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BACKGROUND & AIMS: Lynch syndrome (LS) carriers develop mismatch repair-deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. METHODS: We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. RESULTS: Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair-deficient cancers and precancers via transcriptomics analysis. CONCLUSIONS: Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers.
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Antígenos de Neoplasias , Neoplasias Colorrectales Hereditarias sin Poliposis , Secuenciación del Exoma , Mutación del Sistema de Lectura , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Femenino , Mutación , Masculino , Persona de Mediana Edad , Reparación de la Incompatibilidad de ADN/genética , Repeticiones de Microsatélite , Inestabilidad de Microsatélites , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/prevención & control , Adulto , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéuticoRESUMEN
Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029CAsunto(s)
Neoplasias del Colon
, Neoplasias Colorrectales Hereditarias sin Poliposis
, Neoplasias Colorrectales
, Animales
, Neoplasias del Colon/genética
, Neoplasias Colorrectales/genética
, Neoplasias Colorrectales/patología
, Neoplasias Colorrectales Hereditarias sin Poliposis/genética
, Neoplasias Colorrectales Hereditarias sin Poliposis/patología
, Metilación de ADN/genética
, Reparación de la Incompatibilidad de ADN/genética
, Genómica
, Humanos
, Macaca mulatta/genética
, Ratones
, Inestabilidad de Microsatélites
, Homólogo 1 de la Proteína MutL/genética
RESUMEN
INTRODUCTION: Many patients with mucinous appendiceal adenocarcinoma experience peritoneal recurrence despite complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Prior work has demonstrated that repeat CRS/HIPEC can prolong survival in select patients. We sought to validate these findings using outcomes from a high-volume center. PATIENTS AND METHODS: Patients with mucinous appendiceal adenocarcinoma who underwent CRS/HIPEC at MD Anderson Cancer Center between 2004 and 2021 were stratified by whether they underwent CRS/HIPEC for recurrent disease or as part of initial treatment. Only patients who underwent complete CRS/HIPEC were included. Initial and recurrent groups were compared. RESULTS: Of 437 CRS/HIPECs performed for mucinous appendiceal adenocarcinoma, 50 (11.4%) were for recurrent disease. Patients who underwent CRS/HIPEC for recurrent disease were more often treated with an oxaliplatin or cisplatin perfusion (35%/44% recurrent vs. 4%/1% initial, p < 0.001), had a longer operative time (median 629 min recurrent vs. 511 min initial, p = 0.002), and had a lower median length of stay (10 days repeat vs. 13 days initial, p < 0.001). Thirty-day complication and 90-day mortality rates did not differ between groups. Both cohorts enjoyed comparable recurrence free survival (p = 0.82). Compared with patients with recurrence treated with systemic chemotherapy alone, this select cohort of patients undergoing repeat CRS/HIPEC enjoyed better overall survival (p < 0.001). CONCLUSIONS: In appropriately selected patients with recurrent appendiceal mucinous adenocarcinoma, CRS/HIPEC can provide survival benefit equivalent to primary CRS/HIPEC and that may be superior to that conferred by systemic therapy alone in select patients. These patients should receive care at a high-volume center in the context of a multidisciplinary team.
Asunto(s)
Adenocarcinoma Mucinoso , Neoplasias del Apéndice , Hipertermia Inducida , Neoplasias Peritoneales , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Procedimientos Quirúrgicos de Citorreducción , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Hipertermia Inducida/efectos adversos , Neoplasias Peritoneales/patología , Recurrencia Local de Neoplasia/patología , Neoplasias del Apéndice/patología , Adenocarcinoma Mucinoso/patología , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Rectal MRI provides a detailed depiction of pelvic anatomy; specifically, the relationship of the tumor to key anatomic structures, including the mesorectal fascia, anterior peritoneal reflection, and sphincter complex. However, anatomic inconsistencies, pitfalls, and confusion exist, which can have a strong impact on interpretation and treatment. These areas of confusion include the definition of the rectum itself, specifically differentiation of the rectum from the anal canal and the sigmoid colon, and delineation of the high versus low rectum. Other areas of confusion include the relative locations of the mesorectal fascia and peritoneum and their significance in staging and treatment, the difference between the mesorectal fascia and circumferential resection margin, involvement of the sphincter complex, and evaluation of lateral pelvic lymph nodes. The impact of these anatomic inconsistencies and sources of confusion is significant, given the importance of MRI in depicting the anatomic relationship of the tumor to critical pelvic structures, to triage surgical resection and neoadjuvant chemoradiotherapy with the goal of minimizing local recurrence. Evolving treatment paradigms also place MRI central in management of rectal cancer. ©RSNA, 2024.
