Prognostic assessment in patients operated for brain metastasis from systemic tumors.

BACKGROUND: Established models for prognostic assessment in patients with brain metastasis do not stratify for prior surgery. Here we tested the prognostic accuracy of the Graded Prognostic Assessment (GPA) score model in patients operated for BM and explored further prognostic factors. METHODS: We included 285 patients operated for brain metastasis at the University Hospital Zurich in the analysis. Information on patient characteristics, imaging, staging, peri- and postoperative complications and survival were extracted from the files and integrated into a multivariate Cox hazard model. RESULTS: The GPA score showed an association with outcome. We further identified residual tumor after surgery (p = 0.007, hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.1-2.3) steroid use (p = 0.021, HR 1.7, 95% CI 1.1-2.6) and number of extracranial metastasis sites (p = 0.009, HR 1.4, 95% CI 1.1-1.6) at the time of surgery as independent prognostic factors. A trend was observed for postoperative infection of the subarachnoid space (p = 0.102, HR 3.5, 95% CI 0.8-15.7). CONCLUSIONS: We confirm the prognostic capacity of the GPA score in a cohort of operated patients with brain metastasis. However, extent of resection and steroid use provide additional aid for the prognostic assessment in these patients.

Quantitative Indocyanine Green Fluorescence Imaging Assessment for Nonmucinous Peritoneal Metastases: Preliminary Results of the ICCP Study.

BACKGROUND: In selected patients with peritoneal metastases of colorectal origin, complete cytoreduction has been the main single prognostic factor influencing long-term outcomes. In these patients, indocyanine green fluorescence imaging seems to be useful in detecting small subclinical peritoneal implants. However, quantitative fluorescence analysis has not yet been established as standard. OBJECTIVE: This study aimed to evaluate the sensitivity and specificity of quantitative indocyanine green fluorescence assessment in the detection of peritoneal metastases of nonmucinous colorectal origin. DESIGN: This is a single-center, single-arm, low-intervention prospective trial. SETTINGS: A fluorescence assessment device was used for intraoperative fluorescence quantitative assessment. PATIENTS: Consecutive patients diagnosed with peritoneal metastases of colorectal origin who met the inclusion criteria were selected for curative surgery. INTERVENTIONS: Intravenous indocyanine green was administered 12 hours before surgery. Cytoreduction was performed through nodule identification under white light and then under indocyanine green. Finally, ex vivo fluorescence was assessed. MAIN OUTCOME MEASURES: The primary outcomes measured were the sensitivity and specificity of quantitative fluorescence. RESULTS: The first 11 enrolled patients were included in this preliminary analysis. In total, 52 nodules were resected, with 37 (71.1%) being diagnosed as malignant in the histopathological analysis. Of those, 5 (13.5%) were undetectable under white light and were identified only with fluorescence. A total of 15 nonmalignant nodules were detected under white light, 8 (53.3%) of which were fluorescence negative. Fluorescence greater than 181 units might be the threshold of malignancy, with a sensitivity and specificity of 89.0% and 85.0%, whereas uptake less than 100 units appears to correlate with a benign pathology. LIMITATIONS: The limited sample size, the physiological uptake, and excretion of indocyanine green might interfere with the assessment of unnoticed implants in the bowel serosa and liver. CONCLUSIONS: Quantitative indocyanine green seems to be useful for the assessment of nonmucinous colorectal peritoneal metastases. Fluorescence uptake greater than 181 units appears to correlate with malignancy, whereas uptake less than 100 units appears to correlate with a benign pathology. See Video Abstract at http://links.lww.com/DCR/B743. EVALUACIN CUANTITATIVA DE IMGENES DE FLUORESCENCIA CON VERDE DE INDOCIANINA PARA METSTASIS PERITONEALES NO MUCINOSAS RESULTADOS PRELIMINARES DEL ESTUDIO ICCP: ANTECEDENTES:En pacientes seleccionados con metástasis peritoneales de origen colorrectal, la citorreducción com-pleta ha sido el único factor pronóstico principal que influye en el resultado a largo plazo. En estos pacientes, las imágenes de fluorescencia con verde de indocianina parecen ser útiles para detectar pequeños implantes peritoneales subclínicos. Sin embargo, el análisis cuantitativo de fluorescencia aún no se ha establecido como estándar.OBJETIVO:Evaluar la sensibilidad y especificidad de la evaluación cuantitativa de fluorescencia verde de indo-cianina, en la detección de metástasis peritoneales de origen colorrectal no mucinoso.DISEÑO:Ensayo prospectivo de intervención baja de un solo brazo y un solo centro.ENTORNO CLINICO:El dispositivo se utilizó para la evaluación cuantitativa de fluorescencia intraoperatoria.PACIENTES:Pacientes consecutivos diagnosticados con metástasis peritoneales de origen colorrectal, selecciona-dos para cirugía curativa y que cumplieron con los criterios de inclusión.INTERVENCIONES:Se administró verde de indocianina por vía intravenosa 12 h antes de la cirugía. La citorreducción se realizó mediante identificación de nódulos con luz blanca y luego con verde de indocianina. Final-mente, se evaluó la fluorescencia ex vivo.PRINCIPALES MEDIDAS DE VALORACION:Sensibilidad y especificidad cuantitativa de la fluorescencia.RESULTADOS:Los primeros 11 pacientes fueron incluidos en este análisis preliminar. En total se resecaron 52 nódu-los, siendo 37 (71,1%) diagnosticados como malignos en el análisis histopatológico. De ellos, 5 (13,5%) eran indetectables bajo luz blanca y solamente se identificaron con fluorescencia. Se detec-taron un total de 15 nódulos no malignos bajo luz blanca, de los cuales 8 (53,3%) fueron fluorescen-tes negativos. La fluorescencia superior a 181 unidades podría ser el umbral de malignidad, con una sensibilidad y especificidad del 89,0% y el 85,0% respectivamente; mientras que la captación por debajo de 100 unidades parece correlacionarse con una patología benigna.LIMITACIONES:El tamaño limitado de la muestra; la captación fisiológica y la excreción de verde de indocianina pueden interferir con la evaluación de implantes inadvertidos en la serosa intestinal y el hígado.CONCLUSIONES:La cuantificación del verde de indocianina, parece ser útil en la evaluación de metástasis peritonea-les colorrectales no mucinosas. La captación de fluorescencia por encima de 181 unidades parece correlacionarse con la malignidad, mientras que la captación por debajo de 100 unidades parece co-rrelacionarse con una patología benigna. Consulte Video Resumen en http://links.lww.com/DCR/B743. (Traducción - Dr. Fidel Ruiz Healy).

