECIN SRICA DEL COMPONENTE A DEL COMPLEMENTO SE ASOCIA CON UN AUMENTO DE LA INFLAMACIN Y MALOS RESULTADOS CLNICOS EN PACIENTES CON FSTULAS PERIANALES: ANTECEDENTES:La persistencia de la enfermedad es un problema significativo en el manejo de las fístulas perianales, presente hasta en el 50 % de los pacientes después de la cirugía y que requieren tratamiento adicional.OBJETIVO:DISEÑO:Se trata de un estudio retrospectivo basado en datos recolectados prospectivamente usando una combinación de histopatología, arreglos proteómicos de alto rendimiento y métodos basados en ELISA.ENTORNO CLÍNICO:Este estudio utilizó datos de pacientes que se sometieron a cirugía correctiva por fístulas perianales en el Hospital de la Universidad de Illinois entre junio de 2019 y julio de 2020.PACIENTES:Se incluyó en este estudio una cohorte de 22 pacientes consecutivos que se sometieron a cirugía correctiva de fístulas perianales. Los pacientes se dividieron en 2 grupos: aquellos con fístulas en resolución (N = 13) y aquellos con fístulas persistentes (N = 9).PRINCIPALES MEDIDAS DE VALORACIÓN:Las fístulas que no se resuelven fueron determinadas por la reaparición de la enfermedad dentro de los 2 meses posteriores a la cirugía correctiva.RESULTADOS:Las muestras de suero de pacientes con fístulas perianales persistentes mostraron una disminución constante en la expresión del componente C5a de la vía del complemento en comparación con controles sanos o pacientes con formas de resolución de la enfermedad. Esto fue paralelo a un aumento en la expresión de C5a en la fístula y un aumento asociado en los leucocitos que se infiltran en el tejido y la expresión de IL-1ß.LIMITACIONES:El estudio estuvo limitado por su diseño retrospectivo, tamaño de muestra relativamente pequeño y análisis de datos de un solo centro.CONCLUSIONES:Estos resultados sugieren que C5a se reduce moderadamente en pacientes con formas de enfermedad que no se resuelven y se desplaza al sitio del daño tisular e inflamación. En consecuencia, el C5a sérico justifica una investigación continua como biomarcador pronóstico y predictor de recurrencia en pacientes que presentan fístulas perianales. Consulte Video Resumen en http://links.lww.com/DCR/B982 . (Traducción- Dr. Ingrid Melo ).

Outcomes of perineal wound closure techniques after abdominoperineal resections in rectal cancer: an NSQIP propensity score matched study.

Perineal defects following abdominoperineal resections (APRs) for rectal cancer may require myocutaneous or omental flaps depending upon anatomic, clinical and oncologic variables. However, studies comparing their efficacy have shown contradictory results. We aim to compare postoperative complication rates of APR closure techniques in rectal cancer using propensity score-matching. The American College of Surgeons Proctectomy Targeted Data File was queried from 2016 to 2019. The study population was defined using CPT and ICD-10 codes for patients with rectal cancer undergoing APR, stratified by repair technique. Perioperative demographic and oncologic variables were controlled for by propensity-score matching. Multivariate logistic regression analysis was performed for wound and major complications (MCs). Of the 3291 patients included in the study, 85% underwent primary closure (PC), 8.3% rectus abdominis myocutaneous (RAM) flap, 4.9% pedicled omental flap with PC, and 1.9% lower extremity (LE) flap repair. Primary closure rates were significantly higher for patients with stage T1 and T2 tumors (p < 0.001). RAM and LE flaps were most used with multi-organ resections, 24% and 25%, respectively (p < 0.001). Similarly, cases with T4 tumors used these flaps more frequently, 30% and 40%, respectively (p < 0.001). After propensity score matching for comorbidities and oncologic variables, there was no significant difference in 30-day postoperative wound or MC rates between perineal closure techniques. The complication rates of the different closure techniques are comparable when tumor stage is considered. Therefore, tumor staging and concurrent procedures should guide clinical decision making regarding the appropriate use of each technique.

Plasmablastic Lymphoma Presenting With Rectosigmoid Perforation in a Human Immunodeficiency Virus-Positive Patient.