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Imagen por Resonancia Magnética , Estadificación de Neoplasias , Neoplasias del Recto , Humanos , Canal Anal/diagnóstico por imagen , Canal Anal/patología , Canal Anal/anatomía & histología , Imagen por Resonancia Magnética/métodos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Recto/diagnóstico por imagen , Recto/patologíaRESUMEN
INTRODUCTION: Appendiceal neoplasms have a propensity for peritoneal dissemination. The standard of care for select individuals is CRS/HIPEC. In the current 8th AJCC Staging system, a finding of only intraperitoneal acellular mucin (M1a) is classified as Stage IVa. There is concern that the current AJCC system may over-stage patients. METHODS: This was a single-institution retrospective review of 164 cases of mucinous appendiceal neoplasm. Patients undergoing CRS/HIPEC with M1a disease were compared to patients with peritoneal deposits containing tumor cells (well-differentiated adenocarcinoma; low-grade mucinous carcinoma peritonei-M1b,G1). Overall and recurrence-free survival were assessed. RESULTS: Median age was 51 years, 70% were female, and 75% White. Sixty-four patients had M1a disease and 100 M1b,G1 disease. M1a disease had a lower median PCI score (11 vs. 20, p = .0001) and a higher rate of complete CRS (62% vs. 50%, p = .021). Median follow-up was 7.6 years (IQR 5.6-10.5 years). For M1a disease, there were no recurrences and only one patient died during the study interval. In comparison, for M1b disease, 66/100 (66%) recurred with a 5-year RFS of 40.5% (HR 8.0, 95% CI 4.9-15.1, p < .0001), and 31/100 (31%) died with a 5-year OS of 84.8% (HR 4.5, 95% CI 2.2-9.2, p < .0001). CONCLUSIONS: Acellular mucin (M1a disease) after CRS/HIPEC for appendiceal neoplasm is associated with longer OS and RFS compared to M1b, G1 disease. Current AJCC staging does not accurately reflect the differing outcomes of these two patient populations. The presence of acellular mucin in the peritoneal cavity should not be perceived as a metastatic equivalent.
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Neoplasias del Apéndice , Intervención Coronaria Percutánea , Humanos , Femenino , Persona de Mediana Edad , Masculino , Mucinas , Neoplasias del Apéndice/terapia , Quimioterapia Intraperitoneal Hipertérmica , Procedimientos Quirúrgicos de Citorreducción , PronósticoRESUMEN
OBJECTIVE: Lateral pelvic lymph node (LPLN) metastases are an important cause of preventable local failure in rectal cancer. The aim of this study was to evaluate clinical and oncological outcomes following magnetic resonance imaging (MRI)-directed surgical selection for lateral pelvic lymph node dissection (LPLND) after total neoadjuvant therapy (TNT). METHODS: A retrospective consecutive cohort analysis was performed of rectal cancer patients with enlarged LPLN on pretreatment MRI. Patients were categorized as LPLND or non-LPLND. The main outcomes were lateral local recurrence rate, perioperative and oncological outcomes and factors associated with decision making for LPLND. RESULTS: A total of 158 patients with enlarged pretreatment LPLN and treated with TNT were identified. Median follow-up was 20 months (interquartile range 10-32). After multidisciplinary review, 88 patients (56.0%) underwent LPLND. Mean age was 53 (SD±12) years, and 54 (34.2%) were female. Total operative time (509 vs 429 minutes; P =0.003) was greater in the LPLND group, but median blood loss ( P =0.70) or rates of major morbidity (19.3% vs 17.0%) did not differ. LPLNs were pathologically positive in 34.1%. The 3-year lateral local recurrence rates (3.4% vs 4.6%; P =0.85) did not differ between groups. Patients with LPLNs demonstrating pretreatment heterogeneity and irregular margin (odds ratio, 3.82; 95% confidence interval: 1.65-8.82) or with short-axis ≥5 mm post-TNT (odds ratio 2.69; 95% confidence interval: 1.19-6.08) were more likely to undergo LPLND. CONCLUSIONS: For rectal cancer patients with evidence of LPLN metastasis, the appropriate selection of patients for LPLND can be facilitated by a multidisciplinary MRI-directed approach with no significant difference in perioperative or oncologic outcomes.