Role of Liver Biopsy in Assessment of Radiologically Identified Liver Masses.

BACKGROUND: Despite improvements in imaging techniques that have enhanced the ability to diagnose hepatocellular carcinoma (HCC), histopathological evaluation of many other types of liver masses is critical. AIMS: To evaluate the utility of liver biopsy in patients with radiologically undiagnosed liver masses. METHODS: We retrospectively analyzed 293 consecutive patients who had a liver biopsy for evaluation of an undiagnosed liver mass between January 2014 and January 2018. RESULTS: Out of 293 biopsies, 246 patients were found to have malignancy (84%), including 210 (72%) patients with metastatic malignancy and 36 with primary hepatic malignancies (20 HCC and 16 others). In the 47 patients without malignancy, 17 patients had necrotic abscess/granuloma, 16 patients had normal histology, eight patients had hepatic fibrosis/cirrhosis without malignant foci, and six patients had benign tumors. The most common primary lesion in patients with liver metastasis was breast carcinoma (32/293, 11%), followed by colon and pancreas (31 (each)/293, 11%), and lung (9%) adenocarcinomas. Histopathological analysis confirmed the presence of metastasis in 165/200 (83%) patients with a history of oncological malignancy and in 45/93 (48%) patients who had no malignancy history. CONCLUSIONS: In patients with a radiologically identified liver mass of unclear etiology, liver biopsy/histology made a diagnosis in 95% (277/293) of patients, including 84% (246/293) found to have an oncological malignancy. Liver biopsy/histology also identified malignancy in a high proportion of patients without known underlying cancer. We conclude that liver biopsy is valuable for evaluation of radiologically identified liver masses of unclear etiology.

Eficacia y seguridad de crizotinib en pacientes adultos con cáncer de pulmón de células no pequeñas, ALK positivo, metastásico, con ecog 0-2 y que progresa a quimioterapia / Efficacy and safety of crizotinib in adult patients with metastatic ALK-positive non-small cell lung cancer with echog 0-2 and progressing to chemotherapy

INTRODUCCIÓN: Siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, la Dra. Sally Corrales Sequeiros, médica oncóloga del Hospital Nacional Edgardo Rebagliati Martins, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación ­ IETSI, la solicitud de uso fuera del petitorio del producto alectinib (un inhibidor de ALK de segunda generación) para pacientes adultos con cáncer de pulmón de células no pequeñas (CPCNP), metastásico, ALK positivo que progresa a quimioterapia y crizotinib. El paciente, que motivo dicha solicitud, recibió crizotinib en forma particular. Dado que crizotinib no forma parte del Petitorio Farmacológico de EsSalud (EsSalud 2021), se vio la necesidad de evaluar su uso como opción de tratamiento en pacientes adultos con CPCNP, metastásico, ALK positivo que progresa a quimioterapia. De esta forma, se llevó a cabo una reunión técnica con la Dra. Sally Corrales Sequeiros, médica oncóloga del Hospital Nacional Edgardo Rebagliati Martins y los representantes del equipo técnico del IETSI. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de crizotinib, comparado con la quimioterapia basada en platino, para el tratamiento de pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia. RESULTADOS: La presente sinopsis describe la evidencia científica sobre el uso de crizotinib como tratamiento de pacientes con adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia, según el tipo de publicación. RECOMENDACIONES: El IETSI-EsSalud recomienda el uso de las terapias disponibles en EsSalud para el tratamiento de pacientes adultos pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia. Adicionalmente, se recomienda a los especialistas que, en caso de identificar nueva evidencia que responda a la pregunta PICO de interés, envíen sus propuestas para ser evaluadas en el marco de la Directiva N° 003-ETSI-ESSALUD-2016. CONCLUSIONES: - El objetivo del presente dictamen fue evaluar la mejor evidencia disponible sobre la eficacia y seguridad de crizotinib comparado con la quimioterapia basada en platino para el tratamiento de pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia. Luego de la búsqueda de la literatura se identificó una GPC desarrollada por la NCCN; tres ETS desarrolladas por SMC, NICE e IQWiG; un ECA de fase I/II denominado PROFILE 1007 publicado por Shaw et al. La guía de la NCCN no presenta recomendaciones para la población específica del presente dictamen; no obstante, ha sido incluida por ser considerada una guía de referencia para los médicos especialistas en oncología de EsSalud. Las ETS de NICE y SMC evaluaron el uso de crizotinib en pacientes con CPCNP, metastásico, ALK positivo, tratados previamente, basados en los resultados del ECA PROFILE 1007. Ambas ETS recomendaron el uso de crizotinib; pero, condicionando su uso a un descuento confidencial en el precio del medicamento. En una evaluación previa, IQWiG concluyó que no se ha probado el beneficio adicional de crizotinib en pacientes con CPCNP, metastásico, ALK positivo, tratados previamente. En una siguiente evaluación, basándose en los resultados con los resultados maduros del estudio PROFILE 1007, concluyó que estos no fueron informativos y que su decisión inicial no cambiaba. El ECA PROFILE 1007 de fase III y etiqueta abierta, evaluó crizotinib frente a quimioterapia en pacientes adultos con CPCNP, avanzado o metastásico, ALK positivo, que progresaron a un régimen de quimioterapia basada en platino. Sus resultados no mostraron diferencia en la SG entre los grupos de intervención y una mayor incidencia de EA serios con crizotinib. Además, las limitaciones del estudio afectan la validez interna del estudio y no permite determinar con certeza el efecto del tratamiento con crizotinib sobre los desenlaces evaluados. Por lo expuesto, el IETSI no aprueba el uso de crizotinib para el tratamiento de pacientes adultos con CPCNP, metastásico, ALK positivo, con ECOG 0-2 y que progresa a quimioterapia.

