Citations

BACKGROUND: Primary colorectal lymphoma is rare, representing 0.2% to 0.6% of all colorectal cancers. Because of its low incidence and histologic variety, no treatment guidelines exist. OBJECTIVE: The purpose was to report the experience of primary colorectal lymphoma in an institutional and a national cohort. DESIGN: This was a retrospective cohort study. SETTINGS: The study was conducted with institutional data composed of 3 tertiary referral centers and national data. PATIENTS: Patients with primary colorectal lymphoma were identified within the Mayo Clinic (1990–2016) and the Surveillance, Epidemiology, and End Results database (1990–2014). MAIN OUTCOME MEASURES: Primary outcomes were overall and 5-year survival. RESULTS: For the institutional cohort (N = 82), 5-year survival was 79.9%. Five-year survival was higher for rectal (88.4%) than for colon tumors (77.2%; p = 0.004). On multivariable analysis, age <50 years was associated with higher overall survival ( p = 0.04). Left-sided colon masses and aggressive histological subtypes were associated with worse survival (0.04 and 0.03). No effect of treatment modality on survival was noted. For the national cohort (N = 2942), 5-year survival was 58.4%. Five-year survival for rectal tumors was 61.0% and 57.8% for colon tumors. On multivariable analysis, factors associated with improved survival were age <70 y, ( p < 0.0001), female sex ( p = 0.005), right-sided masses ( p = 0.02), and diagnoses after 2000 compared with 1990–1999 ( p < 0.0001). Aggressive pathology ( p < 0.0001) and stage III or stage IV presentation compared with stage I ( p = 0.02 and p < 0.0001) were associated with worse survival. LIMITATIONS: The institutional cohort was limited by sample size to describe treatment effect on survival. A major limitation of the national cohort was the ability to describe treatment modalities other than surgery, including chemotherapy and/or no additional treatment. CONCLUSIONS: Poorer survival was noted in elderly patients and in those with aggressive pathology. An overall survival advantage was seen in women in the national cohort. Currently, optimal strategies should follow a patient-centered multidisciplinary approach. See Video Abstract at http://links.lww.com/DCR/A807. LINFOMA COLORECTAL PRIMARIO: EXPERIENCIA INSTITUCIONAL Y REVISIÓN DE UNA BASE DE DATOS NACIONAL ANTECEDENTES: El linfoma colorectal primario es poco frecuente, representando del 0.2% al 0.6% de todos los cánceres colorectales. Debido a su baja incidencia y variedad histológica, no existen guías de tratamiento. OBJETIVO: El propósito fue reportar la experiencia en linfoma colorectal primario en una cohorte institucional y una nacional. DISEÑO: Este fue un estudio de cohorte retrospectivo. ESCENARIO: El estudio se realizó con datos institucionales provenientes de 3 centros de referencia terciarios y datos nacionales. PACIENTES: Se identificaron pacientes con linfoma colorectal primario en la base de datos de la Clínica Mayo (1990–2016) y en la base de datos de vigilancia, epidemiología y resultados finales [Surveillance, Epidemiology, and End Results database (1990–2014)]. PRINCIPALES MEDIDAS DE RESULTADO: Los resultados primarios fueron la sobrevida general y a 5 años. RESULTADOS: Para la cohorte institucional (N = 82), la sobrevida a 5 años fue de 79.9%. La sobrevida a cinco años fue mayor en tumores rectales (88.4%) que en los de colon (77.2%; p = 0.004). En el análisis multivariable, la edad <50 años se asoció con una mayor sobrevida general (p = 0,04). Las masas de colon izquierdo y los subtipos histológicos agresivos se asociaron con una peor sobrevida (0.04 y 0.03). No se observó ningún efecto según la modalidad de tratamiento en la sobrevida. Para la cohorte nacional (N = 2942), la sobrevida a 5 años fue del 58.4%. La sobrevida a cinco años fue de 61.0% para los tumores rectales y 57.8% para los tumores de colon. En el análisis multivariable, los factores asociados con una mayor sobrevida fueron edad <70 años, (p <0.0001), sexo femenino (p = 0.005), masas derechas (p = 0.02) y los casos diagnósticados después del año 2000 comparados con los de 1990–1999 (p <0.0001). Histopatología agresiva (p <0.0001) y presentación en estadio III o estadio IV en comparación con estadio I (p = 0.02 y p <0.0001) se asociaron con una peor sobrevida. LIMITACIONES: La cohorte institucional estuvo limitada por el tamaño de la muestra para describir el efecto del tratamiento en la sobrevida. Una limitación mayor en la cohorte nacional fue la habilidad para describir modalidades de tratamiento distintas a la cirugía, incluyendo quimioterapia y/o ningún tratamiento adicional. CONCLUSIONES: Una menor sobrevida fue documentada en pacientes de edad avanzada y en aquellos con histopatología agresiva. Se observó ventaja en cuanto a sobrevida general en las mujeres de la cohorte nacional. Actualmente, las estrategias óptimas deben de seguir un abordaje multidisciplinario centrado en cada paciente. Vea el abstract en video en http://links.lww.com/DCR/A807.