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Terapia Neoadyuvante , Neoplasias del Recto , Toma de Decisiones , Femenino , Humanos , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Recurrencia Local de Neoplasia/patología , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Estudios RetrospectivosRESUMEN
INTRODUCTION: Rectal neuroendocrine carcinomas (rNECs) are poorly characterized and, given their aggressive nature, optimal management is not well-established. We therefore sought to describe clinicopathologic traits, treatment details, and survival patterns for patients with rNECs. METHODS: Patients captured in the National Cancer Database (NCDB; 2004-2016) with rNECs managed with observation, chemotherapy, or proctectomy ± chemotherapy were considered for analysis. RESULTS: The inclusion criteria were met by 777 patients. Mean age was 62.4 years, 45% were male, 80% were Caucasian, 40% presented with lymph nodes metastases, and 49% presented with distant metastases. Chemotherapy and surgical resection were administered in 72 and 19% of cases, respectively. Median overall survival (OS) was 0.83 years (1 year, 41%; 3 years, 13%; 5 years, 10%). During the study interval, 659 (85%) patients died, with a median follow-up of 0.79 years. On multivariable analysis, age ≥60 years, male sex, and distant metastases were associated with worse survival; surgical resection and administration of chemotherapy were associated with a reduced risk of death. Among non-metastatic patients treated with surgical resection, administration of chemotherapy was protective, while a positive lymph node ratio (LNR) ≥42% (median value) was associated with an increased risk of death. There was no difference in the number of examined lymph nodes between LNR cohorts. CONCLUSIONS: Patients with rNECs experience dismal survival outcomes, including those with non-metastatic disease treated with curative-intent surgical resection. Neoadjuvant therapy can serve as a useful biologic test, and surgical resection should be judiciously employed.
Asunto(s)
Carcinoma Neuroendocrino , Neoplasias del Recto , Carcinoma Neuroendocrino/cirugía , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias del Recto/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Patients with T4 colon adenocarcinomas have an increased risk of peritoneal metastases (PM) but the histopathologic risk factors for its development are not well-described. OBJECTIVE: The purpose of this study was to determine factors associated with PM, time to recurrence, and survival after recurrence among patients with T4 colon cancer. PATIENTS AND METHODS: Patients with pathologic T4 colon cancer who underwent curative resection from 2005 to 2017 were identified from a prospectively maintained institutional database and classified by recurrence pattern: (a) none - 68.8%; (b) peritoneal only - 7.9%; (c) peritoneal and extraperitoneal - 9.9%; and (d) extraperitoneal only - 13.2%. Associations between PM development and patient, primary tumor, and treatment factors were assessed. RESULTS: Overall, 151 patients were analyzed, with a median follow-up of 66.2 months; 27 patients (18%) developed PM (Groups B and C) and 20 (13%) patients recurred at non-peritoneal sites only (Group D). Median time to developing metastases was shorter for Groups B and C compared with Group D (B and C: 13.7 months; D: 46.7 months; p = 0.022). Tumor deposits (TDs) and nodal stage were associated with PM (p < 0.05), and TDs (p = 0.048) and LVI (p = 0.015) were associated with additional extraperitoneal recurrence. Eleven (41%) patients with PM underwent salvage surgery, and median survival after recurrence was associated with the ability to undergo cytoreduction (risk ratio 0.20, confidence interval 0.06-0.70). CONCLUSION: PM risk after resection of T4 colon cancer is independently associated with factors related to lymphatic spread, such as N stage and TDs. Well-selected patients can undergo cytoreduction with long-term survival. These findings support frequent postoperative surveillance and aggressive early intervention, including cytoreduction.