Plasmablastic lymphoma (PBL) is a rare variant of diffuse large B-cell lymphoma (DLBCL) associated with human immunodeficiency virus (HIV)-positive patients. It accounts for only 2% of all acquired immune deficiency syndrome (AIDS)-related lymphomas (ARLs). We present the case of a 45-year-old male who presented to the emergency department (ED) with a three-month history of abdominal pain, diarrhea, and unintentional 50-lb weight loss. On an earlier presentation to the ED three months prior, the patient was diagnosed with norovirus and Helicobacter pylori infection and received outpatient treatment without resolution of his symptoms. This prompted further investigation with a CT of the abdomen and pelvis with IV contrast that revealed severe sigmoid colitis with pneumoperitoneum and a pericolonic air-containing fluid collection, consistent with a contained perforation with abscess formation. He was admitted, resuscitated, and initially treated with antibiotics and parenteral nutrition. The patient underwent a laparoscopic converted to open anterior resection with end colostomy. Pathology revealed HIV-related PBL. He was subsequently treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) chemotherapy regimen and an autologous stem cell transplant. Despite its rare association with HIV, PBL should be considered a differential diagnosis for HIV-positive patients who present with gastrointestinal (GI) pathology, and additional investigations should be conducted if symptoms do not resolve despite appropriate medical management at the time.

Leukocyte subtyping predicts for treatment failure and poor survival in anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma (SCC) generally carries a favorable prognosis, as most tumors are highly sensitive to standard of care chemoradiation. However, outcomes are poor for the 20-30% of patients who are refractory to this approach, and many will require additional invasive procedures with no guarantee of disease resolution. METHODS: To identify the patients who are unlikely to respond to the current standard of care chemoradiation protocol, we explored a variety of objective clinical findings as a potential predictor of treatment failure and/or mortality in a single center retrospective study of 42 patients with anal SCC. RESULTS: Patients with an increase in total peripheral white blood cells (WBC) and/or neutrophils (ANC) had comparatively poor clinical outcomes, with increased rates of death and treatment failure, respectively. Using pre-treatment biopsies from 27 patients, tumors with an inflamed, neutrophil dominant stroma also had poor therapeutic responses, as well as reduced overall and disease-specific survival. Following chemoradiation, we observed uniform reductions in nearly all peripheral blood leukocyte subtypes, and no association between peripheral white blood cells and/or neutrophils and clinical outcomes. Additionally, post-treatment biopsies were available from 13 patients. In post-treatment specimens, patients with an inflamed tumor stroma now demonstrated improved overall and disease-specific survival, particularly those with robust T-cell infiltration. CONCLUSIONS: Combined, these results suggest that routinely performed leukocyte subtyping may have utility in risk stratifying patients for treatment failure in anal SCC. Specifically, pre-treatment patients with a high WBC, ANC, and/or a neutrophil-dense tumor stroma may be less likely to achieve complete response using the standard of care chemoradiation regimen, and may benefit from the addition of a subsequent line of therapy.

Management of colorectal cancer during the COVID-19 pandemic: Recommendations from a statewide multidisciplinary cancer collaborative.

COVID-19 has resulted in significant disruptions in cancer care. The Illinois Cancer Collaborative (ILCC), a statewide multidisciplinary cancer collaborative, has developed expert recommendations for triage and management of colorectal cancer when disruptions occur in usual care. Such recommendations would be applicable to future outbreaks of COVID-19 or other large-scale disruptions in cancer care.

Open vs Minimally Invasive Approach for Emergent Colectomy in Perforated Diverticulitis.