Clinical Benefit of Therapeutic Drug Monitoring in Colorectal Cancer Patients Who Received Fluorouracil-Based Chemotherapy.

BACKGROUND The impact of therapeutic drug management (TDM) on reducing toxicity and improving efficacy in colorectal cancer (CRC) patients receiving fluorouracil-based chemotherapy is still unclear. MATERIAL AND METHODS A total of 207 patients (Study Group n=54, Historical Group n=153) with metastatic colorectal cancer were enrolled. All of them received 6 administrations of the 5-FU based regimens. Initial 5-FU dosing of all patients was calculated using body surface area (BSA). In the Study Group, individual exposure during each cycle was measured using a nanoparticle immunoassay, and the 5-FU blood concentration was calculated using the area under the curve (AUC). We adjusted the 5-FU infusion dose of the next cycle based on the AUC data of the previous cycle to achieve the target of 20-30 mg×h/L. RESULTS In the fourth cycle, patients in the target concentration range (AUC mean, 26.3 mg×h/L; Median, 28 mg×h/L; Range, 14-38 mg×h/L; CV, 22.4%) accounted for 46.8% of all patients, which were more than the ones in the first cycle (P<0.001). 5-FU TDM significantly reduced the toxicity of chemotherapy and improved its efficacy. The Study Group (30/289) showed a lower percentage of severe adverse events than that in the Historical Group (185/447) (P<0.001). The incidences of complete response and partial response in the Study Group were higher than those in the Historical Group (P=0.032). CONCLUSIONS TDM in colorectal cancer can reduce toxicity, improve efficacy and clinical outcome, and can be routinely used in 5-FU-based chemotherapy.

Comprehensive pathological assessment of histological subtypes, molecular subtypes based on immunohistochemistry, and tumor-associated immune cell status in muscle-invasive bladder cancer.

Molecular assessments of muscle-invasive bladder cancer (MIBC) have yielded several molecular categorizations associated with basal and luminal subtypes or tumor-associated immune cell status (TAICs). However, the histological relationships among histological subtypes, molecular subtypes, and TAICs and their clinical implications remain unclear. Thus, we aimed to evaluate the histological associations among these factors and their clinicopathological outcomes. We retrospectively analyzed 106 patients with MIBC who underwent radical cystectomy. The histological subtypes and TAICs were evaluated with hematoxylin and eosin staining, while the basal and luminal molecular subtypes were determined by immunohistochemical expression of cytokeratin (CK) 5/6, CK14, CK20, GATA3 and uroplakin II. Urothelial carcinoma with squamous differentiation and the sarcomatoid variant were highly associated with the basal subtype (P < 0.001 and P = 0.04, respectively). Additionally, high TAICs were significantly correlated with the basal subtype (P < 0.001). Although there was no significant difference in the cancer-specific survival (CSS) rate between molecular subtypes (P = 0.295), TAICs significantly discriminated CSS rates (P < 0.001). Furthermore, the combination of molecular subtypes and TAICs significantly stratified cancer-specific mortality rates. In conclusion, a comprehensive pathological evaluation of histological subtypes, molecular subtypes, and TAICs is feasible and can influence the oncological outcome.

Joint modelling of colorectal cancer recurrence and death after resection using multi-state model with cured fraction.