RESUMEN
OBJECTIVE: Patients with Lynch syndrome (LS) are at markedly increased risk for colorectal cancer. It is being increasingly recognised that the immune system plays an essential role in LS tumour development, thus making an ideal target for cancer prevention. Our objective was to evaluate the safety, assess the activity and discover novel molecular pathways involved in the activity of naproxen as primary and secondary chemoprevention in patients with LS. DESIGN: We conducted a Phase Ib, placebo-controlled, randomised clinical trial of two dose levels of naproxen sodium (440 and 220 mg) administered daily for 6 months to 80 participants with LS, and a co-clinical trial using a genetically engineered mouse model of LS and patient-derived organoids (PDOs). RESULTS: Overall, the total number of adverse events was not different across treatment arms with excellent tolerance of the intervention. The level of prostaglandin E2 in the colorectal mucosa was significantly decreased after treatment with naproxen when compared with placebo. Naproxen activated different resident immune cell types without any increase in lymphoid cellularity, and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Naproxen demonstrated robust chemopreventive activity in a mouse co-clinical trial and gene expression profiles induced by naproxen in humans showed perfect discrimination of mice specimens with LS and PDOs treated with naproxen and control. CONCLUSIONS: Naproxen is a promising strategy for immune interception in LS. We have discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. TRIAL REGISTRATION NUMBER: gov Identifier: NCT02052908.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Quimioprevención , Neoplasias Colorrectales Hereditarias sin Poliposis/tratamiento farmacológico , Neoplasias Colorrectales Hereditarias sin Poliposis/inmunología , Naproxeno/farmacología , Adulto , Anciano , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Naproxeno/administración & dosificaciónRESUMEN
BACKGROUND: Appendiceal adenocarcinoma (AA) is an orphan disease with unique clinical attributes but often treated as colorectal cancer (CRC). Understanding key molecular differences between AA and CRC is critical. METHODS: We performed retrospective analyses of AA patients (N = 266) with tumour and/or blood next-generation sequencing (NGS) (2013-2018) with in-depth clinicopathological annotation. Overall survival (OS) was examined. For comparison, CRC cohorts annotated for sidedness, consensus molecular subtypes (CMS) and mutations (N = 3283) were used. RESULTS: Blood-NGS identified less RAS/GNAS mutations compared to tissue-NGS (4.2% vs. 60.9%, P < 0.0001) and showed poor concordance with tissue for well-/moderately differentiated tumours. RAS (56.2%), GNAS (28.1%) and TP53 (26.9%) were most frequent mutations. Well/moderately differentiated tumours harboured more RAS (69.2%/64.0% vs. 40.5%) and GNAS (48.7%/32.0% vs. 10.1%) while moderate/poorly differentiated tumours had more TP53 (26.0%/27.8% vs. 7.7%) mutations. Appendiceal adenocarcinoma (compared to CRC) harboured significantly fewer APC (9.1% vs. 55.4%) and TP53 (26.9% vs. 67.5%) and more GNAS mutations (28.1% vs. 2.0%) (P < 0.0001). Appendiceal adenocarcinoma mutation profile did not resemble either right-sided CRC or any of the four CMS in CRC. High grade, but no mutation, was independently predictive of survival. CONCLUSION: Integrated clinico-molecular profiling of AA identified key molecular drivers distinct from CRC. Appendiceal adenocarcinoma has a predominantly grade-driven biology that trumps mutations.
