RESUMEN
BACKGROUND: Normal carcinoembryonic antigen (CEA) levels (≤ 2.5 ng/ml) after resection of localized colorectal cancer or liver metastases are associated with improved survival, however, these trends are understudied for colorectal peritoneal metastases (CRPM). PATIENTS AND METHODS: We conducted a retrospective single-institution study of patients with CRPM undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) with and without neoadjuvant chemotherapy (NACT). CEA was measured before and after NACT and within 3 months after CRS/HIPEC. RESULTS: A total of 253 patients (mean age 55.3 years) with CRPM undergoing CRS/HIPEC had complete CEA data and 191 also underwent NACT with complete data. The median peritoneal carcinomatosis index score (PCI) of the overall cohort was 12 and 82.7% of patients had complete cytoreduction (CC0). In total, 64 (33.5%) patients had normal CEA levels after NACT with a median overall survival (OS) of 45.2 months compared with those with an elevated CEA (26.4 months, p = 0.004). Patients with normal CEA after NACT had a lower PCI found at the time of surgery than those with elevated CEA (10 versus 14, p < 0.001), 68 (26.9%) patients with an elevated preoperative CEA level experienced normalization after CRS/HIPEC, and 118 (46.6%) patients had elevated CEA after CRS/HIPEC. Patients who experienced normalization demonstrated similar OS to patients that had normal CEA levels pre- and post-surgery and improved OS compared with those with elevated postop CEA (median 41.9 versus 47 months versus 17.1 months, respectively, p < 0.001). CONCLUSIONS: Normal CEA levels after NACT and/or CRS/HIPEC are associated with improved survival for patients with CRPM. Patients that normalize CEA levels after surgery have similar survival to those with normal preoperative levels.
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Neoplasias Colorrectales , Hipertermia Inducida , Neoplasias Peritoneales , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Procedimientos Quirúrgicos de Citorreducción , Antígeno Carcinoembrionario , Neoplasias Colorrectales/patología , Neoplasias Peritoneales/secundario , Estudios Retrospectivos , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Hepatic resection (HR) and thermal ablation of Colorectal Liver Metastases (CRLM) have each individually demonstrated safety and survival benefit. We sought to provide our experience with the combination of HR + ablation within one operation for patients with multiple CRLM. METHODS: Review of a single institution database of patients who underwent HR + ablation between 2010 and 2019. RESULTS: 161 patients were identified who underwent HR + ablation for isolated CRLM (mean age: 59, male 63.4%). 125 (77.6%) patients had bilobar disease and 92 (57.1%) patients had ≥5 tumors. 28 (17.4%) patients experienced minor (grade 1 or 2) complications while 20 (12.4%) had grade 3-5 complications. Patients who underwent simultaneous colon resection with HR + ablation had a higher complication rate (22 of 47, 46.8%) than those undergoing HR + ablation only (26 of 114, 22.8%, p = 0.002). Median and 5-year OS for all patients undergoing HR + ablation was 38.2 months and 33.2%, respectively. 5-year hepatic recurrence free survival was 23.5%. Patients with 5 or more tumors demonstrated no difference in median survival compared to those with fewer than 5 tumors (37.0 months vs 38.4 months, p = 0.326). CONCLUSIONS: In this population of CRLM patients with a relatively high burden of disease, HR + ablation demonstrated an acceptable safety profile as well as durable long-term survival.
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Ablación por Catéter , Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Colorrectales/patología , Ablación por Catéter/efectos adversos , Neoplasias Hepáticas/patología , Hepatectomía/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival. METHODS: This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables' effects on progression-free survival and the effects of immune checkpoint-inhibitors. RESULTS: A total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival. CONCLUSIONS: Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.