Key points We developed a method that allows for real‐time assessment of cellular metabolism in isolated, intact long skeletal muscle fibre bundles from adult mice. This method can be used to study changes in mitochondrial function and fuel utilisation in live skeletal muscle fibre bundles. Our method enables flexibility in experimental design and high‐throughput assessment of mitochondrial parameters in isolated skeletal muscle fibre bundles. Extensor digitorum longus (EDL) fibre bundles obtained from chronic high‐fat diet fed mice had lower basal oxygen consumption under FCCP‐induced maximal respiration, when compared to control chow‐fed mice. EDL fibre bundles obtained from chronic high‐fat diet fed mice had enhanced mitochondrial oxidation capacity under FCCP‐induced maximal respiration, when compared to control chow‐fed mice. AbstractMetabolic dysfunction in skeletal muscle contributes to the aetiology and development of muscle diseases and metabolic diseases. As such, assessment of skeletal muscle cellular bioenergetics provides a powerful means to understand the role of skeletal muscle metabolism in disease and to identify possible therapeutic targets. Here, we developed a method that allows for the real‐time assessment of cellular respiration in intact skeletal muscle fibre bundles obtained from the extensor digitorum longus (EDL) muscle of adult mice. Using this method, we assessed the contribution of ATP turnover and proton leak to basal mitochondrial oxygen consumption rate (OCR). Our data demonstrate that the mitochondria in EDL fibres are loosely coupled. Moreover, in the presence of carbonyl cyanide‐p‐trifluoromethoxyphenylhydrazone (FCCP), we show that palmitate exposure induced comparable peak OCR and higher total OCR in EDL fibre bundles when compared to pyruvate exposure, suggesting that fatty acids might be a more sustainable fuel source for skeletal muscle when mitochondria are driven to maximal respiration. Application of this method to EDL fibre bundles obtained from chronic high‐fat diet fed mice revealed lower basal OCR and enhanced mitochondrial oxidation capacity in the presence of FCCP when compared to the chow‐diet fed control mice. By using a 96‐well microplate format, our method provides a flexible and efficient platform to investigate mitochondrial parameters of intact skeletal muscle fibres obtained from adult mice.

Abstract Resistance is one the main reason for overall decrease in survival of cancer patient treated with cisplatin in different types of cancer. Cisplatin kills cancer cells by various mechanisms, but mainly through formation of inter- and intra stand crosslinks of DNA. Different types of translesion polymerase including Polymerase kappa (POLK) are involved in repair of DNA lesions. We observed high expression levels of POLK in cisplatin resistant bladder and ovarian cancer cells compared to parental cells. Due to its low proof-reading activity POLK can incorporate 8-oxo-dGTP into DNA. The MTH1 protein (Nudix hydrolase- NUDT1) sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Recently we have generated MTH1 inhibitors that damage the DNA and induce cancer specific cell death through incorporation of more oxidized dNTPs. We found cisplatin resistant bladder cancer cells (NTUB1/P) were more sensitive to MTH1 inhibitors in comparison to parental NTUB1 cells. As POLK is involved in incorporation of 8-oxo-dGTP into DNA, we hypothesized that high expression levels of POLK in cisplatin resistant cells make them more sensitive to MTH1 inhibitors as more 8-oxo-dGTP would be incorporated into DNA, resulting in more DNA damage and cell death in comparison to parental cells. Indeed, we observes higher induction of cleaved-PARP, γH2AX, cleaved-Caspase 3 and more annexin v positive cells in cisplatin resistant NTUB1/P cells in comparison to parental NTUB1 cells upon treatment with MTH1 inhibitors. MTH1 inhibitor also significantly delays the NTUB1/P xenograft tumor growth in comparison to vehicle treatment in immunosuppressive mice. Knocking down POLK in cisplatin resistant NTUB1/P cells by siRNA resulted in decreased incorporation of 8-oxo-dGTP and sensitivity to MTH1 inhibitors compared to non target control cells. Overexpression of POLK in NTUB1 and NTUB1/P cells results in further sensitization to MTH1 inhibitors. In conclusion elevated levels of POLK in cisplatin resistance cells determines increased sensitivity towards MTH1 inhibitors. Thus MTH1 inhibitors can be a potential promising therapy for the treatment of cisplatin resistant tumors in patients. Citation Format: Kumar Sanjiv, Helge Gad, Sean Rudd, Rachel Hurley, Patric Herr, José Manuel Calderón Montaño, Oliver Mortusewicz, Tobias Koolmeister, Sylvain Jaques, Estefanía Burgos Morón, Andreas Hoglund, Te-Chang Lee, Martin Scobie, Scott Kaufmann, John Weroha, Ulrika Warpman Berglund, Andrea Wahner Hendrickson, Thomas Helleday. Polymerase kappa determines the sensitivity of MTH1 inhibitors to cisplatin-resistant cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1260.

Abstract Purpose: Pathologic fractures could be prevented if reliable methods of fracture risk assessment were available. A multicenter prospective study was conducted to identify significant predictors of physicians' treatment plan for skeletal metastasis based on clinical fracture risk assessments and the proposed CT-based Rigidity Analysis (CTRA). Experimental Design: Orthopedic oncologists selected a treatment plan for 124 patients with 149 metastatic lesions based on the Mirels method. Then, CTRA was performed, and the results were provided to the physicians, who were asked to reassess their treatment plan. The pre- and post-CTRA treatment plans were compared to identify cases in which the treatment plan was changed based on the CTRA report. Patients were followed for a 4-month period to establish the incidence of pathologic fractures. Results: Pain, lesion type, and lesion size were significant predictors of the pre-CTRA plan. After providing the CTRA results, physicians changed their plan for 36 patients. CTRA results, pain, and primary source of metastasis were significant predictors of the post-CTRA plan. Follow-up of patients who did not undergo fixation resulted in 7 fractures; CTRA predicted these fractures with 100% sensitivity and 90% specificity, whereas the Mirels method was 71% sensitive and 50% specific. Conclusions: Lesion type and size and pain level influenced the physicians' plans for the management of metastatic lesions. Physicians' treatment plans and fracture risk predictions were significantly influenced by the availability of CTRA results. Due to its high sensitivity and specificity, CTRA could potentially be used as a screening method for pathologic fractures. Clin Cancer Res; 21(11); 2514–9. ©2015 AACR.