Asunto(s)
Adenocarcinoma/genética , Neoplasias del Apéndice/genética , Neoplasias Colorrectales/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Neoplasias del Apéndice/mortalidad , Neoplasias del Apéndice/patología , Cromograninas/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Genes ras , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Estudios Retrospectivos , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BACKGROUND: Moderately and poorly differentiated adenocarcinoma of the appendix represents an aggressive histological variant with a high risk of recurrence and death. METHODS: Overall, 178 patients with moderately and poorly differentiated appendiceal adenocarcinoma were identified from a prospective database. Clinical, pathologic, and treatment factors were analyzed for outcomes. RESULTS: Diagnostic laparoscopy (DL) identified radiographic occult peritoneal metastasis in 25 (42%) patients. These patients had a significantly lower peritoneal carcinomatosis index (PCI) and improved overall survival (OS) compared with those with radiographic disease. Twenty-seven (41%) patients were excluded from cytoreductive surgery (CRS) because of findings on DL, while 116 (65%) patients underwent CRS and hyperthermic intraperitoneal chemotherapy (HIPEC), with a median disease-free survival (DFS) of 23 months. Mucinous histology (hazard ratio [HR] 0.52, p = 0.04) and PCI (HR 1.054, p = 0.02) were independent predictors of DFS. The median OS following CRS and HIPEC was 48 months. Mucinous histology (HR 0.352, p = 0.018), signet ring cells (HR 3.34, p = 0.02), positive peritoneal cytology (HR 0.081, p = 0.04), and PCI (HR 1.076, p = 0.004) were independently associated with OS. Eight-five (73.3%) patients received neoadjuvant chemotherapy, and 40 (47.1%) patients achieved a radiographic response; 36 (42.3%) had stable disease, while 9 (10.6%) had progressive disease. Stable or responsive disease was associated with improved median OS of 44 months, compared with 21 months for those with progressive disease (p = 0.011). CONCLUSIONS: In selected patients, long-term survival can be obtained. Mucinous histology, absence of signet ring cells, negative peritoneal cytology, PCI ≤ 20, and response/stable disease after neoadjuvant chemotherapy are important selection criteria for CRS and HIPEC.
Asunto(s)
Adenocarcinoma Mucinoso/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Apéndice/terapia , Procedimientos Quirúrgicos de Citorreducción , Hipertermia Inducida , Neoplasias Peritoneales/terapia , Adenocarcinoma Mucinoso/diagnóstico por imagen , Adenocarcinoma Mucinoso/secundario , Adulto , Neoplasias del Apéndice/diagnóstico por imagen , Neoplasias del Apéndice/patología , Diferenciación Celular , Quimioterapia Adyuvante , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Selección de Paciente , Neoplasias Peritoneales/diagnóstico por imagen , Neoplasias Peritoneales/secundario , Tasa de SupervivenciaRESUMEN
BACKGROUND: Mucinous appendiceal neoplasms can contain radiopaque calcifications. Whether appendiceal radiographic calcifications indicate the presence of an appendiceal epithelial neoplasm is unknown. This study aimed to determine whether appendiceal calcifications detected by computed tomography (CT) correlate with the presence of appendiceal epithelial neoplasms. METHODS: From prospective appendiceal and pathology databases, 332 cases of appendiceal neoplasm and 136 cases of control appendectomy were identified, respectively. Only cases with preoperative CT scans available for review were included in the study. Images were reviewed by two abdominal radiologists. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated, and the kappa statistic was used to determine agreement between the radiologists' interpretations. RESULTS: Interobserver agreement between the radiologists was substantial, with a kappa of 0.74. Appendiceal mural calcifications were identified on CT scans in 106 appendiceal neoplasm cases (32%) and in 1 control case (1%) (P = 0.0001). In the appendiceal neoplasm subgroup, the presence of radiographic calcifications was associated with mucinous histology (35% vs 17%; P = 0.006; odds ratio [OR], 0.38; 95% confidence interval [CI], 0.18-0.78) and with well-differentiated histologic grade (40% vs 24%; P = 0.002; OR, 0.47; 95% CI, 0.29-0.76). The findings showed a sensitivity of 31.9% (95% CI, 26.9-37.2%), a specificity of 99.3% (95% CI, 96-100%), a PPV of 99.1% (95% CI, 94.9-100%), and an NPV of 37.4% (95% CI, 32.4-42.6%). CONCLUSION: This case-control study showed that appendiceal mural calcifications detected on CT are associated with underlying appendiceal epithelial neoplasms and that the identification of incidental mural appendiceal calcifications may have an impact on decisions regarding surgical intervention.