Curing of colorectal cancer (CRC) occurs at the time of resection but it is not immediately observable. If the cancer is not completely eliminated, the patient will not be cured of cancer and will experience recurrence as the tumor has regrown to a detectable size. The main propose of the present study was to assess the effects of different covariates on the probability of being cured as well as the time-to-recurrence, and time-to-death in CRC patients by using multi-state cure model. The information of 283 patients with CRC, who underwent resection, from 2000 to 2015 in Imam Khomeini Hospital of Hamadan, Iran, were analyzed. The results of multi-state cure model reveal that females and who experience metastasis were more likely to be apparently cured. It has been shown that sex has a significant effect on the time-to-recurrence given patient was in the not cured group. The survival time of patients of the not cured group was affected by the stage of disease. However, the survival of the apparently cured patients were affected by age at diagnosis and metastasis status. The multi-state cure model provided a flexible framework to study the effects of prognostic factors simultaneously on the transition between different states and the probability of being apparently cured of CRC.

Cetuximab para el tratamiento en primera línea de pacientes con cáncer colorrectal metastásico de localización izquierda y genes RAS no mutados / Cetuximab for first treatment colorectal cancer patient line location metastasis izquierda y genes non-mutated RAS

INTRODUCCIÓN: Este documento técnico se realiza a solicitud del Hospital Santa Rosa, a través de la Gerencia de Riesgos y Evaluación de las Prestaciones del Seguro Integral de Salud; la pregunta PICO fue la siguiente: P: adultos con cáncer colorrectal metastásico de localización izquierda y genes RAS no mutados; I: cetuximab + quimioterapia (C+Qt); C: quimioterapia (Qt) o panitumumab + quimioterapia (P+Qt); O: Sobrevida global, sobrevida libre de progresión, tasa de respuesta y eventos adversos. a. Cuadro clínico: En Perú, el cáncer colorrectal constituye el quinto tipo de cáncer más frecuente y el sexto con mayor mortalidad. En el diagnóstico inicial, un 25% de pacientes presenta enfermedad metastásica distante. En los últimos veinte años, la sobrevida global de pacientes con cáncer colorrectal metastásico se ha extendido, gracias a la aprobación de nuevas terapias administradas en combinación con agentes citotóxicos y la identificación de mutaciones genéticas que pueden predecir la respuesta al tratamiento. b. Tecnología sanitaria: Cetuximab es un antagonista del receptor de factor del crecimiento epidérmico, indicado para el tratamiento del cáncer colorrectal metastásico en tumores con sobreexpresión del EGFR y de tipo KRAS no mutado. Actúa mediante inhibición del crecimiento celular, inducción de apoptosis y disminución de la producción de metaloproteinasas de matriz y del factor de crecimiento endotelial vascular. Se recomienda una dosis inicial de 400 mg/m2, seguida de dosis semanales de 250 mg/m2, administradas en monoterapia o en combinación con quimioterapia. Cuenta con aprobación de la FDA desde el año 2004. En Perú, cuenta con dos registros sanitarios con vigencia prorrogada provisional. OBJETIVO: Describir la evidencia científica disponible sobre la eficacia y seguridad de cetuximab para el tratamiento en primera línea de pacientes con cáncer colorrectal metastásico de localización izquierda y genes RAS no mutados. METODOLOGÍA: Búsqueda sistemática en Medline, EMBASE, The Cochrane Library y LILACS, complementada con la búsqueda en páginas de agencias gubernamentales y buscadores genéricos. La calidad se valoró usando AMSTAR 2 para revisiones sistemáticas (RS), la herramienta de la colaboración Cochrane para ensayos clínicos y AGREE II para las Guías de Práctica Clínica (GPC). RESULTADOS: Sobrevida global: C+Qt mejoró la sobrevida global, en comparación con solo Qt, tanto en combinación con FOLFIRI (hazard ratio [HR]: 0,65; IC 95%: 0,50 a 0,86; 28,7 meses vs. 21,7 meses), como con FOLFOX (HR: 0,69; IC 95%: 0,53 a 0,90; 22 meses vs. 18,7 meses). No se observó diferencias entre C+Qt y P+Qt. Sobrevida libre de progresión: C+Qt mejoró la sobrevida global, en comparación con solo Qt, tanto en combinación con FOLFIRI (HR: 0,50; IC 95%: 0,34 a 0,72; 12 meses vs. 8,9 meses) como con FOLFOX (HR: 0,68; IC 95%: 0,50 a 0,91; 9,2 meses vs. 7,6 meses). No se observó diferencias entre C+Qt y P+Qt. Tasa de respuesta objetiva: C+Qt produjo una tasa de respuesta objetiva significativamente más alta, en comparación con solo Qt, tanto en combinación con FOLFIRI (odds ratio [OR]: 3,99; IC 95%: 2,40 a 6,62), como con FOLFOX (OR: 2,60; IC 95%: 1,64 a 4,14). No se observó diferencias entre C+Qt y P+Qt. Eventos adversos grado: C+Qt incrementó hasta el doble la probabilidad de sufrir algún evento adverso, en comparación con solo Qt, con un riesgo incrementado de toxicidad dermatológica (RR: 20,76; IC 95%: 3,87 a 111,33), diarrea (RR: 1,48; IC 95%: 1,33 a 1,64), hipertensión (RR: 1,69; IC 95%: 1,17 a 2,46), anorexia (RR: 1,57; IC 95%: 1,18 a 2,10) y mucositis/estomatitis (RR: 2,69; IC 95%: 1,90 a 3,80). Recomendaciones en GPC: Sólo NCCN y ASCO incluyen recomendaciones específicas para cáncer colorrectal metastásico con tumores RAS no mutadas de localización izquierda. Ambas incluyen como opciones de tratamiento a C+Qt y P+Qt. Evaluaciones de Tecnología Sanitaria: Dos ETS nacionales no recomiendan dar cobertura a C+Qt en cáncer colorrectal metastásico RAS de tipo salvaje, citando aspectos relacionados con su eficacia y costo-efectividad. NICE recomienda, tanto C+Qt como P+Qt sin especificar la lateralidad del tumor. Evaluación de la calidad metodológica: Dos RS fueron consideradas como nivel de confianza bajo y dos como nivel de confianza críticamente bajo. Las GPC obtuvieron un puntaje en la valoración global de calidad que varío entre 60,1% y 84,6%. CONCLUSIONES: La evidencia sobre el uso de C+Qt para cáncer colorrectal de lado izquierdo es limitada. Los desenlaces de eficacia que comparan C+Qt provienen de análisis de subgrupos no especificados de dos ensayos clínicos, mientras que los desenlaces de seguridad provienen de evidencia que no considera la lateralidad del tumor. Las comparaciones entre C+Qt y P+Qt proceden de meta-análisis en red de comparaciones indirectas. En pacientes con cáncer colorrectal metastásico de lado izquierdo con genes RAS no mutados, la adición de cetuximab a la quimioterapia incrementó la sobrevida global alrededor de 7 meses cuando se combinó con FOLFIRI y alrededor de 3,3 meses cuando se combinó con FOLFOX. No se hallaron diferencias entre cetuximab y panitumumab. La sobrevida libre de progresión se incrementó en alrededor de 3,1 meses tras la adición de cetuximab a FOLFIRI y alrededor de 1,6 meses cuando se adicionó a FOLFOX. No se hallaron diferencias entre cetuximab y panitumumab. Los pacientes tratados con cetuximab más quimioterapia tuvieron el doble de probabilidad de sufrir algún evento adverso, en comparación con solo quimioterapia, siendo común observar un riesgo incrementado de presentar toxicidad dermatológica, diarrea, hipertensión, anorexia y mucositis/dermatitis. Cetuximab y panitumumab presentaron diferente perfil de eventos adversos. Sólo las GPC de NCCN y ASCO incluyen recomendaciones específicas para cáncer colorrectal metastásico con tumores RAS no mutados de localización izquierda. Ambas GPC incluyen como opciones de tratamiento a cetuximab y panitumumab acompañados por quimioterapia. Dos ETS nacionales recomiendan no dar cobertura a C+Qt en pacientes con cáncer colorrectal metastásico con tumores RAS de tipo salvaje, citando aspectos relacionados con su eficacia y costo-efectividad. La ETS de NICE recomienda, tanto C+Qt como P+Qt, para cáncer colorrectal metastásico con tumores RAS de tipo salvaje sin especificar la lateralidad del tumor. Dos RS fueron consideradas como nivel de confianza bajo y dos como nivel de confianza críticamente bajo. Las GPC obtuvieron un puntaje en la valoración global de calidad que varío entre 60,1% y 84,6%. Ambas RS fueron consideradas como nivel de confianza bajo. Las GPC incluidas obtuvieron un puntaje en la valoración global de calidad que varío grandemente entre 60,1% y 84,6%.

