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BACKGROUND: Local treatment options for locally recurrent pancreatic adenocarcinoma (LR-PAC) are limited, with median survival time (MST) of 9-13 months (mos) following recurrence. MRI-guided stereotactic body radiation therapy (MRgSBRT) provides the ability to dose escalate while sparing normal tissue. Here we report on the early outcomes of MRgSBRT for LR-PAC. METHODS: Patients with prior resection of pancreatic adenocarcinoma with local recurrence treated with MRgSBRT at a single tertiary referral center from 5-2021 to 2-2023 were identified from our prospective database. MRgSBRT was delivered to 40-50 Gy in 4-5 fractions with target and OAR delineation per institutional standards. Endpoints included local control per RECIST v1.1, distant failure, overall survival (OS), and acute and chronic toxicities per Common Terminology Criteria for Adverse Events, v5. RESULTS: Fifteen patients with LR-PAC were identified with median follow-up of 10.6 mos (2.8-26.5 mos) from MRgSBRT. There were 8 females and 7 males, with a median age of 69 years (50-83). One patient underwent neoadjuvant radiation for 50.4 Gy in 28 fractions followed by resection, and one underwent adjuvant radiation for 45 Gy in 25 fractions prior to recurrence. MRgSBRT was delivered a median of 18.8 mos (3.5-52.8 mos) following resection. OS following recurrence at 6 and 12 mos were 87% and 51%, respectively, with a median survival time of 14.1 mos (3.2-27.4 mos). Three patients experienced local failure at 5.9, 7.8, and 16.6 months from MgSBRT with local control of 92.3% and 83.9% at 6 and 12 months. 10 patients experienced distant failure at a median of 2.9 mos (0.3-6.7 mos). Grade 1-2 acute GI toxicity was noted in 47% of patients, and chronic GI toxicity in 31% of patients. No grade > 3 toxicities were noted. CONCLUSIONS: This is the first report on toxicity and outcomes of MRgSBRT for LR-PAC in the literature. MRgSBRT is a safe, feasible treatment modality with the potential for improved local control in this vulnerable population. Future research is necessary to better identify which patients yield the most benefit from MRgSBRT, which should continue to be used with systemic therapy as tolerated. TRIAL REGISTRATION: Jefferson IRB#20976, approved 2/17/21.
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Adenocarcinoma , Recurrencia Local de Neoplasia , Neoplasias Pancreáticas , Radiocirugia , Humanos , Masculino , Neoplasias Pancreáticas/radioterapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Femenino , Anciano , Radiocirugia/métodos , Radiocirugia/efectos adversos , Persona de Mediana Edad , Adenocarcinoma/radioterapia , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adenocarcinoma/mortalidad , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/patología , Anciano de 80 o más Años , Imagen por Resonancia Magnética , Radioterapia Guiada por Imagen/métodos , Tasa de Supervivencia , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Outpatient chemotherapy often leaves patients to grapple with a range of complex side effects at home. Leveraging tailored evidence-based content to monitor and manage these symptoms remains an untapped potential among patients with gastrointestinal (GI) cancer. OBJECTIVE: This study aims to bridge the gap in outpatient chemotherapy care by integrating a cutting-edge text messaging system with a chatbot interface. This approach seeks to enable real-time monitoring and proactive management of side effects in patients with GI cancer undergoing intravenous chemotherapy. METHODS: Real-Time Chemotherapy-Associated Side Effects Monitoring Supportive System (RT-CAMSS) was developed iteratively, incorporating patient-centered inputs and evidence-based information. It synthesizes chemotherapy knowledge, self-care symptom management skills, emotional support, and healthy lifestyle recommendations. In a single-arm 2-month pilot study, patients with GI cancer undergoing chemotherapy received tailored intervention messages thrice a week and a weekly Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events-based symptom assessment via a chatbot interface. Baseline and postintervention patient surveys and interviews were conducted. RESULTS: Out of 45 eligible patients, 34 were enrolled (76% consent rate). The mean age was 61 (SD 12) years, with 19 (56%) being females and 21 (62%) non-Hispanic White. The most common cancer type was pancreatic (n=18, 53%), followed by colon (n=12, 35%) and stomach (n=4, 12%). In total, 27 (79% retention rate) participants completed the postintervention follow-up. In total, 20 patients texted back at least once to seek additional information, with the keyword "chemo" or "support" texted the most. Among those who used the chatbot system checker, fatigue emerged as the most frequently reported symptom (n=15), followed by neuropathy (n=7). Adjusted for multiple comparisons, patients engaging with the platform exhibited significantly improved Patient Activation Measure (3.70, 95% CI -6.919 to -0.499; P=.02). Postintervention interviews and satisfaction surveys revealed that participants found the intervention was user-friendly and were provided with valuable information. CONCLUSIONS: Capitalizing on mobile technology communication holds tremendous scalability for enhancing health care services. This study presents initial evidence of the engagement and acceptability of RT-CAMSS, warranting further evaluation in a controlled clinical trial setting.