Asunto(s)
Neoplasias del Apéndice/patología , Calcinosis/patología , Neoplasias Glandulares y Epiteliales/patología , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Apéndice/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Glandulares y Epiteliales/diagnóstico por imagen , Valor Predictivo de las Pruebas , Estudios Prospectivos , Tomografía Computarizada por Rayos X/métodos , Adulto JovenAsunto(s)
Carcinoma Hepatocelular , Embolización Terapéutica , Neoplasias Hepáticas , Malformaciones Vasculares , Adulto , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/terapia , Vena Porta/diagnóstico por imagen , Vena Porta/cirugía , Derivación Portosistémica Quirúrgica , Malformaciones Vasculares/complicaciones , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/terapiaRESUMEN
BACKGROUND: Advances in multidisciplinary care are changing the prognostic impact of colorectal lung metastases. Resection of colorectal liver metastases (CLM) may benefit patients with synchronous lung metastases even when lung metastases are not resected. The aim of this study was to investigate the survival of patients undergoing complete resection of CLM in the setting of unresected lung metastases. PATIENTS AND METHODS: We compared survival among 98 patients who underwent resection of CLM with unresected lung metastases, 64 who received only chemotherapy for limited colorectal liver and lung metastases, and 41 who underwent resection of both liver and lung metastases. Prognostic factors were investigated in the patients who underwent resection of CLM only. RESULTS: The 3-year/5-year overall survival (OS) rates of patients with CLM resection only (42.9 %/13.1 %) were better than those of patients treated with chemotherapy only (14.1 %/1.6 %; p < 0.01) but worse than those of patients with resection of liver and lung metastases (68.9 %/56.9 %; p < 0.01). Multivariate analysis of patients with CLM resection only revealed that KRAS mutation [hazard ratio (HR) 2.10; 95 % confidence interval (CI) 1.21-3.64; p < 0.01] and rectal primary tumor (HR 1.72; 95 % CI 1.02-2.88; p = 0.04) were independent predictors of worse OS. Survival of patients without these risk factors was similar to that of patients with curative metastasectomy. CONCLUSIONS: Complete resection of metastases remains the primary goal of treatment for stage IV colorectal cancer. Resection of CLM without resection of lung metastases is associated with an intermediate survival between that of patients treated with palliative and curative intent and should be considered in selected patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/mortalidad , Hepatectomía/mortalidad , Neoplasias Hepáticas/mortalidad , Neoplasias Pulmonares/mortalidad , Metastasectomía/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Selección de Paciente , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Primary sinonasal tumors with neuroendocrine differentiation (STNDs) are uncommon, with overlapping histology. According to the amount of neuroendocrine component, they can be subcategorized into esthesioneuroblastoma, high-grade sinonasal neuroendocrine carcinoma/small cell carcinoma, and sinonasal undifferentiated carcinoma. Achaete-scute homolog 1 (ASH1) is a master gene for neuroendocrine differentiation and is expressed in fetal and adult neuroendocrine tissues. Expression of ASH1 protein may be a useful marker for cancers with neuroendocrine features. The aim of this study was to compare and assess the value of ASH1 protein expression/levels in STND. We reviewed the morphological features and performed immunohistochemical analyses for ASH1 in 30 samples of surgically resected cancers with neuroendocrine differentiation from our institution. Achaete-scute homolog 1 was found to be expressed in STND, indicating that it is instrumental in the development of a subset of neurons and neuroendocrine cells and plays a key role in regulating neuroendocrine differentiation in tumor cells. Achaete-scute homolog 1 levels were associated with the degree of STND tumor differentiation (high-grade tumors show increased expression of this protein), correlating well with studies indicating that expression of ASH1 appears to be restricted to immature cells.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Carcinoma Neuroendocrino/patología , Carcinoma de Células Pequeñas/patología , Estesioneuroblastoma Olfatorio/genética , Estesioneuroblastoma Olfatorio/patología , Neoplasias de los Senos Paranasales/metabolismo , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/metabolismo , Carcinoma Neuroendocrino/cirugía , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/metabolismo , Carcinoma de Células Pequeñas/cirugía , Diferenciación Celular/fisiología , Estesioneuroblastoma Olfatorio/cirugía , Humanos , Neoplasias de los Senos Paranasales/patología , FenotipoRESUMEN
