Combinatorial Inhibition of Complement Factor D and BCL2 for Early-Onset Colorectal Cancer.

BACKGROUND: The tumor immune microenvironment is distinct between early-onset and late-onset colorectal cancer, which facilitates tumor progression. We previously identified several genes, including complement factor D, as having increased expression in patients with early-onset colorectal cancer. OBJECTIVE: This study aimed to assess and validate the differential expression of immune genes in early-onset and late-onset colorectal cancer. We also aimed to test known drugs targeting genes increased in early-onset colorectal cancer in preclinical mouse models. DESIGN: A retrospective cohort study with analysis was performed using tumor RNA from formalin-fixed paraffin-embedded cell culture and immunohistochemistry to validate gene expression and function and in vivo preclinical tumor study to assess drug efficacy. SETTINGS: The Oregon Colorectal Cancer Registry was queried to identify patients with colorectal cancer. PATIENTS: The study included 67 patients with early-onset colorectal cancer and 54 patients with late-onset colorectal cancer. INTERVENTIONS: Preclinical animal models using the HCT-116 colon cancer cell line were treated with the complement factor D inhibitor danicopan and the BCL2 inhibitor venetoclax, or with vehicle controls. MAIN OUTCOME MEASURES: Elevated RNA signatures using NanoString data were evaluated by the retrospective cohort. When inhibiting these markers in the mouse preclinical model, tumor volume and weight were the main outcome measures. RESULTS: After updating our sample size from our previously published data, we found that complement factor D and BCL2, genes with known function and small molecule inhibitors, are elevated in patients with early-onset colorectal cancer. When inhibiting these markers with the drugs danicopan and venetoclax in a mouse model, we found that the combination of these drugs decreased tumor burden but also resulted in toxicity. LIMITATIONS: This study is limited by a small sample size and a subcutaneous tumor model. CONCLUSIONS: Combinatorial inhibition of early-onset associated genes complement factor D and BCL2 slows the growth of early-onset colorectal cancer in a mouse preclinical model. See Video Abstract . INHIBICIN COMBINADA DEL FACTOR DCOMPLEMENTARIO Y DEL BCL EN CASOS DE CNCER COLORRECTAL DE APARICIN TEMPRANA: ANTECEDENTES:El microambiente inmunológico del tumor es distinto entre el cáncer colorrectal de aparición temprana y el de aparición tardía, lo que facilita la progresión de dicho tumor. Anteriormente identificamos varios genes, incluidos el factor D-Complementario, con una mayor expresión en pacientes con cáncer colorrectal de aparición temprana.OBJETIVO:El presente estudio tuvo como objetivo el evaluar y validar la expresión diferenciada de genes inmunes en casos de cáncer colorrectal de aparición temprana y tardía. También nos propusimos evaluar los fármacos conocidos dirigidos sobre los genes aumentados en el cáncer colorrectal de aparición temprana en modelos pre-clínicos en ratones.DISEÑO:Estudio de cohortes con análisis retrospectivo utilizando el ARN tumoral procedente de cultivos celulares fijados con formalina e incluidos en parafina, y el analisis por inmunohistoquímica para validar la expresión y la función genética. Se realizó el estudio pre-clínico de los tumores in vivo para evaluar la eficacia de los fármacos.AJUSTES:Se consultó el Registro de Oregon de casos de Cáncer Colorrectal para encontrar los pacientes afectados.SUJETOS:67 pacientes con cáncer colorrectal de aparición temprana y 54 pacientes con cáncer colorrectal de aparición tardía.INTERVENCIONES (SI LAS HUBIESE):Los modelos animales pre-clínicos que utilizaron la línea celular de cáncer de colon HCT-116 se trataron con el inhibidor del factor D-Complementario o Danicopan y con el inhibidor de BCL-2 o Venetoclax, ambos con control del transportador.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron las firmas de ARN elevadas utilizando los datos del NanoString a partir de la cohorte retrospectiva. Al inhibir estos marcadores del modelo pre-clínico en los ratones, el volumen y el peso del tumor fueron las principales medidas de resultado.RESULTADOS:Después de actualizar el tamaño de nuestra muestra a partir de datos publicados con anterioridad, encontramos que el factor D-Complementario y BCL-2, genes con función conocida e inhibidores de moléculas pequeñas, se encuentran elevados en aquellos pacientes con cáncer colorrectal de aparición temprana. Al inhibir estos marcadores con los medicamentos Danicopan y Venetoclax en el modelo de ratones vivos, encontramos que la combinación de estos dos farmacos disminuyó la carga tumoral pero también produjo toxicidad.LIMITACIONES:Estudio limitado por un tamaño de muestra pequeño y el modelo de tumor subcutáneo.CONCLUSIONES:La inhibición combinada de genes asociados de aparición temprana, el factor D-Complementario y el BCL-2, enlentecen el crecimiento del cáncer colorrectal de aparición temprana del modelo preclínico en ratones. (Traducción-Dr. Xavier Delgadillo ).

