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Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites, and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity.
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Infecções por HIV/virologia , HIV-1/fisiologia , Sangue/virologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , DNA Viral/genética , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Leucócitos Mononucleares , Linfonodos/virologia , Provírus/imunologia , Análise de Sequência de DNA , Fenômenos Fisiológicos Virais , Replicação ViralRESUMO
OBJECTIVE: Pancreatic neuroendocrine tumors (PNETs) are uncommon tumors which are increasing in incidence. The management of these tumors continues to evolve. This review examines the current role of surgery in the treatment of these tumors. METHODS: Studies published over the past 10 years were identified using several databases including PubMed, MEDLINE, and Science Direct. Search terms included PNETs, treatment, and surgery. Clinical practice guidelines and updates from several major groups were reviewed. RESULTS: Surgery continues to have a major role in the treatment of sporadic functional and nonfunctional PNETs. Pancreas-sparing approaches are increasingly accepted as alternatives to formal pancreatic resection in selected patients. Options such as watch and wait or endoscopic ablation may be reasonable alternatives to surgery for non-functional PNETs < 2 cm in size. Surgical decision-making in multiple endocrine neoplasia type 1 patients remains complex and in some situations such as gastrinoma quite controversial. The role of surgery has significantly diminished in patients with advanced disease due to the advent of more effective systemic and liver-directed therapies. However, the optimal treatments and sequencing in advanced disease remain poorly defined, and it has been suggested that surgery is underutilized in these patients. CONCLUSIONS: Surgery remains a major treatment modality for PNETs. Given the plethora of available treatments, ongoing controversies and the changing landscape, management has become increasingly complex. An experienced multidisciplinary team which includes surgery is essential to manage these patients.
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Adrenocortical carcinoma (ACC) is a rare aggressive malignancy that originates in the outer layer of the adrenal gland. Most ACCs are sporadic, but a small percentage of cases are due to hereditary cancer syndromes such as Li-Fraumeni syndrome (LFS), Lynch syndrome (LS), and familial adenomatous polyposis (FAP). Multiple endocrine neoplasia type 2A (MEN2A) is an inherited disorder that predisposes to medullary thyroid cancer, pheochromocytoma, and parathyroid hyperplasia. We present here a case of ACC with both LS and MEN2A; the family and medical history were consistent with Lynch. This is, to our knowledge, the first report of a patient with ACC associated with germline mutations in RET and MSH2, and no phenotypical characteristics of MEN2A.
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Carcinoma Adrenocortical/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteína 2 Homóloga a MutS/genética , Proteínas Proto-Oncogênicas c-ret/genética , Carcinoma Adrenocortical/complicações , Carcinoma Adrenocortical/patologia , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 2a/complicações , Neoplasia Endócrina Múltipla Tipo 2a/patologia , LinhagemRESUMO
INTRODUCTION: Malignant peritoneal mesothelioma (MPM) is a lethal cancer, with approximately 2% of diagnoses occurring in patients less than 40 years of age. The purpose of this study is to report the only long-term follow up and survival of pediatric patients with MPM after multi-modality therapy including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: We retrospectively investigated a prospectively maintained database including patients <21 years old who underwent CRS and HIPEC from 1994 through 2014. Follow-up information was available through 2019 and is included in this report. RESULTS: Seven young patients underwent CRS and HIPEC. Final histology was epithelioid in all patients. Three patients had received neo-adjuvant systemic chemotherapy. At the time of the operation Peritoneal Cancer Index ranged from 6 to 25. Completeness of cytoreduction score after CRS was 0 in 4 patients, 1 in two patients, and 2 in one patient. Post-operative complications included acute kidney injury (n = 1), hyperbilirubinemia (n = 1), bilateral pleural effusions (n = 1) and pneumothorax requiring chest tube placement (n = 1). At last available follow-up, 71% of patients (n = 5) were alive with minimal or no evaluable disease. The remaining two patients had passed away from their disease at 14 and 26 months, respectively, following CRS and HIPEC. Overall survival ranged between 14 and 281 months. CONCLUSION: Our surgical experience shows that CRS and HIPEC is a feasible and safe treatment option in pediatric patients, potentially improving overall survival.
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Hipertermia Induzida , Mesotelioma , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Criança , Cisplatino , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Seguimentos , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Mesotelioma/terapia , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.