AIMS: We have observed glandular downgrowth in some gastric neuroendocrine tumours (NETs), in which nonneoplastic appearing gastric glands are admixed with submucosal neuroendocrine nests, that could potentially be confused with composite tumours. METHODS AND RESULTS: We reviewed 68 gastric NETs with at least submucosal invasion, and evaluated associations between glandular downgrowth, clinical parameters (age, gender, NET setting) and tumour characteristics (size, depth of invasion, grade). Controls included 45 duodenal NETs. Glandular downgrowth was present in 28 (41%) gastric NETs but only 2 (4.4%) duodenal NETs (P < 0.0001). It was not related to age, gender, hypergastrinemia (downgrowth present in 43% of NETs arising in autoimmune gastritis, 41% of Zollinger-Ellison syndrome, 36% of sporadic NETs), tumour size, depth of invasion, or grade. Glandular downgrowth was confined to the submucosa even though 12 (18%) gastric NETs invaded muscularis propria. Submucosal gastric glands (pyloric type in 79%, intestinal in 50%, fundic in 29%) showed metaplastic changes similar to overlying mucosa, were usually mitotically inactive (64% of cases lacked mitotic figures), were geographically restricted to the NET, and never metastasized. CONCLUSIONS: Our findings support the frequent occurrence and nonneoplastic nature of glandular downgrowth in gastric NETs, which should not be mistaken for composite tumours.
Asunto(s)
Mucosa Gástrica/patología , Neoplasias Complejas y Mixtas/patología , Tumores Neuroendocrinos/patología , Neoplasias Gástricas/patología , Adulto , Anciano , Diagnóstico Diferencial , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA. AA tumors implanted in the peritoneal microenvironment tended to grow faster and displayed greater nuclear expression of Ki-67 relative to the same tumors implanted in the flank. Comparing the tumor-specific transcriptome (excluding stromal transcription), the peritoneal microenvironment relatively upregulated genes related to proliferation, including MKI67 and EXO1. Peritoneal tumors were also enriched for proliferative gene sets, including E2F and Myc Targets. Proteomic studies found a 2.5-fold increased ratio of active-to-inactive phosphoforms of the YAP oncoprotein in peritoneal tumors, indicating downregulation of Hippo signaling. IMPLICATIONS: The peritoneal microenvironment promotes growth of appendiceal tumors and expression of proliferative pathways in PDXs.
Asunto(s)
Adenocarcinoma , Neoplasias del Apéndice , Neoplasias Peritoneales , Humanos , Neoplasias del Apéndice/genética , Neoplasias del Apéndice/patología , Neoplasias Peritoneales/genética , Multiómica , Xenoinjertos , Proteómica , Ensayos Antitumor por Modelo de Xenoinjerto , Adenocarcinoma/patología , Microambiente TumoralRESUMEN
PURPOSE: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously. EXPERIMENTAL DESIGN: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow-up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, P = 0.041). CONCLUSIONS: In light of recent data demonstrating a lack of efficacy of 5-fluorouracil-based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted. SIGNIFICANCE: AA remains an orphan disease with limited systemic therapy options for patients who are not candidates for surgical resection. These data suggest activity from combined VEGF and PD-L1 inhibition that warrants further study.
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Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Apéndice , Bevacizumab , Humanos , Bevacizumab/uso terapéutico , Bevacizumab/efectos adversos , Bevacizumab/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adenocarcinoma/mortalidad , Anciano , Neoplasias del Apéndice/tratamiento farmacológico , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/mortalidad , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Anciano de 80 o más AñosRESUMEN
The pathogenesis of duodenal tumors in the inherited tumor syndromes familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) is poorly understood. This study aimed to identify genes that are significantly mutated in these tumors and to explore the effects of these mutations. Whole exome and whole transcriptome sequencing identified recurrent somatic coding variants of phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) in 19/70 (27%) FAP and MAP duodenal adenomas, and further confirmed the established driver roles for APC and KRAS. PIGA catalyzes the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Flow cytometry of PIGA-mutant adenoma-derived and CRISPR-edited duodenal organoids confirmed loss of GPI anchors in duodenal epithelial cells and transcriptional profiling of duodenal adenomas revealed transcriptional signatures associated with loss of PIGA. IMPLICATIONS: PIGA somatic mutation in duodenal tumors from patients with FAP and MAP and loss of membrane GPI-anchors may present new opportunities for understanding and intervention in duodenal tumorigenesis.