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Neoplasias Colorrectales , Hipertermia Inducida , Neoplasias Peritoneales , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/patología , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/terapia , Neoplasias Peritoneales/secundario , Proteínas Proto-Oncogénicas B-raf/genética , Procedimientos Quirúrgicos de Citorreducción , Estudios Retrospectivos , Genómica , Tasa de Supervivencia , Terapia CombinadaRESUMEN
BACKGROUND: CRS-HIPEC provides oncologic benefit in well-selected patients with peritoneal carcinomatosis; however, it is a morbid procedure. Decision tools for preoperative patient selection are limited. We developed a risk score to predict severity of 90 day complications for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). PATIENTS AND METHODS: Adults who underwent CRS-HIPEC at the University of Pittsburgh Medical Center (March 2001-April 2020) were analyzed as part of this study. Primary endpoint was severe complications within 90 days following CRS-HIPEC, defined using Comprehensive Complication Index (CCI) scores as a dichotomous (determined using restricted cubic splines) and continuous variable. Data were divided into training and test sets. Several machine learning and traditional algorithms were considered. RESULTS: For the 1959 CRS-HIPEC procedures included, CCI ranged from 0 to 100 (median 32.0). Adjusted restricted cubic splines model defined severe complications as CCI > 61. A minimum of 20 variables achieved optimal performance of any of the models. Linear regression achieved the highest area under the receiving operator characteristic curve (AUC, 0.74) and outperformed the NSQIP Surgical Risk calculator (AUC 0.80 vs. 0.66). Factors most positively associated with severe complications included peritoneal carcinomatosis index score, symptomatic status, and undergoing pancreatectomy, while American Society of Anesthesiologists 2 class, appendiceal diagnosis, and preoperative albumin were most negatively associated with severe complications. CONCLUSIONS: This study refines our ability to predict severe complications within 90 days of discharge from a hospitalization in which CRS-HIPEC was performed. This advancement is timely and relevant given the growing interest in this procedure and may have implications for patient selection, patient and referring provider comfort, and survival.
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Hipertermia Inducida , Neoplasias Peritoneales , Adulto , Humanos , Neoplasias Peritoneales/terapia , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Juicio , Hipertermia Inducida/efectos adversos , Tasa de Supervivencia , Estudios RetrospectivosRESUMEN
BACKGROUND: Appendiceal mucinous neoplasms (AMNs) with disseminated disease (pseudomyxoma peritonei) are heterogeneous tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients. METHODS: Targeted NGS was performed for 183 patients and correlated with clinicopathologic features to include American Joint Committee on Cancer/World Health Organization (AJCC/WHO) histologic grade, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). RESULTS: Genomic alterations were identified for 179 (98%) disseminated AMNs. Excluding mitogen-activated protein kinase genes and GNAS due to their ubiquitous nature, collective genomic alterations in TP53, SMAD4, CDKN2A, and the mTOR genes were associated with older mean age, higher AJCC/WHO histologic grade, lymphovascular invasion, perineural invasion, regional lymph node metastasis, and lower mean PCI (p < 0.040). Patients harboring TP53, SMAD4, ATM, CDKN2A, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, compared with 88% at 5 years and 88% at 10 years for patients without the aforementioned alterations (p < 0.001). Based on univariate and multivariate analyses, genomic alterations in TP53, SMAD4, ATM, CDKN2A, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). CONCLUSIONS: Targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients who may require increased surveillance and/or aggressive management.
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Adenocarcinoma Mucinoso , Neoplasias del Apéndice , Neoplasias Peritoneales , Seudomixoma Peritoneal , Humanos , Seudomixoma Peritoneal/genética , Seudomixoma Peritoneal/terapia , Seudomixoma Peritoneal/metabolismo , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/terapia , Neoplasias del Apéndice/genética , Neoplasias del Apéndice/terapia , Neoplasias Peritoneales/genética , Neoplasias Peritoneales/terapia , Neoplasias Peritoneales/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Serina-Treonina Quinasas TOR/genética , Procedimientos Quirúrgicos de CitorreducciónRESUMEN
OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.