Cost-Effectiveness Analysis of Stereotactic Ablative Radiation Therapy in Patients With Oligometastatic Cancer.

PURPOSE: The Stereotactic Ablative Radiation therapy for Comprehensive Treatment of Oligometastatic Tumors phase 2 randomized clinical trial found that stereotactic ablative radiation therapy (SABR) improved outcomes among cancer patients with oligometastatic disease. Yet, the cost of SABR along with the large number of patients with oligometastatic disease raises the important question of value. This study sought to evaluate the cost-effectiveness of the addition of SABR compared with standard therapy alone among cancer patients with oligometastatic disease. METHODS AND MATERIALS: We constructed a Markov model to simulate treatment with stereotactic ablative radiation therapy or standard therapy among patients with oligometastatic cancers. The model derived transition probabilities from Stereotactic Ablative Radiation therapy for Comprehensive Treatment of Oligometastatic Tumors clinical trial data to estimate risks of toxicity, disease progression and survival. Health care costs and health utilities were estimated from the literature. Probabilistic and one-way sensitivity analyses evaluate model uncertainty. Cost-effectiveness was estimated from both the health care sector and societal perspectives with an incremental cost-effectiveness ratio (ICER) defined as dollars per quality-adjusted life year (QALY). An ICER less than $100,000/QALY was considered cost-effective. One-way and probabilistic sensitivity analyses were used to examine model uncertainty. RESULTS: The addition of SABR increased total costs by $54,260 (health care sector perspective) or $72,799 (societal perspective) and improved effectiveness by 1.88 QALYs compared with standard therapy, leading to an ICER of $28,906/QALY (health care sector perspective) or $38,783/QALY (societal perspective). The model was modestly sensitive to assumptions about tumor progression, although the model was not sensitive to assumptions about survival or cost of treatment. Probabilistic sensitivity analyses demonstrated that SABR was the cost-effective treatment option 99.8% (health care sector perspective) or 98.7% (societal perspective) of the time. CONCLUSIONS: The addition of SABR increased costs and improved quality adjusted survival, overall leading to a cost-effective treatment strategy for patients with oligometastatic cancer.