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Poliposis Adenomatosa del Colon , Neoplasias Duodenales , Glicosilfosfatidilinositoles , Mutación , Humanos , Glicosilfosfatidilinositoles/metabolismo , Glicosilfosfatidilinositoles/genética , Neoplasias Duodenales/genética , Neoplasias Duodenales/metabolismo , Neoplasias Duodenales/patología , Poliposis Adenomatosa del Colon/genética , Poliposis Adenomatosa del Colon/metabolismo , Poliposis Adenomatosa del Colon/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Carcinogénesis/genética , Masculino , FemeninoRESUMEN
Importance: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma. Objective: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma. Design, Setting, and Participants: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD Anderson internal patient database to identify patients with a diagnosis of appendiceal adenocarcinoma and at least 1 tumor marker measured at MD Anderson between March 2016 and May 2023. Data were analyzed from January to December 2023. Main Outcomes and Measures: Association of serum tumor markers with survival in patients with appendiceal adenocarcinoma. Cox proportional hazards regression analyses were also performed to assess associations between clinical factors (serum tumor marker levels, demographics, and patient and disease characteristics) and patient outcomes (overall survival). Results: A total of 1338 patients with appendiceal adenocarcinoma were included, with a median (range) age at diagnosis of 56.5 (22.3-89.6) years. The majority of the patients had metastatic disease (1080 patients [80.7%]). CEA was elevated in 742 of the patients tested (56%), while CA19-9 and CA125 were elevated in 381 patients (34%) and 312 patients (27%), respectively. Individually, elevation of CEA, CA19-9, or CA125 were associated with worse 5-year survival; elevated vs normal was 81% vs 95% for CEA (hazard ratio [HR], 4.0; 95% CI, 2.9-5.6), 84% vs 92% for CA19-9 (HR, 2.2; 95% CI, 1.4-3.4), and 69% vs 93% for CA125 (HR, 4.6; 95% CI, 2.7-7.8) (P < .001 for all). Quantitative evaluation of tumor markers was associated with outcomes. Patients with highly elevated (top 10th percentile) CEA, CA19-9, or CA125 had markedly worse survival, with 5-year survival rates of 59% for CEA (HR, 9.8; 95% CI, 5.3-18.0), 64% for CA19-9 (HR, 6.0; 95% CI, 3.0-11.7), and 57% for CA125 (HR, 7.6; 95% CI, 3.5-16.5) (P < .001 for all). Although metastatic tumors had higher levels of all tumor markers, when restricting survival analysis to 1080 patients with metastatic disease, elevated CEA, CA19-9, or CA125 were all still associated worse survival (HR for CEA, 3.4; 95% CI, 2.5-4.8; P < .001; HR for CA19-9, 1.8; 95% CI, 1.2-2.7; P = .002; and HR for CA125, 3.9; 95% CI, 2.4-6.4; P < .001). Interestingly, tumor grade was not associated with CEA or CA19-9 level, while CA-125 was slightly higher in high-grade tumors relative to low-grade tumors (mean value, 18.3 vs 15.0; difference, 3.3; 95% CI, 0.9-3.7; P < .001). Multivariable analysis identified an incremental increase in the risk of death with an increase in the number of elevated tumor markers, with an 11-fold increased risk of death in patients with all 3 tumor markers elevated relative to those with none elevated. Somatic mutations in KRAS and GNAS were associated with significantly higher levels of CEA and CA19-9. Conclusions and Relevance: In this retrospective study of serum tumor markers in patients with appendiceal adenocarcinoma, CEA, CA19-9, and CA125 were associated with overall survival in appendiceal adenocarcinoma. Given their value, all 3 biomarkers should be included in the initial workup of patients with a diagnosis of appendiceal adenocarcinoma.