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Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.
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Enfermedades Genéticas Congénitas , Glucagón , Hipertensión Portal , Trasplante de Hígado , Femenino , Humanos , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/cirugía , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Glucagón/sangre , Glucagón/genética , Hipertensión Portal/sangre , Hipertensión Portal/etiología , Hipertensión Portal/genética , Hipertensión Portal/cirugía , Hipertrofia/genética , Cirrosis Hepática , Enfermedades Genéticas Congénitas/sangre , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/cirugía , Enfermedades Pancreáticas/genética , Enfermedades Pancreáticas/patología , Enfermedades Pancreáticas/cirugía , Células Secretoras de Glucagón/patologíaRESUMEN
BACKGROUND: Malignant perivascular epithelioid cell tumors (PEComas) are exceedingly rare malignant mesenchymal neoplasms with characteristic morphological and immunohistochemical (IHC) patterns. However, some malignant PEComas are poorly differentiated with atypical histopathological features, making a definitive diagnosis difficult. PEComas are most commonly found in females and often show either TSC1 or TSC2 alterations, which result in the activation of the mTOR pathway, or TFE3 fusions. Given these molecular characteristics, mTOR inhibitors have recently been approved by the FDA in the treatment of malignant PEComas, particularly in those with TSC1/2 alterations. Therefore, molecular analyses may be helpful for both the diagnostic workup of and predicting response to mTOR inhibitors in cases of malignant PEComas. CASE PRESENTATION: Here, we report a case of an aggressive, 23 cm mesenteric malignant PEComa with multiple peritoneal metastases in a young male patient. Pathological examination of the initial biopsy showed a malignant epithelioid neoplasm with high-grade morphology and atypical immunoprofile, which precluded a definitive diagnosis. Because of the patient's excessive transfusion requirements due to intra-tumoral hemorrhage, a palliative R2 resection was performed. Histopathological examination of the tumor revealed focal immunoreactivity for Melan-A, HMB-45, desmin, and CD117. Although a diagnosis of malignant PEComa was favored, other entities such as epithelioid gastrointestinal stromal tumor (GIST) or melanoma could not be definitively ruled out. Given the favored diagnosis, the patient was started on sirolimus, an mTOR inhibitor, rather than chemotherapy. Molecular analyses were performed and the tumor was found to harbor mutations in TP53 and TSC2, supporting a definitive diagnosis of malignant PEComa. The patient was then switched to nab-sirolimus, with initial stabilization of the disease. CONCLUSIONS: This report details a multidisciplinary approach for the diagnosis and management of a highly aggressive, metastatic malignant PEComa in a young male patient. The basis for the treatment of malignant PEComas with the recently FDA-approved mTOR inhibitor, nab-sirolimus, is also reviewed. In summary, this case highlights the importance of molecular analysis, particularly TSC1/2 alterations, for both the definitive diagnosis of malignant PEComas and predicting their response to nab-sirolimus.