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Discapacidad Intelectual , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Talasemia alfa , Proteínas Co-Represoras/genética , Genes Homeobox , Proteínas de Homeodominio , Humanos , Discapacidad Intelectual/genética , Chaperonas Moleculares/genética , Recurrencia Local de Neoplasia/genética , Tumores Neuroendocrinos/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/patología , Telómero/genética , Telómero/patología , Factores de Transcripción/genética , Proteína Nuclear Ligada al Cromosoma X/genética , Talasemia alfa/genéticaRESUMEN
BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/cirugía , Endosonografía , Humanos , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Pancreatectomía , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/cirugía , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Appendiceal cancer with peritoneal metastases (ACPM) is a complex disease requiring multidisciplinary care. Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS HIPEC) can significantly improve survival but requires evaluation by a surgical oncologist and significant treatment endurance. The impacts of socioeconomic status (SES) and other social determinants of health on rates of surgical evaluation and treatment have not been examined. METHODS: We conducted a retrospective cohort study examining all patients with ACPM from 2010 to 2018 in a regional healthcare system. Patient characteristics, oncologic details, treatment strategies, and survival were examined. The primary outcomes of interest were referral to Surgical Oncology, receipt of CRS HIPEC, and survival. RESULTS: Of 194 patients identified, 94% had synchronous ACPM. The majority of patients (95%) were referred to surgical oncology. Advanced age was the only predictor of nonreferral (p < 0.001). A total of 147 patients (76%) ultimately underwent CRS HIPEC. After adjusting for medical and tumor characteristics, CRS HIPEC was less likely for patients who were unmarried [odds ratio (OR) 0.253, p = 0.004] or of low SES (OR 0.372, p = 0.03). On subanalysis of patients undergoing CRS HIPEC, median overall survival was worse for patients of low SES [51 months versus not reached (NR), p = 0.05], and this disparity persisted on multivariate analysis [hazard ratio (HR) = 2.278, p = 0.001]. CONCLUSIONS: This analysis is the first to evaluate barriers to CRS HIPEC for ACPM. While most patients were evaluated by a multidisciplinary team, nonmedical factors may play a role in the treatment received and ultimate outcomes. Addressing these disparities is crucial for ensuring equitable outcomes and improving patient care.
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Neoplasias del Apéndice , Hipertermia Inducida , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Apéndice/terapia , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción , Hospitales , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Renta , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Failure to thrive (FTT) is a complex syndrome of nutritional failure and functional decline. Readmission for FTT following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS HIPEC) is common but underexamined. This study aims to determine features, risk factors, and prognostic significance of FTT following CRS HIPEC. PATIENTS AND METHODS: We reviewed patients who underwent CRS HIPEC from 2010 to 2018 at our institution. Patients were categorized into no readmission, FTT readmission, and other readmission. FTT was determined by coding and chart review. We compared baseline characteristics, oncologic data, perioperative outcomes, and survival among the three cohorts. RESULTS: Of 1068 discharges examined, 379 patients (36%) were readmitted within 90 days, of which 134 (12.5%) were labeled as FTT. Patients with FTT readmission had worse preoperative functional status, higher rates of malnutrition, more complex resections, longer hospital stays, and more postoperative complications (all p < 0.001). Ostomy creation [relative risk ratio (RRR) 4.06], in-hospital venous thromboembolism (VTE), discharge to nursing home (RRR 2.48), pre-CRS HIPEC chemotherapy (RRR 1.98), older age (RRR 1.84), and female gender (RRR 1.69) were all independent predictors for FTT readmission on multinomial regression (all p < 0.01). FTT readmission was associated with worse median overall survival on multivariate analysis [hazard ratio (HR) 1.60, p < 0.001] after controlling for oncologic, perioperative, and baseline factors. CONCLUSIONS: FTT is common following CRS HIPEC and appears to be associated with baseline patient characteristics, operative burden, and postoperative complications. Perioperative strategies for improving nutrition and activity, along with early recognition and intervention in FTT may improve patient outcomes.
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Hipertermia Inducida , Neoplasias Peritoneales , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Insuficiencia de Crecimiento/complicaciones , Femenino , Humanos , Hipertermia Inducida/efectos adversos , Readmisión del Paciente , Neoplasias Peritoneales/cirugía , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Appendiceal goblet cell adenocarcinomas (GCC) are rare tumors with clinical behavior between classic carcinoids and adenocarcinomas. Current guidelines recommend right hemicolectomy for all GCCs. PATIENTS AND METHODS: The National Cancer Database was retrospectively queried for appendiceal GCCs undergoing appendectomy or right hemicolectomy between 2004 and 2016. Demographics, tumor characteristics, and post-operative outcomes were collected. The primary outcome was overall survival, which was examined by surgical type and tumor T stage. Multivariate logistic regression was utilized to identify predictors of survival. RESULTS: In total, 1083 GCCs were included, and 81.8% underwent right hemicolectomy. Mean age was 57 years, and 89% were White. Patients undergoing hemicolectomy had higher T-stage tumors (66.6%/14.4% T3/T4 vs. 55.8%/8.1%, p < 0.001). Lymph node positivity increased with T stage (1.1%, 2.1%, 9.9%, and 29.1% for T1-T4). GCCs undergoing colectomy were more frequently moderately or poorly differentiated (16.7%/9.0% vs. 12.2%/6.6%, p = 0.011). Appendectomy surgical margins were positive in 17.3% (3.4% hemicolectomy, p < 0.001). In T3/T4 tumors, a significant survival benefit at 5 years was observed in patients undergoing colectomy as compared with appendectomy (85.4% vs. 82.0%, p = 0.028). On multivariate analysis, lymph node positivity markedly decreased survival overall for the entire cohort (HR 7.58, p < 0.001) and for T3/T4 tumors (HR 7.63, p < 0.001). In patients with T3/T4 tumors, there was a trend towards improved survival with right hemicolectomy (HR 0.42, p = 0.068). CONCLUSION: Omitting right hemicolectomy can be considered for select T1/T2 appendiceal GCCs with negative appendectomy margins, given low rates of lymph node metastases and lack of survival benefit with right hemicolectomy.