CT-based assessment of body composition following neoadjuvant chemohormonal therapy in patients with castration-naïve oligometastatic prostate cancer.

BACKGROUND: The purpose of this study is to assess the body composition changes in men with recently diagnosed oligometastatic prostate cancer following neoadjuvant chemohormonal therapy. Further, we evaluated whether CT-based body composition parameters are associated with biochemical recurrence or imaging progression. MATERIAL AND METHODS: Recently diagnosed castration-naïve oligometastatic prostate cancer patients who received neoadjuvant docetaxel chemotherapy and androgen deprivation treatment (ADT) before prostatectomy and consolidation of local and oligometastatic disease (total eradication therapy), as part of a phase-II prospective clinical trial were included. Body composition parameters including cross-sectional areas of the psoas muscle, total, visceral, and subcutaneous adipose tissue were measured on serial CT scans obtained before and following completion of neoadjuvant treatment. RESULTS: A total of 22 prostate cancer patients were included (median age 58 years, median Gleason score 8). The median time intervals between commencement of neoadjuvant chemohormonal therapy and first and second follow-up CTs were 3 and 12 months, respectively. Compared to the baseline scan, there were significant declines in psoas muscle cross-sectional areas with estimated percentage declines of -13.9% (IQR: 7.6%-16.5%, p < .001) and -13.2% (IQR: 6%-11.2%, p < .001) on first and second follow-up CTs. There were significant increases in subcutaneous adipose tissue following neoadjuvant chemohormonal therapy with percentage increases of +8.9% (IQR: 5.1%-21.5%, p = .002) and +18.9% (IQR: 6.1%-33.8%, p < .001), respectively. The median follow-up was 34.5 months. The estimated 2-year prostate-specific antigen progression-free and radiologic progression-free survival were 95.5%. No significant association between baseline or percentage change in body composition parameters and disease progression were identified. CONCLUSIONS: Our findings showed a significant reduction in muscle mass and an increase in subcutaneous adiposity in men treated with neoadjuvant docetaxel and ADT, more pronounced on the first follow-up scan after completion of neoadjuvant treatment. Body composition parameters were not found to be significant predictors of disease progression in our cohort.

Primary De novo ductal adenocarcinoma of the lacrimal gland.

BACKGROUND: Primary ductal adenocarcinoma of the lacrimal gland is a rare and aggressive malignant epithelial lacrimal gland neoplasm, morphologically and phenotypically resembles salivary duct carcinoma, and both strongly resemble infiltrating ductal carcinoma of breast. METHOD: Retrospective Chart review of cases of malignant lacrimal gland tumors from 2013 July to 2020 July. Authors describe the clinico radiological, morphological and immunohistochemical features of primary ductal adenocarcinoma (PDA) of lacrimal gland. Extensive review of literature of PDA of lacrimal gland and salivary gland ductal carcinoma has been performed. RESULTS: Retrospective chart review of the last 7 years yielded 22 malignant lacrimal gland neoplasms of which 4 cases demonstrated features of primary ductal adenocarcinoma of lacrimal gland, 2/4 cases showed an evidence of a pre existing pleomorphic adenoma and 2 were found to be de novo ductal adenocarcinomas. PDA of lacrimal gland showed expression of CK7, CK19, AR, HER2, cyclin D1 and were negative for CK5/14, CK 20, ER, PR, PSA, TTF-1, S-100 and SMA. Expression of GCDFP-15 was noted in one case. The presence of multiple events of loco-regional recurrences and/or distant metastasis necessitated a multidisciplinary approach. CONCLUSIONS: Authors have expressed the need of clinical correlation; thorough tissue sampling and extensive immunohistochemical work up in identification of de novo PDA's and their molecular subtypes. A multi-institutional study might help in formulating the diagnostic criteria, identification of actionable targets, and thus study the role of targeted therapy in this rare and aggressive tumor which may result in better patient outcomes.

Assessment of Trends in Second Primary Cancers in Patients With Metastatic Melanoma From 2005 to 2016.

Importance: To date, the risk of developing second primary cancers (SPCs) after the first primary melanoma has not been studied in the era of immune checkpoint inhibitors (ICIs). Objective: To assess differences in the risk of SPCs in patients with primary melanoma before (2005-2010) and after (2011-2016) the introduction and approval of ICIs. Design, Setting, and Participants: Population-based cohort study using the Surveillance, Epidemiology, and End Results database from January 2005 to December 2016 of patients diagnosed with metastatic melanoma. Data were analyzed from January 4 to June 30, 2020. Exposures: Receipt of immunotherapy or other anticancer agents. Main Outcomes and Measures: The primary outcome was the development of second primary cancers in patients with melanoma. Standardized incidence ratios (SIRs) were calculated for the development of SPCs before and after the introduction of ICIs. Results: Among 5016 patients with diagnosed metastatic melanoma, 2888 (58%) were younger than 65 years at the time of diagnosis, and 3441 (69%) were male. From 2005 to 2010, SIRs were 3.24 (95% CI, 0.08-18.04) for small intestine cancer, 1.93 (95% CI, 1.14-3.05) for lung and bronchus cancer, 2.77 (95% CI, 1.02-6.03) for kidney cancer, and 7.29 (95% CI, 2.93-15.02) for myeloma. From 2011 to 2016, SIRs were 9.23 (95% CI, 1.12-33.35) for small intestine cancer, 1.54 (95% CI, 0.71-2.93) for lung and bronchus cancer, 2.66 (95% CI, 0.73-6.82) for kidney cancer, and 5.90 (95% CI, 1.61-15.10) for myeloma. The overall risk of developing SPCs in individuals who survived the first primary melanoma was 65% higher (SIR, 1.65; 95% CI, 1.35-2.00) in the pre-ICIs period and 98% higher (SIR, 1.98; 95% CI, 1.57-2.45) in the post-ICIs period than the overall cancer incidence rate in the general population. Conclusions and Relevance: In this study, an increase in the overall risk of second primary cancers after melanoma after the introduction of immune checkpoint inhibitors was observed. The pattern of SPCs has been altered in the era of systemic therapy. Close monitoring and screening for SPCs may be warranted in patients with metastatic melanoma.