BACKGROUND: Traditionally, perforated diverticulitis has been managed with an open approach, with a Hartmann procedure or a colectomy with primary anastomosis. Minimally invasive surgery is associated with postoperative advantages in the elective setting and may show a benefit in the emergent setting. OBJECTIVE: The aim of this study was to compare postoperative outcomes of open vs minimally invasive approaches for emergent perforated diverticulitis. DESIGN: This was a retrospective review of the American College of Surgeons National Surgical Quality Improvement Program targeted colectomy database using propensity score matching. SETTINGS: Interventions were performed in hospitals participating in the national database. PATIENTS: Patients who underwent emergent colectomy from 2012 to 2017 were included. Procedures were divided into Hartmann procedure and primary anastomosis. Open vs minimally invasive groups were defined by intention to treat. MAIN OUTCOME MEASURES: Outcomes measures included length of stay and overall morbidity and mortality. RESULTS: Of 130,616 patients, 7105 met inclusion criteria (4486 Hartmann procedure and 2619 primary anastomosis). A total of 1989 open Hartmann procedure cases were matched to 663 minimally invasive cases. The minimally invasive group underwent longer operations and had lower rates of respiratory failure. There were no differences in overall complications, mortality, length of stay, or home discharge. In the primary anastomosis group, 1027 cases were matched 1:1. The minimally invasive approach was associated with longer operative times, but reduced wound dehiscence, sepsis, bleeding, overall complications, and length of stay. No difference was detected in anastomotic leak, mortality, reoperation, or readmission rates. LIMITATIONS: Limitations include retrospective nature, data loss, nonuniformity, selection bias, and coding errors. CONCLUSIONS: Emergent minimally invasive primary anastomosis results in a shorter length of stay and decreased 30-day morbidity in comparison with open primary anastomosis for perforated diverticulitis. Emergent open and minimally invasive Hartmann procedures for perforated diverticulitis have comparable outcomes, perhaps because of a 40% conversion rate. See Video Abstract at http://links.lww.com/DCR/B421. ABORDAJE ABIERTO VERSUS MNIMAMENTE INVASIVO PARA COLECTOMA DE EMERGENCIA EN DIVERTICULITIS PERFORADA: ANTECEDENTES:Tradicionalmente, la diverticulitis perforada se ha tratado con un abordaje abierto, con un procedimiento de Hartmann o una colectomía con anastomosis primaria. La cirugía mínimamente invasiva se asocia con ventajas posoperatorias en el escenario electivo y puede mostrar beneficio en el escenario emergente.OBJETIVO:El objetivo de este estudio fue comparar los resultados posoperatorios del abordaje abierto versus el mínimamente invasivo para la diverticulitis perforada emergente.DISEÑO:Ésta fue una revisión retrospectiva de la base de datos de colectomía dirigida del Programa Nacional de Mejoramiento de la Calidad Quirúrgica del Colegio Americano de Cirujanos utilizando el pareamiento por puntaje de propensión.ESCENARIO:Las intervenciones se realizaron en los hospitales participantes en la base de datos nacional.PACIENTES:Se incluyeron pacientes que fueron sometidos a colectomía emergente de 2012 a 2017. Los procedimientos se dividieron en procedimiento de Hartmann y anastomosis primaria. Los grupos abierto versus mínimamente invasivo se definieron por intención de tratar.PRINCIPALES MEDIDAS DE RESULTADO:Las medidas de resultado incluyeron la duración de la estancia, la morbilidad general y la mortalidad.RESULTADOS:De 130,616 pacientes, 7,105 cumplieron los criterios de inclusión (4,486 procedimiento de Hartmann y 2,619 anastomosis primaria). 1,989 casos abiertos de procedimientos de Hartmann se emparejaron con 663 casos mínimamente invasivos. El grupo mínimamente invasivo se sometió a operaciones más prolongadas y tuvo tasas más bajas de insuficiencia respiratoria. No hubo diferencias en las complicaciones generales, la mortalidad, la duración de la estancia o el alta domiciliaria. En el grupo de anastomosis primaria, 1,027 casos se emparejaron 1: 1. El abordaje mínimamente invasivo se asoció con tiempos quirúrgicos más prolongados, pero también con tasas reducidas de dehiscencia de herida, sepsis, sangrado, complicaciones generales y la duración de la estancia. No se detectaron diferencias en las tasas de fuga anastomótica, mortalidad, reintervención o reingreso.LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva, pérdida de datos, falta de uniformidad, sesgo de selección y errores de codificación.CONCLUSIONES:La anastomosis primaria mínimamente invasiva emergente resulta en una estancia más corta y una disminución de la morbilidad a los 30 días en comparación con la anastomosis primaria abierta para la diverticulitis perforada. El procedimiento de Hartmann abierto y mínimamente invasivo de emergencia para la diverticulitis perforada tiene resultados comparables, quizás debido a una tasa de conversión del 40%. Consulte el Video Resumen en http://links.lww.com/DCR/B421.