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Adenocarcinoma , Neoplasias del Apéndice , Tumor Carcinoide , Adenocarcinoma/cirugía , Apendicectomía , Neoplasias del Apéndice/cirugía , Tumor Carcinoide/cirugía , Colectomía , Células Caliciformes , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
INTRODUCTION: Early recurrence (ER) is a significant challenge for patients with colorectal peritoneal metastases (CRPM) following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS HIPEC). Preoperative risk stratification for ER would improve preoperative decision making. METHODS: We conducted a retrospective study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Optimal definition of ER was determined via minimum p-value approach based on differentiation of post-recurrence survival. Risk factors for ER were assessed in a derivation cohort by uni- and multivariate logistic regression. A predictive score for ER was generated using preoperative variables and validated in an independent cohort. RESULTS: 384 patients were analyzed, 316 (82%) had documented recurrence. Optimal length of post-operative RFS to distinguish ER (n = 144, 46%) vs. late recurrence (LR) (n = 172, 63%) was 8 mos (p<0.01). ER patients had shorter median OS post-CRS-HIPEC (13.6 vs. 39.4 mos, p<0.01). Preoperative BMI (OR 1.88), liver lesions (OR 1.89), progression on chemotherapy (OR 2.14), positive lymph nodes (OR 2.47) and PCI score (16-20: OR 1.7; >20: OR 4.37) were significant predictors of ER (all p<0.05). Using this model, patients were assigned risk scores from 0 to 9. Intermediate (scores 4-6) and high-risk patients (score 7-9) had observed rates of ER of 56% and 79% and overall 2-year survival rates of 27% and 0% respectively. The model showed fair discrimination (AUC 0.72) and good calibration (Hosmer-Lemeshow GOF p = 0.68). CONCLUSIONS: ER predicts markedly worse OS following surgery. Preoperative factors can accurately stratify risk for ER and identify patients in whom CRS-HIPEC for CPRM is futile.
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Neoplasias Colorrectales , Hipertermia Inducida , Intervención Coronaria Percutánea , Neoplasias Peritoneales , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Inutilidad Médica , Recurrencia Local de Neoplasia/terapia , Neoplasias Peritoneales/tratamiento farmacológico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Ninety-day hospital readmission rates following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) range from 20 to 40%. OBJECTIVE: The aim of this study was to develop and validate a simple score to predict readmissions following CRS/HIPEC. STUDY DESIGN: Using a prospectively maintained database, we retrospectively reviewed clinicopathologic, perioperative, and day-of-discharge data for patients undergoing CRS/HIPEC for peritoneal surface malignancies between 2010 and 2018. In-hospital mortalities and discharges to hospice were excluded. Multivariate logistic regression was utilized to identify predictors of unplanned readmission, with three-quarters of the sample randomly selected as the derivation cohort and one-quarter as the validation cohort. Using regression coefficient-based scoring methods, we developed a weighted 7-factor, 10-point predictive score for risk of readmission. RESULTS: Overall, 1068 eligible discharges were analyzed; 379 patients were readmitted within 90 days (35.5%). Seven factors were associated with readmission: stoma creation, Peritoneal Cancer Index score ≥ 15, hyponatremia, in-hospital major complication, preoperative chemotherapy, anemia, and discharge to nursing home. In the validation cohort, 25 patients (9.2%) were categorized as high risk for readmission, with a predicted rate of readmission of 69.3% and an observed rate of 76.0%. The score had fair discrimination (area under the curve 0.70) and good calibration (Hosmer-Lemeshow goodness-of-fit p-value of 0.77). CONCLUSION: Our proposed risk score, easily obtainable on day of discharge, distinguishes patients at high risk for readmission over 90 days following CRS/HIPEC. This score has the potential to target high-risk individuals for intensive follow-up and other interventions.