Association of Sociodemographic Factors With Immunotherapy Receipt for Metastatic Melanoma in the US.

Importance: Strides to improve survival in metastatic melanoma have been made with the use of immunotherapeutic agents in the form of immune checkpoint inhibitors. Objective: To examine the factors associated with immunotherapy receipt in patients with metastatic melanoma in the era of immune checkpoint inhibitors and the Patient Protection and Affordable Care Act. Design, Setting, and Participants: This cohort study used data on 9882 patients with metastatic melanoma diagnosed from January 1, 2013, to December 31, 2016, from the National Cancer Database. Patients who did not have documentation regarding immunotherapy receipt were excluded. Data analysis was performed from July 1, 2019, to December 15, 2019. Exposure: Receipt of immunotherapy. Main Outcomes and Measures: The primary outcome was the association of receipt of immunotherapy as first-line therapy with sociodemographic factors. The secondary outcome was overall survival by receipt of immunotherapy. Results: A total of 9512 patients (mean [SD] age, 65.1 [14.4] years; 6481 [68.1%] male; 9217 [96.9%] White) met the criteria for treatment analysis. A total of 3428 (36.0%) received immunotherapy, and 6084 (64.0%) did not. Increasing age (odds ratio [OR], 0.98; 95% CI, 0.97-0.98; P < .001) and increasing Charlson-Deyo comorbidity index (OR, 0.86; 95% CI, 0.80-0.92; P < .001) were associated with lower odds of receiving immunotherapy on regression analysis. Diagnosis in Medicaid expansion states (OR, 1.16; 95% CI, 1.05-1.27; P = .003), treatment at an academic or integrated cancer network program (OR, 1.59; 95% CI, 1.45-1.75; P < .001), and residence within the highest quartile of high school graduation rate zip code area (OR, 1.31; 95% CI, 1.09-1.56; P = .003) were associated with an increased likelihood of receiving immunotherapy. Median overall survival was 10.1 months (95% CI, 9.6-10.6 months) among all patients. Patients who received first-line immunotherapy had a median overall survival of 18.4 months (95% CI, 16.6-20.1 months) compared with 7.5 months (95% CI, 7.0-7.9 months) (P < .001) among patients who did not. Conclusions and Relevance: In this cohort study, patients who received immunotherapy for metastatic melanoma had improved overall survival. Residence in Medicaid expansion states, younger age, low comorbidity index, care at academic medical centers or integrated network cancer programs, and residence in zip codes within the highest quartile of high school graduation were associated with an increased likelihood of receiving immunotherapy. Recognizing sociodemographic associations with treatment receipt is important to identify potential barriers to treatment.

A plausible accelerating function of intermediate states in cancer metastasis.

Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process and plays an essential role in development, tissue regeneration, and cancer metastasis. Interestingly, EMT is not a binary process but instead proceeds with multiple partial intermediate states. However, the functions of these intermediate states are not fully understood. Here, we focus on a general question about how the number of partial EMT states affects cell transformation. First, by fitting a hidden Markov model of EMT with experimental data, we propose a statistical mechanism for EMT in which many unobservable microstates may exist within one of the observable macrostates. Furthermore, we find that increasing the number of intermediate states can accelerate the EMT process and that adding parallel paths or transition layers may accelerate the process even further. Last, a stabilized intermediate state traps cells in one partial EMT state. This work advances our understanding of the dynamics and functions of EMT plasticity during cancer metastasis.

Distant metastasis of salivary gland cancer: Incidence, management, and outcomes.

BACKGROUND: Distant metastases (DMs) are the primary cause of treatment failure in patients with salivary gland carcinoma. There is no consensus on the standard treatment. METHODS: Patients with DMs were identified from an institutional database of 884 patients with salivary gland cancer who underwent resection of the primary tumor between 1985 and 2015. Survival outcomes for patients with DMs were determined with the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify factors associated with DM. RESULTS: Of the 884 patients identified, 137 (15%) developed DMs during follow-up. Most of the primary tumors (n = 77 [56%]) were located in a major salivary gland. At clinical presentation, 53% of the tumors were classified as T3 or T4, and 32% had clinical node metastases. The median time to DM was 20.3 months. The factors associated with shorter distant recurrence-free survival were male sex, high-risk tumor histology, and advanced pathological T and N classifications. Patients with bone metastases had a lower survival rate than patients with lung metastases. The total number of DMs in a patient was inversely associated with survival. Patients who underwent surgical resection of DMs had a significantly higher 5-year rate of metastatic disease-specific survival than patients who underwent observation or nonsurgical treatment (44%, 29%, and 19%, respectively; P = .003). CONCLUSIONS: In patients with DMs of salivary gland carcinoma, survival is negatively associated with high-grade histology, bone DMs, and the total number of DMs. Metastasectomy can help to lengthen disease-free survival.