Renal pathology in hematopoietic cell transplant recipients: a contemporary biopsy, nephrectomy, and autopsy series.

Renal injury in hematopoietic cell transplant recipients may be related to a combination of factors including chemotherapy, radiation, infection, immunosuppressive agents, ischemia, and graft-versus-host disease, and can involve glomerular, tubulointerstitial, and vascular structures. We reviewed renal pathology from 67 patients at a single institution (2009-2014), including 14 patients with biopsy for clinical dysfunction, 6 patients with surgical kidney resection for other causes, and 47 autopsy patients. Kidney specimens frequently contained multiple histopathologic abnormalities. Thrombotic microangiopathy, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis were the most common glomerular findings. Pathologies not previously reported in the hematopoietic cell transplant setting included collapsing glomerulopathy, antiglomerular basement membrane disease, fibrillary glomerulonephritis, and in the case of two surgical resections distinctive cellular segmental glomerular lesions that defied classification. Kidney specimens frequently demonstrated acute tubular injury, interstitial fibrosis, arteriolar hyaline, and arteriosclerosis. Other kidney findings at autopsy included leukemia and amyloid (both recurrent), diabetic nephropathy, bacterial infection, fungal invasion, and silver deposition along glomerular and tubular basement membranes. Also in the autopsy cohort, C4d immunohistochemistry demonstrated unexpected membranous nephropathy in two patients, yet C4d also colocalized with arteriolar hyaline. This retrospective hematopoietic cell transplant cohort illustrates multifaceted renal injury in patients with renal dysfunction, as well as in patients without clinically recognized kidney injury.

Mixed Adenosquamous Cell Carcinoma of the Prostate with Paired Sequencing on the Primary and Liver Metastasis.

This report aims to shed light on the intricate challenges encountered during the diagnosis and treatment of an uncommon variant of prostate cancer-mixed adenosquamous cell carcinoma of the prostate. Prostate cancers of this nature pose distinctive diagnostic and therapeutic dilemmas due to their rarity and complex histological composition. We present a case of a 63-year-old man with metastatic prostate cancer, featuring adenocarcinoma with squamous cell differentiation, who underwent a multimodal treatment approach. The patient responded to first-line carboplatin, docetaxel, and androgen deprivation therapy, followed by androgen receptor pathway inhibitor (ARPI) maintenance. However, disease progression led to radiation therapy and a subsequent switch to Lutetium (177Lu) vipivotide tetraxetan after chemotherapy challenges. Comprehensive genetic profiling revealed shared mutations in the prostate and liver lesions, emphasizing the role of targeted therapies. Prostate-specific membrane antigen (PSMA)-targeted therapy resulted in a notable PSA decline. This case highlights the evolving treatment landscape for rare prostate cancers, integrating genetic insights for tailored interventions. In conclusion, squamous cell carcinoma (SCC) of the prostate is rare, emphasizing the imperative for enhanced comprehension in diagnosis and management. Our case suggests the potential efficacy of ARPI and PSMA-targeted therapies. Our findings advocate for a more nuanced approach to the management of this rare prostate cancer variant, leveraging genomic insights for personalized treatment strategies. This exploration serves as a foundation for further research and clinical considerations in addressing the challenges posed by mixed adenosquamous cell carcinoma of the prostate.

Intravenous and topical intranasal bevacizumab (Avastin) in hereditary hemorrhagic telangiectasia.

Current treatment of severe epistaxis in patients with hereditary hemorrhagic telangiectasia is not durable in reducing the frequency and severity of bleeds. Recent reports have demonstrated marked improvement of epistaxis with administration of either intravenous or topical bevacizumab. We present the long-term outcome of a patient who received repeated treatments of intravenous bevacizumab followed by maintenance intranasal bevacizumab. We demonstrate durable control of epistaxis with intranasal bevacizumab. This allows delivery of bevacizumab effectively, reduces cost, and obviates the risk of systemic adverse effects related to bevacizumab.