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Procedimientos Quirúrgicos de Citorreducción , Hipertermia Inducida , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Humanos , Hipertermia Inducida/efectos adversos , Readmisión del Paciente , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS HIPEC) can offer significant survival advantage for select patients with colorectal peritoneal metastases (CRPM). Low socioeconomic status (SES) is implicated in disparities in access to care. We analyze the impact of SES on postoperative outcomes and survival at a high-volume tertiary CRS HIPEC center. PATIENTS AND METHODS: We conducted a retrospective cohort study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Patients were grouped according to SES. Baseline characteristics, perioperative outcomes, and survival were examined between groups. RESULTS: A total of 226 patients were analyzed, 107 (47%) low-SES and 119 (53%) high-SES patients. High-SES patients were younger (52 vs. 58 years, p = 0.01) and more likely to be White (95.0% vs. 91.6%, p = 0.06) and privately insured (83% vs. 57%, p < 0.001). They traveled significantly further for treatment and had lower burden of comorbidities and frailty (p = 0.01). Low-SES patients more often presented with synchronous peritoneal metastases (48% vs. 35%, p = 0.05). Following CRS HIPEC, low-SES patients had longer length of stay and higher burden of postoperative complications, 90-day readmission, and 30-day mortality. Median overall survival following CRS HIPEC was worse for low-SES patients (17.8 vs. 32.4 months, p = 0.02). This disparity persisted on multivariate survival analysis (low SES: HR = 1.46, p = 0.03). CONCLUSIONS: Despite improving therapies for CRPM, low-SES patients remain at a significant disadvantage. Even patients who overcome barriers to care experience worse short- and long-term outcomes. Improving access and addressing these disparities is crucial to ensure equitable outcomes and improve patient care.
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Neoplasias Colorrectales , Hipertermia Inducida , Neoplasias Peritoneales , Neoplasias Colorrectales/terapia , Terapia Combinada , Procedimientos Quirúrgicos de Citorreducción , Humanos , Neoplasias Peritoneales/terapia , Estudios Retrospectivos , Clase Social , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN: We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS: The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with ERBB2-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response. CONCLUSIONS: The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.
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Colangiopancreatografia Retrógrada Endoscópica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/patología , Enfermedades de las Vías Biliares/diagnóstico , Enfermedades de las Vías Biliares/genética , Enfermedades de las Vías Biliares/patología , Biomarcadores de Tumor/sangre , Antígeno CA-19-9/sangre , Constricción Patológica/diagnóstico , Constricción Patológica/genética , Diagnóstico Diferencial , Femenino , Humanos , Cirrosis Hepática Biliar/diagnóstico , Cirrosis Hepática Biliar/genética , Cirrosis Hepática Biliar/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y Especificidad , Manejo de Especímenes/métodos , Adulto JovenRESUMEN
Mutations in RAS occur in 30-50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS, NRAS, HRAS, BRAF, and PIK3CA. Molecular testing was performed on 1286 consecutive mCRC from 1271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS, NRAS, and HRAS for 15, 5, and 2 cases, respectively (6-21 gene copies). Patients with a KRAS-amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology, and MMR proficiency (p ≤ 0.017). Four patients with a KRAS-amplified mCRC and no concomitant RAS/BRAF/PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS-amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS-amplified mCRCs is limited, our data suggest the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.