Evaluation of a Minimally Invasive Bipolar Coagulation System for the Treatment of Grade I and II Internal Hemorrhoids.

BACKGROUND: Hemorrhoids are common and affect mainly the young and middle-aged populations. Current guidelines recommend treating grade I and II hemorrhoids with office-based procedures. These therapies usually require multiple applications. Hemorrhoid energy therapy treats the hemorrhoids at 1 treatment session. OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of hemorrhoid energy therapy. DESIGN: This was a prospective pilot study evaluating patients with symptomatic grade I and II internal hemorrhoids. SETTINGS: The study was conducted at a tertiary academic center. PATIENTS: Patients over the age of 18 years with chronic, symptomatic grade I and II internal hemorrhoids who failed 2 weeks of conservative therapy were enrolled between July 2015 and January 2019. Exclusion criteria included patients with grade III or IV internal hemorrhoids, external hemorrhoids, nonhemorrhoidal GI bleeding, active proctitis, and IBD. INTERVENTIONS: Hemorrhoid energy therapy was administered in clinic, and 2 postprocedure visits were completed. A pretreatment hemorrhoid symptom score was obtained from each patient. A visual analog score was assessed posttreatment. MAIN OUTCOME MEASURES: The primary end point was to evaluate the effect of hemorrhoid energy therapy on hemorrhoid symptoms and its safety. The secondary end point was evaluation of postprocedural pain. RESULTS: A total of 35 patients were enrolled. The mean duration of hemorrhoid symptoms was 3.3 ± 6.4 years, and rectal bleeding and hemorrhoidal prolapse were the most common symptoms. After the procedure, patient hemorrhoid symptom scores decreased from mean 5.5 to 1.4. The mean immediate postprocedural visual analog score was 2.4 ± 2.1 and decreased to <1.0 after 14 days. LIMITATIONS: The limitations include lack of comparative groups, single-center design, and small cohort of patients. CONCLUSIONS: The application of hemorrhoid energy therapy in the treatment of grade I and II internal hemorrhoids is safe and results in reduction of symptoms, low rate of short-term complications, and minimal pain. See Video Abstract at http://links.lww.com/DCR/B491. EVALUACIÓN DE UN SISTEMA DE COAGULACIÓN BIPOLAR MÍNI-INVASIVA PARA EL TRATAMIENTO DE HEMORROIDES INTERNAS GRADOS I Y II: La enfermedad hemorroidal es muy común y afecta principalmente poblaciones jóvenes y de mediana edad. Las guías actuales recomiendan tratar las hemorroides de grado I y II con procedimientos en el consultorio. Estos tratamientos suelen requerir múltiples aplicaciones. La aplicación de energía para tratar las hemorroides requiere de una sola sesión.Evaluar la seguridad y eficacia del tratamiento hemorroidal con una fuente de energía.Estudio piloto prospectivo que evalúa los pacientes con hemorroides internas de grado I y II sintomáticas.El estudio se realizó en un centro académico terciario.Entre julio de 2015 y enero de 2019 se inscribieron pacientes mayores de 18 años con hemorroides intomáticas internas crónicas grado I y II que fracasaron luego de 2 semanas de tratameinto conservador. Los criterios de exclusión incluyeron pacientes con hemorroides internas de grado III o IV, hemorroides externas, sangrado de orígen gastrointestinal no hemorroidal, proctitis activa y enfermedad inflamatoria intestinal.Se realizó la aplicación de energía sobre las hemorroides en el consultorio y se completó el procedimiento con dos visitas posteriores. Se obtuvo una puntuación analógica de síntomas hemorroidarios en cada paciente antes del tratamiento. Se evaluó la puntuación analógica visual luego del procedimiento.El principal criterio final fué evaluar el efecto de la terapia energética hemorroidaria con relación a los síntomas y la seguridad del dispositivo. El segundo criterio final fué el evaluar el dolor posoperatorio.Se registraron un total de 35 pacientes. La duración media de los síntomas hemorroidarios fué de 3,3 ± 6,4 años, el sangrado rectal y el prolapso hemorroidal fueron los síntomas más frecuentes. Después del procedimiento, las puntuaciones de los síntomas hemorroidarios disminuyeron en una media de 5,5 a 1,4. La puntuación analógica visual media inmediatamente posterior al procedimiento fue de 2,4 ± 2,1 y disminuyó a <1 después de 14 días.Las limitaciones incluyen la falta de grupos comparativos, el diseño de un solo centro y una pequeña cohorte de pacientes.La aplicación de energía como tratamiento de la enfermedad hemorroidal interna grado I y II es segura y da como resultados la reducción de los síntomas, una baja tasa de complicaciones a corto plazo y mínimo dolor. Consulte Video Resumen en http://links.lww.com/DCR/B491. (Traducción-Dr Xavier Delgadillo).