Conservative management of malignant colorectal polyps in select cases is safe in long-term follow-up: An institutional review.

BACKGROUND: Non-operative management of early-stage polypectomy-identified colorectal cancer (CRC) may be a safe alternative, but limited data exist. METHODS: We compared outcomes between adults with post-polypectomy CRC who did and did not ultimately undergo resection from 2003 to 2018. Overall (OS) and recurrence-free (RFS) survival were calculated via log rank analysis using the Mantel-Cox method and plotted on Kaplan-Meier curves with significance evaluated at P < 0.05. RESULTS: N = 78 patients were included, most commonly with rectal/rectosigmoid CRC (45%). Almost half (47%) had resections, and the remaining 41 patients (53%) underwent organ-sparing techniques. Chemoradiation was administered to 5 of these 41 patients (12%), all with rectal cancer. At median follow-up of 52 months, 5-year OS and RFS were 78% and 100% with no significant differences when compared to resection (all P > 0.1). DISCUSSION: Using evidence-based patient selection and adjuvant therapy, organ-sparing management provides equal survival when compared to resection for post-polypectomy CRC.

Hepatocarcinogenesis: Radiology-Pathology Correlation.

In the background of chronic liver disease, hepatocellular carcinoma develops via a complex, multistep process called hepatocarcinogenesis. This article reviews the causes contributing to the process. Emphasis is made on the imaging manifestations of the pathologic changes seen at many stages of hepatocarcinogenesis, from regenerative nodules to dysplastic nodules and then to hepatocellular carcinoma.

Oncologic outcomes in resected ampullary cancer: Relevance of histologic subtype and adjuvant chemotherapy.

BACKGROUND: Outcomes in ampullary cancer (AC) may differ by pathologic subtype. No guidelines exist for the administration of adjuvant therapy (AT). We sought to evaluate the effect of subtype and AT on survival. METHODS: An institutional review of patients undergoing resection for AC from 2008-17 was performed. Recurrence-free (RFS) and overall survival (OS) were assessed by Kaplan-Meier and Cox proportional hazards modeling. RESULTS: Of 53 patients, two-thirds (62%) were stage III. Histologic subtype was evenly split between intestinal and pancreatobiliary (43% and 40%). Half of patients received AT. RFS and OS were 25 (95% CI 16-32) and 41 (CI 22-60) months, respectively, without significant difference by subtype. Stage II/III disease was associated with worse OS (HR 3.7, P = 0.03), which was improved with receipt of AT (HR 0.44, P < 0.05). CONCLUSION: Stage is the primary determinant of survival in AC, which may be improved with AT.

Detection of Tumor Multifocality in Resectable Intrahepatic Cholangiocarcinoma: Defining the Optimal Pre-operative Imaging Modality.

BACKGROUND: Multiple tumor foci (MTF) in intrahepatic cholangiocarcinoma (ICC), including satellitosis and true multifocality, is a known negative prognostic factor and can inform pre-operative decision-making. Lack of standardized pre-operative liver staging practices may contribute to undiagnosed MTF and poor outcomes. We sought to investigate the sensitivity of different cross-sectional imaging modalities for MTF at our institution. METHODS: We identified n = 52 patients with ICC who underwent curative-intent resection from 2004 to 2017 in a multidisciplinary hepato-pancreato-biliary cancer program. Timing and modality of pre-operative imaging were recorded. Blinded review of imaging was performed and modalities were evaluated for false-negative rate (FNR) in detecting MTF, satellitosis, and true multifocality. RESULTS: Forty-one (79%) patients underwent CT and 20 (38%) underwent MRI prior to hepatectomy. MTF was pre-operatively identified in six (12%) patients. An additional seven patients had MTF discovered on final surgical pathology, despite a median interval from CT/MRI to surgery of 20 days. On blinded review the FNR of MRI compared to CT for multifocality was 0% vs. 38%, 50% vs 80% for satellitosis, and 22% vs 46% for MTF as a whole. CONCLUSION: CT is inadequate for pre-operative diagnosis of MTF in resectable ICC, even when performed within 30 days of hepatectomy. We recommend liver-protocol MRI as the standard pre-operative imaging modality in non-metastatic ICC.