Asunto(s)
Adenocarcinoma/complicaciones , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias del Colon/complicaciones , Resistencia a Antineoplásicos/genética , Enfermedades Inflamatorias del Intestino/complicaciones , Proteínas Proto-Oncogénicas p21(ras)/genética , Adenocarcinoma/genética , Adenocarcinoma/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Receptores ErbB/antagonistas & inhibidores , Femenino , Amplificación de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/patología , Masculino , Persona de Mediana Edad , Panitumumab/uso terapéutico , Estudios Retrospectivos , Adulto JovenRESUMEN
AIMS: Peritoneal spread is the most common route of metastasis in appendiceal goblet cell adenocarcinoma. The aim of this study was to assess the prognostic significance of the World Health Organization (WHO) 5th edition grading criteria in peritoneal metastases of goblet cell adenocarcinoma. METHODS AND RESULTS: We evaluated the clinicopathological features and survival of 63 patients with peritoneal metastasis of goblet cell adenocarcinoma who underwent cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC), stratified according to the WHO 5th edition and the Tang et al. grading schemes. The patients were also compared with 120 patients with peritoneal metastasis of appendiceal mucinous neoplasia. Most (73%) peritoneal metastases of goblet cell adenocarcinoma were WHO Grade 3 (G3), there being fewer cases of Grade 2 (G2) (16%) and Grade 1 (G1) (11%) disease. No significant differences in overall survival were observed between WHO G1 and G2 tumours or between the three Tang grades. In the multivariable model of survival, WHO G3 [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.02-7.70] and the presence of >50% extracellular mucin (HR 2.30, 95% CI 1.09-4.88) were associated with reduced overall survival for patients with goblet cell adenocarcinoma. As compared with patients with peritoneal metastasis of mucinous neoplasia, patients with goblet cell adenocarcinoma had significantly reduced survival (median overall survival of 37 months versus 102 months, P < 0.001), which was attributed to the reduced survival of patients with G1/G2 goblet cell adenocarcinoma as compared with patients with G1 mucinous neoplasia (median survival of 98 months versus 204 months, P < 0.001). CONCLUSIONS: Grade of peritoneal goblet cell adenocarcinoma determined according to the WHO 5th edition criteria is a clinically relevant measure that independently predicts survival in patients treated with CRS-HIPEC.
Asunto(s)
Neoplasias del Apéndice/patología , Tumor Carcinoide/secundario , Neoplasias Peritoneales/secundario , Adulto , Anciano , Neoplasias del Apéndice/mortalidad , Neoplasias del Apéndice/terapia , Tumor Carcinoide/mortalidad , Tumor Carcinoide/terapia , Procedimientos Quirúrgicos de Citorreducción/mortalidad , Femenino , Humanos , Quimioterapia Intraperitoneal Hipertérmica/mortalidad , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/terapia , Estudios Retrospectivos , Resultado del Tratamiento , Organización Mundial de la SaludRESUMEN
DNA was obtained from matching micro-dissected, primary tumor cells, paired metastases, and peripheral blood mononuclear cells (germline) from patients with appendiceal mucinous neoplasms. We compared specimens from patient cohorts comprising low-grade adenomucinous neoplasm versus high-grade mucinous adenocarcinoma using a targeted, amplicon sequencing panel of 409 cancer related genes (Ion Torrent Comprehensive Cancer Panel, Thermo-Fisher, Waltham, MA). Copy number variants, single nucleotide variants and small insertions/deletions were identified using a multiplex algorithm pipeline (GATK, VarScan2, MuTect2, SIFT, SIFT-INDEL, PolyPhen-2, Provean). There were significantly more damaging variants in high-grade versus low-grade tumor cohorts. Both cohorts contained damaging, heterozygous germline variants (catenin ß1; notch receptor 1 and 4) in pathways associated with cell-lineage specification (WNT, NOTCH). Damaging, somatic KRAS proto-oncogene, GTPase mutations were present in both cohorts, while somatic GNAS complex locus mutations were confined to low-grade neoplasms. Variants predominantly affected transcription factors, kinases, and stem cell signaling molecules in canonical pathways including epithelial to mesenchymal transition, stem cell pluripotency, p53, PTEN, and NF-ÒB signaling pathways. High-grade tumors demonstrated MYC proto-oncogene, bHLH transcription factor (MYC) and death domain associated protein (DAXX) amplification and damaging somatic variants in tumor protein p53 (TP53), likely to amplify an aggressive phenotype. Damaging APC, WNT signaling pathway regulator (APC) deletions were identified in metastatic tissue of both cohorts suggesting a role in invasive disease. Our data suggest that germline dysregulation of WNT and/or NOTCH pathways predisposes patients toward a secretory cell phenotype (i.e., goblet-like cells) upon acquisition of somatic KRAS mutations. Additional somatically acquired variants activating oncogenes MYC and DAXX and inhibiting the critical tumor suppressor, tumor protein TP53, were consistent with manifestation of a high-grade phenotype. These additional changes within the epithelial to mesenchymal transition signaling network (WNT, NOTCH, RAS/ERK/PI3K, PTEN, NF-ÒB), produce aggressive high-grade tumor characteristics by actively driving cells towards dedifferentiation, proliferation, and migration.