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Neoplasias de Células Epitelioides Perivasculares , Sarcoma , Humanos , Masculino , Inhibidores mTOR , Mutación , Neoplasias de Células Epitelioides Perivasculares/tratamiento farmacológico , Neoplasias de Células Epitelioides Perivasculares/metabolismo , Neoplasias de Células Epitelioides Perivasculares/patología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
OBJECTIVES: As few large studies identify correlative biomarkers in chordoma, our objective was to use our large, single-center chordoma tumor bank to identify novel signaling pathways. METHODS: Clinical and pathologic data for 73 patients with chordoma were retrospectively collected. Tumor microarrays were built from 61 archived chordoma specimens; immunohistochemistry for TOMM20, TIGAR, and MCT1 were performed; and semiquantitative analysis of staining intensity and percentage of positive tumor cells was performed. Average composite scores of MCT1, TIGAR, and TOMM20 expression were compared by disease status and anatomic location. RESULTS: Higher expression of TOMM20 was seen in recurrent and metastatic chordomas compared with primary lesions. Comparing composite scores of primary lesions in patients with primary disease only vs those with recurrent disease showed that TIGAR and TOMM20 expressions are significantly higher in primary lesions, followed by a history of recurrence. A TOMM20 composite score of greater than or equal to 3 significantly decreased overall survival (hazard ratio [HR], 5.83) and recurrence-free survival (HR, 8.95). CONCLUSIONS: Identifying novel signaling pathways that promote chordoma growth and recurrence is critical for developing targeted therapy for chordoma. TOMM20 may be a biomarker associated with chordoma disease progression.
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Cordoma , Humanos , Cordoma/patología , Estudios Retrospectivos , Pronóstico , Receptores de Superficie Celular/metabolismo , Modelos de Riesgos Proporcionales , Proteínas del Complejo de Importación de Proteínas Precursoras MitocondrialesRESUMEN
Importance: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. Objective: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. Design, Setting, and Participants: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. Interventions: Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. Main Outcomes and Measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. Results: A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. Conclusions and Relevance: In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. Trial Registration: ClinicalTrials.gov Identifier: NCT01834235.
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Adenocarcinoma , Anticuerpos Monoclonales , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Gemcitabina/uso terapéutico , Mucina 5AC/uso terapéutico , Paclitaxel/uso terapéutico , Adulto , Anciano , Neoplasias PancreáticasRESUMEN
INTRODUCTION: Immune checkpoint inhibitors (ICIs) have changed the treatment landscape for multiple cancer types. Sex plays an important role in both the development of cancer as well as the functioning of the immune system. Though a difference in response to immune therapy is emerging between men and women it is unclear how this difference affects cancer outcomes and what the potential underlying mechanisms are for those effects. The objective of this study is to describe the influence that sex has on the outcomes experienced by cancer patients on ICI therapy and to identify and analyse any knowledge gaps in the field. METHOD AND ANALYSIS: The framework for this methodology was guided by the Joanna Briggs Institute Manual for Evidence Synthesis. The search and review will be conducted from January 2022 to June 2022. Two independent researchers will screen titles and abstracts followed by full-text screening for manuscript inclusion. Full length studies published between 2010 and December 2021 found in PubMed, Cochrane, CINAHL, and Scopus describing the influence of sex differences on cancer outcomes in patients treated with ICIs will be included. After data are extracted it will be summarised for presentation. ETHICS AND DISSEMINATION: The findings of this scoping review will be published in a peer-reviewed journal. The results will be used to inform future studies on the potential differential impacts of ICIs. All data are from published openly accessible sources and therefore no ethical clearance is necessary.