Robotic Combined Anterior & Posterior Repair of a Rectal Prolapse, Rectocele, and Sigmoidocele with a Mesh.

Rectal prolapse (RP) is often seen in patients over the age of fifty, particularly women. These patients frequently suffer from other concomitant pathologies like rectocele, sigmoidocele, cystocele, or even enterocele. Rectopexy with a mesh has been an established treatment for rectal prolapse. The utilization of the robotic system allows for a successful repair within a confined pelvic space, especially for precise suture placement when working with the mesh. A 77-year-old female presented with obstructed defecation syndrome (ODS) symptoms found to be caused by a progressive rectal prolapse. Her pre-operative ODS score was 9/20. Pelvic floor evaluation revealed concomitant rectocele and sigmoidocele. The patient was offered a robotic-assisted rectopexy with mesh placement to address the three concomitant pathologies. During the procedure, a posterior mesorectal mobilization with autonomic nerves preservation was performed to address the posterior leading edge of the prolapse. Subsequently, the vagina was separated from the anterior portion of the rectum and dissected down to the levator ani muscles and the perineal body. This allowed for the affixation of a polypropylene mesh to the anterior portion of the rectum. Anterior suspension of the mobilized rectum with the mesh addressed all three pathologies. No recurrence or complications occurred at two-year follow up. The patients ODS score decreased to 1/20.

Poly(ADP-Ribose) Polymerase Inhibition Sensitizes Colorectal Cancer-Initiating Cells to Chemotherapy.

Colorectal cancer (CRC) remains a leading killer in the U.S. with resistance to treatment as the largest hurdle to cure. Colorectal cancer-initiating cells (CICs) are a self-renewing tumor population that contribute to tumor relapse. Here, we report that patient-derived CICs display relative chemoresistance compared with differentiated progeny. In contrast, conventional cell lines failed model therapeutic resistance. CICs preferentially repaired chemotherapy-induced DNA breaks, prompting us to interrogate DNA damage pathways against which pharmacologic inhibitors have been developed. We found that CICs critically depended on the key single-strand break repair mediator, poly(ADP-ribose) polymerase (PARP), to survive treatment with standard-of-care chemotherapy. Small molecule PARP inhibitors (PARPi) sensitized CICs to chemotherapy and reduced chemotherapy-treated CIC viability, self-renewal, and DNA damage repair. Although PARPi monotherapy failed to kill CICs, combined PARPi therapy with chemotherapy attenuated tumor growth in vivo. Clinical significance of PARPi for CRC patients was supported by elevated PARP levels in colorectal tumors compared with normal colon, with further increases in metastases. Collectively, our results suggest that PARP inhibition serves as a point of fragility for CICs by augmenting therapeutic efficacy of chemotherapy. Stem Cells 2019;37:42-53.

NPTX2 is associated with neoadjuvant therapy response in rectal cancer.