Do brain mets grow while you wait? A volumetric natural history assessment of brain metastases from time of diagnosis to gamma knife treatment.

Brain metastasis (BM) is a common neurologic complication of cancers such as lung, breast, and melanoma. Recently, there has been a shift in treatment of BM from whole brain radiation therapy to stereotactic radiosurgery (SRS) and the success is dependent on tumor volume. While most metastases grow over time, data on growth rate is lacking. Therefore, we document volume changes of metastases before treatment. We retrospectively reviewed MRI imaging records of 82 patients with a total of 294 BMs, treated in our cancer center by one neurosurgeon and one radiation oncologist with Gamma Knife SRS over a three-year period. We measured tumor volume at the time of diagnosis and compared with tumor volume on the day of treatment. Volumes were compared using the Wilcoxon signed-rank test. Lung, melanoma and breast made up the majority of metastases diagnosed. More than 75% of tumors grew and these changes in volume and percent changes in volume were statistically significant. Thirty percent of tumors doubled in size before treatment. Patients with the largest mean pretreatment tumor size were urgently treated within 6 days, yet still demonstrated the largest change in volume. This study is one of the first to document volume changes of brain metastases from the time of diagnosis to SRS treatment. Our results indicate that brain metastases can grow rapidly and it is imperative that we streamline patient management processes to minimize delays in treating patients with SRS, since outcomes are dependent on tumor size.

Adverse Surgical Outcomes Associated with Robotic Retroperitoneal Lymph Node Dissection Among Patients with Testicular Cancer.

Surgery for metastatic testicular disease has been an essential factor in the long-term cure rates for men with testicular germ cell tumors. Robotic approaches to retroperitoneal lymph node dissection (R-RPLND) have been proposed as an alternative to open surgery with few if any adverse events reported. We report the clinical course for five recent patients referred to our center for recurrences after R-RPLND, focusing on recurrence patterns, treatment burden, and treatment-related morbidity and mortality. The median time to recurrence after R-RPLND was 259d. The recurrence patterns after R-RPLND were aberrant from our past experience in managing recurrences after open RPLND. One man experienced an in-field recurrence located in close proximitry to an undivided lumbar vessel. Four patients had out-of-field recurrence in abnormal locations: pericolic space invading the sigmoid colon, peritoneal carcinomatosis with a perinephric mass, large-volume liver lesions with suprahilar disease extending into the retrocrural space, and lymph nodes in the celiac axis. The treatment burden was high: the five men were subjected to 12 different chemotherapy regimens and three underwent additional surgeries. Three patients developed significant cisplatin-induced toxicity. One patient died due to progression of testicular cancer after failing all chemotherapy and surgical options. PATIENT SUMMARY: We report our initial experience in managing patients with testicular cancer referred to our institution after robotic retroperitoneal lymph node dissection (RPLND). We found that the recurrences were highly variable and in unusual locations and were associated with a high treatment burden. We conclude that further investigation into the safety and long-term oncologic efficacy of robotic RPLND is necessary before widespread implementation.

Micromanipulation of Circulating Tumor Cells for Downstream Molecular Analysis and Metastatic Potential Assessment.

Blood-borne metastasis accounts for most cancer-related deaths and involves circulating tumor cells (CTCs) that are successful in establishing new tumors at distant sites. CTCs are found in the bloodstream of patients as single cells (single CTCs) or as multicellular aggregates (CTC clusters and CTC-white blood cell clusters), with the latter displaying a higher metastatic ability. Beyond enumeration, phenotypic and molecular analysis is extraordinarily important to dissect CTC biology and to identify actionable vulnerabilities. Here, we provide a detailed description of a workflow that includes CTC immunostaining and micromanipulation, ex vivo culture to assess proliferative and survival capabilities of individual cells, and in vivo metastasis-formation assays. Additionally, we provide a protocol to achieve the dissociation of CTC clusters into individual cells and the investigation of intra-cluster heterogeneity. With these approaches, for instance, we precisely quantify survival and proliferative potential of single CTCs and individual cells within CTC clusters, leading us to the observation that cells within clusters display better survival and proliferation in ex vivo cultures compared to single CTCs. Overall, our workflow offers a platform to dissect the characteristics of CTCs at the single cell level, aiming towards the identification of metastasis-relevant pathways and a better understanding of CTC biology.

Oligometastatic Prostate Cancer Should Be Studied and Treated Differently to High-volume Disease. Con: The Underlying Biology is the Same, So They Should Not Be Treated Differently.

The biology of oligo- and polymetastatic disease is likely to be similar. However, the prognosis is different and this may drive different therapy choices. Men should not be deprived of life-prolonging therapies unless the benefits of these therapies are outweighed by the risks from competing causes of mortality.