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Inhibidores de Puntos de Control Inmunológico , Neoplasias , Atención a la Salud , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Neoplasias/tratamiento farmacológico , Revisión por Pares , Proyectos de Investigación , Literatura de Revisión como AsuntoRESUMEN
Purpose: Multi-tyrosine kinase inhibitors (TKI) have shown clinical activity in patients with metastatic colorectal cancer. Cabozantinib, a multi-TKI, exhibited potent antitumor activity superior to regorafenib in preclinical colorectal cancer patient-derived tumor xenograft models. This phase II study aimed to investigate cabozantinib, a multi-TKI, in patients with refractory, metastatic colorectal cancer (mCRC). Experimental Design: A nonrandomized, two-stage, phase II clinical trial evaluating 12-week progression-free survival (PFS) was conducted in eight cancer centers across the United States between May 2018 and July 2020. Results: A total of 44 patients were enrolled between May 2018 and May 2019, 40 of which were response evaluable. Of the total 769 reported adverse events (AE), 93 (12%) were ≥ grade 3. Five grade 5 AEs were reported of which four were unrelated to study drug and one was reported as possibly related due to bowel perforation. Eighteen patients (45%) achieved 12-week PFS with stable disease or better (confidence interval, 0.29-0.62; P < 0.001). One patient (3%) had a partial response, and 27 other patients achieved stable disease as best response per RECISTv1.1. Median PFS was 3.0 months, and median overall survival was 8.3 months. Of the 18 patients who achieved 12-week PFS, 12 had left-sided primary tumors, 11 were RAS wild type, 11 were PIK3CA wild type, and 6 had previous regorafenib therapy. The 12-week PFS rate was higher in RAS wild-type tumors compared with RAS mutant tumors (0.61 vs. 0.32; P = 0.11). Conclusions: This phase II study demonstrated clinical activity of cabozantinib in heavily pretreated, patients with refractory mCRC, and supports further investigation. Significance: Targeting angiogenesis through VEGF axis blockade provides incremental survival benefit in patients with mCRC. The hepatocyte growth factor/MET signal transduction pathway has been observed as a mechanism for acquired resistance. Dual inhibition of VEGF plus MET is an attractive therapeutic strategy. This phase II trial demonstrated clinical activity with cabozantinib, a multi-TKI targeting VEGFR2 and MET, in patients with refractory, mCRC.
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Neoplasias Colorrectales , Factor A de Crecimiento Endotelial Vascular , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Piridinas/efectos adversos , Factor A de Crecimiento Endotelial Vascular/uso terapéutico , Estudios ProspectivosRESUMEN
BACKGROUND: Cancer therapies are associated with multiple adverse effects, including (but not limited to) cancer-related fatigue (CRF). Fatigue is one of the most common side effects of immune checkpoint inhibitors (ICIs), occurring in up to 25% of patients. Physical activity has been shown to help reduce CRF through modulating the immune system, and may synergistically aid in the anti-tumor effects of ICIs. This review describes the nature and scope of evidence for the effects associated with concurrent physical activity while undergoing ICI therapy. METHOD: Scoping review methodology was utilized to identify studies, extract data, and collate and summarize results. RESULTS: In literature published from January 2010 through to August 2021, only one human study and three pre-clinical studies met inclusion criteria. CONCLUSION: Existing evidence supports that physical activity is associated with decreased treatment-related toxicities such as CRF. However, further investigation is warranted. The dearth of clinical studies illustrates the need for more research to address this question, to guide patients and their providers in the application of appropriate physical activity interventions in those patients undergoing ICI.
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Purpose: Current literature reports increased incidence of postpancreaticoduodenectomy (PD) nonalcoholic fatty liver disease (NAFLD), a precursor for nonalcoholic steatohepatitis and cirrhosis. The incidence of and risk factors (RFs) for NAFLD in the PD population, however, are not well elucidated. Methods: A cohort of 421 patients from a single institution who underwent PD for carcinoma and followed for at least 6 months were assessed retrospectively for age, gender, pathology, surgical complications (operative blood loss and length of stay [LOS]), comorbidities (diabetes, hypertension, hyperlipidemia, obesity), tobacco use, pre- and postoperative nutritional status (albumin and body mass index [BMI]), use of pancreatic enzyme replacement, and perioperative laboratory values (hemoglobin and liver function test). Cox proportional hazards model was used to examine these potential RFs as predictors of time to development of post-PD NAFLD. Results: Sixty (14.3%) patients developed post-PD NAFLD. Patients with NAFLD were younger (61.10 vs. 65.01 years old) and had higher preoperative BMI (28.92 vs. 26.61). Multivariate Cox proportional hazard model identified higher preoperative BMI, shorter postoperative LOS, and female gender as RFs for post-PD NAFLD. After excluding 12 patients with rare histology, there was a lower unadjusted hazard of developing NAFLD (p-value = 0.018) in the adenocarcinoma group than in the neuroendocrine and periampullary tumor groups. There was no statistically significant association between post-PD NAFLD and other characteristics. Conclusion: Female gender, higher preoperative BMI, and shorter LOS deserve closer monitoring for earlier detection and management of NAFLD.