BACKGROUND: Neoadjuvant chemoradiation (CRT) is recommended for locally advanced rectal cancer. Tumor response varies from pathologic complete response (pCR) to no tumor regression. The mechanisms behind CRT resistance remain undefined. In our previously generated complementary DNA microarrays of pretreatment biopsies from rectal cancer patients, neuronal pentraxin 2 (NPTX2) expression discriminated patients with pCR from those with residual tumor. As tumor response is prognostic for survival, we sought to evaluate the clinical relevance of NPTX2 in rectal cancer. MATERIALS AND METHODS: Real-time quantitative polymerase chain reaction was used to evaluate NPTX2 messenger RNA expression in individual rectal cancers before CRT. Tumors with NPTX2 expression <50% of normal rectum were defined as NPTX2-low and those with >50% were defined as NPTX2-high. NPTX2 levels were compared to response to therapy and oncologic outcomes using Mann-Whitney, Kruskal-Wallis, chi-square, and Mantel-Cox (log-rank) tests, as appropriate. RESULTS: Rectal cancers from 40 patients were included. The mean patient age was 56.8 years, and 30% were female. pCR was achieved in eight of 40 patients (20%). In these patients, messenger RNA NPTX2 levels were significantly decreased compared to those with residual cancer (fold change 30.4, P = 0.017). Patients with NPTX2-low tumors (n = 13) achieved improved response to treatment (P = 0.012 versus NPXT2-high tumors), with 38.5% and 46.1% of patients achieving complete or moderate response, respectively. Of patients with NPTX2-high tumors (n = 27), 11.1% and 18.5% achieved complete or moderate response, respectively. No recurrence or death was recorded in patients with NPTX2-low tumors, reflecting more favorable disease-free survival (P = 0.045). CONCLUSIONS: Decreased NPTX2 expression in rectal adenocarcinomas is associated with improved response to CRT and improved prognosis. Further studies to validate these results and elucidate the biological role of NPTX2 in rectal cancer are needed.

Laparoscopy mitigates adverse oncological effects of delayed adjuvant chemotherapy for colon cancer.

BACKGROUND: Delaying initiation of adjuvant chemotherapy more than 8 weeks after surgical resection for colorectal cancer adversely affects overall patient survival. The effect of a laparoscopic surgical approach on initiation of chemotherapy has not been studied. The goal of this study was to determine if a laparoscopic approach to colon cancer resection affects the timing of adjuvant chemotherapy and outcomes. METHODS: Patients who underwent curative surgery for stage II or III colon cancer and received adjuvant chemotherapy between 2003 and 2010 were identified from a prospectively maintained database. Patients were categorized according to surgical approach: open or laparoscopic. Patient demographics, clinicopathologic variables, postoperative complications, time from surgery to initiation of chemotherapy, and long-term oncologic outcomes were compared. RESULTS: Age, gender, ASA class, BMI, tumor stage, and postoperative complications were similar for laparoscopic and open cases, while length of stay was 2 days shorter for laparoscopic cases (5.4 vs 7.6 days, p < 0.01). The proportion of patients who received adjuvant chemotherapy more than 8 weeks after surgery did not differ between the groups (35.6 % open vs 38.7 % laparoscopic, p = 0.77). In the open group, delay in chemotherapy after surgery was associated with decreased disease-free and overall survival (p = 0.01, 0.01, respectively). However, delay in chemotherapy more than 8 weeks did not affect disease-free or overall survival in the laparoscopy group (p = 0.93, 0.51, respectively). CONCLUSIONS: The benefits of quicker recovery after laparoscopic surgery did not translate into earlier initiation of adjuvant chemotherapy in this retrospective study. However, a laparoscopic approach negated the inferior oncologic outcomes of patients who received delayed initiation of chemotherapy.

Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A.