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Adenocarcinoma Mucinoso/genética , Neoplasias del Apéndice/genética , Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Dosificación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Polimorfismo de Nucleótido Simple , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Neoplasias del Apéndice/mortalidad , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/cirugía , Variaciones en el Número de Copia de ADN , Diagnóstico Diferencial , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Humanos , Clasificación del Tumor , Fenotipo , Valor Predictivo de las Pruebas , Proto-Oncogenes MasRESUMEN
INTRODUCTION: We hypothesized that repeat cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) for peritoneal metastases (PM) may be associated with suboptimal resection, more frequent postoperative complications, and worse oncologic outcomes. METHODS: Using a prospectively maintained database, we compared clinicopathologic, perioperative, and oncologic outcome data in patients undergoing single or repeat CRS-HIPEC procedures. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with perioperative and oncologic outcomes. RESULTS: Of the 1294 patients undergoing CRS-HIPEC procedures at our institution, only one CRS-HIPEC procedure (single HIPEC cohort) was performed in 1169 patients (90.3%), whereas 125 patients (9.7%) underwent repeat CRS-HIPEC procedures (repeat HIPEC cohort). Of the 1440 CRS-HIPEC procedures at our institution, a first CRS-HIPEC procedure was performed in 1294 patients (89.9%), whereas subsequent second, third, and fourth CRS-HIPEC procedures were performed in 125 patients (8.7%), 18 patients (1.3%), and 3 patients (0.2%), respectively. Progression-free survival (PFS) following the second CRS-HIPEC procedure was negatively impacted by shorter PFS following the first CRS-HIPEC procedure, independent of other significant variables related to the second procedure, including completeness of cytoreduction and postoperative complications. Patients undergoing multiple CRS-HIPEC procedures were not at higher risk for suboptimal resection or postoperative complications and demonstrated equivalent PFS following each successive procedure compared to the first procedure. CONCLUSIONS: Repeat CRS-HIPEC procedures for PM were not associated with suboptimal perioperative and oncologic outcomes. Our data confirmed our ability to select patients appropriately for repeat CRS-HIPEC procedures.
Asunto(s)
Quimioterapia del Cáncer por Perfusión Regional/mortalidad , Neoplasias Colorrectales/mortalidad , Procedimientos Quirúrgicos de Citorreducción/mortalidad , Hipertermia Inducida/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Peritoneales/mortalidad , Reoperación/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/terapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Recurrencia Local de Neoplasia/terapia , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/cirugía , Neoplasias Peritoneales/terapia , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
In the original article, the Comprehensive Complication Index (CCI) was incorrectly identified as the Comprehensive Comorbidity Index. Wherever CCI appears, it refers to the Comprehensive Complication Index.
RESUMEN
BACKGROUND: Diagnostic terminology and grading of primary appendiceal mucinous neoplasms lacks uniformity. We sought to identify discordance in pathologic reporting by reviewing pathology slides for cases referred to our institution. METHODS: Using guidelines from Peritoneal Surface Oncology Group International (PSOGI) and American Joint Committee on Cancer 8th edition (AJCC8), we compared diagnostic terminology/grading of primary appendiceal mucinous neoplasms (n = 115) between pathology reports from referring institutions and review of slides by pathologists at our high-volume institution. RESULTS: There was discordance in pathologic terminology and grading of primary appendiceal mucinous neoplasms between referring institutions and our institution in 28% and 50% of patients, respectively. In particular, 24% of patients referred with mucinous adenocarcinoma (MACA) had LAMN on our review, and a higher grade MACA was found in 48% of patients referred with low-grade (G1) MACA and 16% of patients referred with high-grade (G2) MACA following our review. Discordance in tumor grade between primary and metastatic disease was seen in 19% of cases based on referred primary tumor grading compared with only 4% following our review. Systemic chemotherapy was unnecessarily administered to four cases of LAMN (6%) and inappropriately not administered to four cases of MACA (6%) before referral due to inaccurate diagnosis/grading by referring institutions. CONCLUSIONS: We found significant discordance in diagnostic terminology/grading of primary appendiceal mucinous neoplasms following review of referred cases. Inaccurate pathologic assessment was associated with overtreatment or undertreatment with chemotherapy. These data highlight the need for pathologic review of such rare cases at high-volume centers.