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PURPOSE OF REVIEW: To highlight the new developments in the management of advanced giant cell tumor of bone, a rare locally aggressive benign tumor, which was traditionally managed with surgery alone by either curettage and local adjuvant therapy, wide resection, or marginal excision. Here, we review the current role of systemic therapy for management of locally advanced or metastatic giant cell tumor of bone (GCTB). RECENT FINDINGS: The elucidation of the pathophysiology of giant cell tumor of bone, especially with regards to the role of nuclear factor kappa B ligand (RANKL), has led to the Food and Drug Administration (FDA) approval of denosumab in the management of locally advanced or metastatic GCTB. For advanced giant cell tumor where surgical resection alone can cause severe morbidity, the paradigm has shifted from local treatment alone to multidisciplinary management with the consideration of use of denosumab.
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Antineoplásicos/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Tumor Óseo de Células Gigantes/tratamiento farmacológico , Neoplasias Óseas/patología , Quimioterapia Adyuvante/métodos , Terapia Combinada , Tumor Óseo de Células Gigantes/patología , HumanosRESUMEN
PURPOSE: To compare overall survival (OS) in patients who underwent surgery for early-stage pancreatic adenocarcinoma (rPca) based on sequence (NAT, neoadjuvant therapy and/or AT, adjuvant therapy) and type (SA, single-agent or MA, multi-agent) of chemotherapy received. METHODS: Using the National Cancer Database, patients with clinical stage I/II rPca diagnosed between 2010 and 2014 were identified and five comparison matches (1: NAT vs. upfront resection (UR); 2: multi-agent neoadjuvant (MA NAT) vs. single-agent adjuvant therapy (SA AT), single-agent neoadjuvant therapy (SA NAT), multi-agent adjuvant therapy (MA AT); 3: MA NAT vs. MA AT; 4: NAT + AT vs NAT; 5: NAT + AT vs AT) were constructed using minimum distance matching strategy. Median OS (mOS) was analysed using Kaplan-Meier method, log-rank test and Cox proportional hazard model. RESULTS: A total of 18,470 patients with stage I/II rPca were eligible for analysis. NAT showed a 5 month (mo.) improved OS compared with UR (3271 patients/group, 28.1 vs 23.2 mo. P < 0.0001 hazard ratio [HR]: 0.79). MA-NAT was shown to be superior to other chemotherapy approaches SA AT, SA NAT, and MA AT (1349 patients/group: 30 vs. 25.9 mo., P = 0.0001 [HR: 0.82]). MA NAT showed a survival advantage over MA-AT (1349 patients/group, 30 vs 26.1 mo., P = 0.0008 [HR: 0.86]). The combination of NAT and AT showed a better outcome when compared with NAT alone (1128 patients/group, 31.6 vs 27.4 mo., P = 0.0011 [HR: 0.81]) or AT alone (1128 patients/group, 31.6 vs. 25.2 mo., P < 0.0001 [HR: 0.76]). CONCLUSIONS: In patients with stage I/II rPca, MA NAT showed improved mOS compared to UR and all other chemotherapy sequences except both NAT plus AT. These findings support the use of MA NAT in stage I/II rPca patients and warrant prospective trials evaluating MA NAT and post-resection maintenance therapies.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Neoadyuvante , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Bases de Datos Factuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/mortalidad , Estadificación de Neoplasias , Pancreatectomía , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados UnidosRESUMEN
Chondrosarcoma is the second most common primary bone malignancy, representing one fourth of all primary bone sarcomas. It is typically resistant to radiation and chemotherapy treatments. However, the molecular mechanisms that contribute to cancer aggressiveness in chondrosarcomas remain poorly characterized. Here, we studied the role of mitochondrial transporters in chondrosarcoma aggressiveness including chemotherapy resistance. Histological grade along with stage are the most important prognostic biomarkers in chondrosarcoma. We found that high-grade human chondrosarcoma tumors have higher expression of the mitochondrial protein, translocase of the outer mitochondrial membrane complex subunit 20 (TOMM20), compared to low-grade tumors. TOMM20 overexpression in human chondrosarcoma cells induces chondrosarcoma tumor growth in vivo. TOMM20 drives proliferation, resistance to apoptosis and chemotherapy resistance. Also, TOMM20 induces markers of epithelial to mesenchymal transition (EMT) and metabolic reprogramming in these mesenchymal tumors. In conclusion, TOMM20 drives chondrosarcoma aggressiveness and resistance to chemotherapy.