Many solid cancers display cellular hierarchies with self-renewing, tumorigenic stemlike cells, or cancer-initiating cells (CICs) at the apex. Whereas CICs often exhibit relative resistance to conventional cancer therapies, they also receive critical maintenance cues from supportive stromal elements that also respond to cytotoxic therapies. To interrogate the interplay between chemotherapy and CICs, we investigated cellular heterogeneity in human colorectal cancers. Colorectal CICs were resistant to conventional chemotherapy in cell-autonomous assays, but CIC chemoresistance was also increased by cancer-associated fibroblasts (CAFs). Comparative analysis of matched colorectal cancer specimens from patients before and after cytotoxic treatment revealed a significant increase in CAFs. Chemotherapy-treated human CAFs promoted CIC self-renewal and in vivo tumor growth associated with increased secretion of specific cytokines and chemokines, including interleukin-17A (IL-17A). Exogenous IL-17A increased CIC self-renewal and invasion, and targeting IL-17A signaling impaired CIC growth. Notably, IL-17A was overexpressed by colorectal CAFs in response to chemotherapy with expression validated directly in patient-derived specimens without culture. These data suggest that chemotherapy induces remodeling of the tumor microenvironment to support the tumor cellular hierarchy through secreted factors. Incorporating simultaneous disruption of CIC mechanisms and interplay with the tumor microenvironment could optimize therapeutic targeting of cancer.

Statin therapy is associated with improved pathologic response to neoadjuvant chemoradiation in rectal cancer.

BACKGROUND: Achieving a pathologic complete response to neoadjuvant chemoradiation improves prognosis in rectal cancer. Statin therapy has been shown to enhance the impact of treatment in several malignancies, but little is known regarding the impact on rectal cancer response to neoadjuvant chemoradiation. OBJECTIVE: The purpose of this study was to determine whether statin use during neoadjuvant chemoradiation improves pathologic response in rectal cancer. DESIGN: This was a retrospective cohort study based on data from a prospectively maintained colorectal cancer database. The 2 cohorts were defined by statin use during neoadjuvant chemoradiation. SETTING: This study was performed at a single tertiary referral center. PATIENTS: Four hundred seven patients with primary rectal adenocarcinoma who underwent neoadjuvant therapy then proctectomy between 2000 and 2012 were included. Ninety-nine patients (24.3%) took a statin throughout the entire course of neoadjuvant therapy. MAIN OUTCOME MEASURES: The primary outcome measure was pathologic response to neoadjuvant chemoradiotherapy as defined by the American Joint Committee on Cancer tumor regression grading system, grades 0 to 3. RESULTS: Patients in the statin cohort had a lower median regression grade (1 vs 2, p = 0.01) and were more likely to have a better response (grades 0-1 vs 2-3) than those not taking a statin (65.7% vs 48.7%, p = 0.004). Statin use remained a significant predictor of an American Joint Committee on Cancer grade 0 to 1 (OR, 2.25; 95% CI, 1.33-3.82) in multivariate analyses. Although statin use itself did not significantly improve oncologic outcomes, an American Joint Committee on Cancer grade 0 to 1 response was associated with statistically significant improvements in overall survival, disease-free survival, cancer-specific mortality, and local recurrence. LIMITATIONS: This was a retrospective study and subject to nonrandomization of patients and incorporated patients on variable statin agents and doses. CONCLUSIONS: Statin therapy is associated with an improved response of rectal cancer to neoadjuvant chemoradiation. These data provide the foundation for a prospective clinical trial.

Demographically associated variations in outcomes after bariatric surgery.

BACKGROUND: The incidence of morbid obesity and the use of bariatric surgery as a weight loss tool have increased significantly over the past decade. Despite this increase, there has been limited large-scale database evaluation of the effects of demographics on postoperative occurrences. METHODS: An analysis of the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2007 was performed. The bariatric procedures identified were open Roux-en-Y gastric bypass, laparoscopic Roux-en-Y gastric bypass, adjustable gastric banding, vertical banded gastroplasty, restrictive procedures other than vertical banded gastroplasty, and biliopancreatic diversion/duodenal switch. Outcomes examined were 30-day mortality and American College of Surgeons National Surgical Quality Improvement Program-defined morbidities. Multivariate analysis was performed. RESULTS: A total of 18,682 bariatric procedures were identified. Increased body mass index, age, and undergoing open Roux-en-Y gastric bypass were associated with increased rates of postoperative complications. Hispanic and African American patients were noted to have increased rates of certain postoperative complications. CONCLUSIONS: Demographic factors may influence the postoperative course of patients undergoing bariatric surgery. Prospective studies may further elucidate the associations between demographic factors and specific postoperative complications.