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Neoplasias Óseas/metabolismo , Condrosarcoma/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Proliferación Celular/efectos de los fármacos , Condrosarcoma/tratamiento farmacológico , Condrosarcoma/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Membranas Mitocondriales/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Células Tumorales CultivadasRESUMEN
Chondrosarcomas are rare tumors and, historically, investigation of these tumors has been limited to small series and single-institution studies. There have been no studies that evaluated the identification or comparison of differences in prognostic factors between the five known non-conventional chondrosarcoma subtypes (myxoid, juxtacortical, clear-cell, mesenchymal, and dedifferentiated). The purpose of this paper was to determine the demographic, clinical, incidence, and tumor characteristics of all five known non-conventional chondrosarcoma subtypes, determine the 1-, 5-year, and median survival differences between these subtypes, and to determine the demographic and clinical variables that are significant prognostic indicators for each chondrosarcoma subtypes. We retrospectively reviewed the SEER database for all patients with non-conventional chondrosarcoma. χ2 testing was used for correlations between clinical variables. Kaplan-Meier and Cox proportional hazard analysis were used to compare survival of the subtypes, and to assess the prognostic value of age group, race, sex, grade, anatomic location, and metastatic involvement. Several demographic characteristics including gender, race, age, and grade varied between chondrosarcoma subtypes. The tumor characteristics showed marked differences in presence of metastasis on presentation between the subtypes with increasing order of rate of metastasis with juxtacortical (2.1%), clear cell (5.7%), myxoid (7.6%), mesenchymal (10.6%), and the highest in dedifferentiated (19.8%). One-, 5-year, and median survival differed significantly between chondrosarcomas subtypes. The highest median survival was found in the juxtacortical subtype (97 months), followed by clear cell (79 months), myxoid (60 months), mesenchymal (33.5 months), and lowest in dedifferentiated (11 months). The only prognostic variable that was shown to significantly impact the survival of each non-conventional chondrosarcoma subtype was a metastatic disease at diagnosis (p = 0.03 to p < 0.001). Subtyping classification of chondrosarcoma should be made whenever possible, given differences in survival and prognostic factors between chondrosarcoma subtypes. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:311-319, 2020.
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Condrosarcoma/mortalidad , Adulto , Anciano , Condrosarcoma/diagnóstico , Condrosarcoma/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Programa de VERF , Estados Unidos/epidemiologíaRESUMEN
Fever is a common occurrence in cancer patients and often attributed to the disease or treatment complications. Here we present a case of prolonged fever of undetermined origin in a patient undergoing neoadjuvant chemoradiotherapy for gastroesophageal junction (GEJ) adenocarcinoma. An initial detailed work-up remained elusive to the cause of the fever. However, a positron emission tomography (PET) scan prior to the planned surgical procedure identified a lesion in the liver concerning for hepatic metastasis. A prompt biopsy was obtained and revealed radiation-induced liver disease (RILD). Following treatment with corticosteroids, patient's fever completely subsided. While RILD is a recognized complication of radiotherapy, prolonged fever in this setting has not been previously reported. This case illustrates that RILD can sometimes present as prolonged fever. Furthermore, clinicians should be cognizant of radiation necrosis as a potential treatment complication that should be confirmed with a biopsy to avoid missing the chance at potential cure.
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Treatment of bone sarcoma requires careful planning and involvement of an experienced multidisciplinary team. Significant advancements in systemic therapy, radiation, and surgery in recent years have contributed to improved functional and survival outcomes for patients with these difficult tumors, and emerging technologies hold promise for further advancement.
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Neoplasias Óseas/terapia , Manejo de la Enfermedad , Osteosarcoma/terapia , Terapia Combinada , HumanosRESUMEN
PURPOSE: To identify novel genetic markers predictive of clinical benefit from epidermal growth factor receptor-directed antibody therapy in patients with metastatic colorectal cancer. PATIENTS AND METHODS: Seventy-six consecutive patients who received cetuximab or panitumumab, either alone or in combination with chemotherapy and with available tumor tissue were included. Tumor tissue was tested by pyrosequencing for mutations at known hot spots in the KRAS, BRAF, PIK3CA, PIK3R1, AKT1, and PTEN genes. PTEN promoter methylation status was analyzed by methylation-specific polymerase chain reaction, and expression was determined by immunohistochemistry (IHC). Forty-four patients had 4 weeks of therapy and were considered for clinical correlates. RESULTS: Consistent with previous studies, KRAS gene mutations were associated with a shorter progression-free survival (PFS) and overall survival (OS). Among the patients with wild-type KRAS, preservation of PTEN expression and PIK3CA wild-type status was associated with improved OS (median OS, 80.4 vs. 32.5 weeks; hazard ratio, 0.33; P = .0008) and a trend toward improved PFS (median PFS, 24.8 vs. 15.2 weeks; hazard ratio, 0.51; P = .06), compared with PTEN-negative or PIK3CA-mutant tumors. PTEN methylation was more common in the metastatic samples than in the primary samples (P = .02). The simultaneous presence of methylation and mutation in the PTEN gene was associated with IHC negativity (P = .026). CONCLUSION: In addition to KRAS mutation, loss of PTEN expression (by IHC) and PIK3CA mutation is likely to be predictive of a lack of benefit to anti-EGFR therapy in metastatic colorectal cancer. PTEN promoter methylation and mutation status was predictive of PTEN expression and may be used as an alternative means of predicting response to EGFR-targeted therapy.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Resistencia a Antineoplásicos/genética , Mutación , Fosfohidrolasa PTEN/genética , Fosfatidilinositol 3-Quinasas/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Cetuximab , Fosfatidilinositol 3-Quinasa Clase I , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Receptores ErbB/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Fosfohidrolasa PTEN/biosíntesis , Panitumumab , Pronóstico , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas p21(ras) , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas ras/genéticaRESUMEN
BACKGROUND: Oxaliplatin is used to treat patients with colorectal cancer (CRC); however, half the patients fail to benefit. The excision repair cross-complementing group-1 (ERCC1) gene was studied and it was hypothesized that its inducible expression contributes to cellular resistance. MATERIALS AND METHODS: Thirty CRC cell lines were treated with oxaliplatin and sensitivity was determined by apoptosis. Four sensitive and resistant cell lines were analyzed for oxaliplatin effect on ERCC1 expression and two resistant cell lines were subjected to siRNA-mediated gene silencing. RESULTS: There was no correlation of basal ERCC1 mRNA expression with response to oxaliplatin. ERCC1 mRNA was induced at 24, 48, and 72 hours (71-264%, p<0.05) and ERCC1 protein at 48 hours (123-521%, p<0.05) post-oxaliplatin treatment in resistant cells only. siRNA-mediated silencing of ERCC1 sensitized the CRC cells to oxaliplatin-induced apoptosis, and increased cleaved PARP. CONCLUSION: ERCC1 gene expression is inducible, contributes to oxaliplatin resistance, and is reversible by targeted suppression of ERCC1, identifying ERCC1 as a potential target for drug development.