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Quimioembolização Terapêutica/métodos , Irinotecano/farmacocinética , Neoplasias Hepáticas/terapia , Inibidores da Topoisomerase I/farmacocinética , Adulto , Idoso , Quimioembolização Terapêutica/efeitos adversos , Monitoramento de Medicamentos , Feminino , Genótipo , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Humanos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/sangue , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Testes Farmacogenômicos , Variantes Farmacogenômicos , Fenótipo , Projetos Piloto , Estudos Prospectivos , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/sangue , Resultado do TratamentoRESUMO
BACKGROUND: Recurrent adrenocortical carcinoma (ACC) is an aggressive disease with few options offering durable survival benefit. Despite metastasectomy, recurrence is common. Cytoreduction and intraperitoneal chemotherapy have offered improved survival in other advanced cancers. We sought to evaluate the use of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of recurrent intraperitoneal ACC. METHODS: A phase II, single institution clinical trial was approved for patients with radiographic evidence of resectable ACC limited to the peritoneum. Patients underwent treatment if optimal cytoreduction was deemed possible at exploratory laparotomy. Primary outcome was intraperitoneal progression-free survival. Secondary outcomes were treatment-related morbidities and overall survival. RESULTS: Sixty-three patients were evaluated, of whom 11 met eligibility criteria. Nine patients underwent cytoreduction and HIPEC, including one patient who recurred and was re-treated (n = 10 treatments). One patient could not be optimally cytoreduced for HIPEC and therefore did not receive intraperitoneal chemotherapy. There was no perioperative mortality; perioperative comorbidities were limited to Clavien-Dindo grade 2 or 3 and included hematologic, infectious, and neurologic complications. Seven patients experienced disease recurrence and two patients died of disease during follow-up (median 24 mo). Intraperitoneal progression-free survival was 19 mo, and median overall survival has not yet been reached. CONCLUSIONS: Cytoreduction and HIPEC can be performed safely in selected patients. Patients with recurrent ACC confined to the peritoneal cavity can be considered for regional therapy in experienced hands. However, disease recurrence is common, and other treatment options should be explored.
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Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Hipertermia Induzida/efeitos adversos , Recidiva Local de Neoplasia/terapia , Neoplasias Peritoneais/terapia , Neoplasias do Córtex Suprarrenal/mortalidade , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/mortalidade , Carcinoma Adrenocortical/secundário , Adulto , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Feminino , Seguimentos , Humanos , Hipertermia Induzida/métodos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Seleção de Pacientes , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Prognóstico , Intervalo Livre de ProgressãoRESUMO
BACKGROUND & AIMS: Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. METHODS: Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36-76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks. RESULTS: No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1-51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). CONCLUSIONS: Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. LAY SUMMARY: Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. CLINICAL TRIAL NUMBER: ClinicalTrials.gov: NCT01853618.
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Anticorpos Monoclonais/uso terapêutico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Técnicas de Ablação , Adulto , Idoso , Anticorpos Monoclonais Humanizados , Antineoplásicos/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Carcinoma Hepatocelular/imunologia , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
BACKGROUND & AIMS: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from enterochromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to the formation of SI-NETs, although little is known about tumor formation or development. We investigated the relationship between EC cells, ISCs, and SI-NETs. METHODS: We analyzed jejuno-ileal tissue specimens from 14 patients with familial SI-NETs enrolled in the Natural History of Familial Carcinoid Tumor study at the National Institutes of Health from January 2009 to December 2014. Frozen and paraffin-embedded tumor tissues of different stages and isolated crypts were analyzed by in situ hybridization and immunohistochemistry. Tumor clonality was assessed by analyses of mitochondrial DNA. RESULTS: We identified multifocal aberrant crypt-containing endocrine cell clusters (ACECs) that contain crypt EC cell microtumors in patients with familial SI-NETs. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free mucosa indicated widespread, independent, multifocal tumorigenesis. Analyses of mitochondrial DNA confirmed the independent origin of the ACECs. CONCLUSIONS: Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. Increasing our understanding of the role of these reserve EC cells in the genesis of multifocal SI-NETs could improve diagnostic and therapeutic strategies for this otherwise intractable disease.
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Carcinogênese/genética , Neoplasias do Íleo/genética , Neoplasias do Jejuno/genética , Família Multigênica/genética , Tumores Neuroendócrinos/genética , Células Enterocromafins/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Hibridização In Situ , Intestino Delgado/citologia , Complexo Repressor Polycomb 1/genética , Receptores Acoplados a Proteínas G/genética , Células-Tronco/metabolismo , Triptofano Hidroxilase/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Immunotherapeutic treatment strategies including adoptive cell transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated. METHODS: Records of patients with metastatic melanoma treated with ACT at a single institution between 2000 and 2014 were reviewed. Patients with an objective response by RECIST criteria or disease stabilization of at least 6 months and who subsequently developed progressive melanoma and were managed with metastasectomy as the next therapeutic strategy were studied for progression-free survival (PFS) and overall survival (OS). Five additional clinical parameters were also reviewed for association with outcomes. RESULTS: Of 115 patients treated with ACT who met our response criteria and then developed progressive disease, 26 (23%) had surgery. There were no mortalities related to surgical intervention. Median follow-up after surgery was 62 months. Median PFS after surgery was 11 months and five-year OS was 57%. The development of a new site of metastasis after ACT was associated with poor PFS and OS. CONCLUSIONS: Surgery after immunotherapy is safe. Long PFS and OS can be achieved by metastasectomy in selected patients with progressive melanoma following treatment with ACT. Clinical variables important for patient selection for metastasectomy after immunotherapy remain largely undefined. Improvements in immunotherapeutic treatment strategies may increase the role of surgery for patients with advanced disease.
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Transferência Adotiva , Melanoma/terapia , Metastasectomia , Terapia Combinada , Progressão da Doença , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Terapia de Salvação , Taxa de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: The use of routine CT imaging for surveillance in asymptomatic patients with cutaneous melanoma is controversial. We report our experience using a surveillance strategy that included CT imaging for a cohort of patients with high-risk melanoma. METHODS: A total of 466 patients with high-risk cutaneous melanoma enrolled in adjuvant immunotherapy trials were followed for tumor progression by physical examination, labs, and CT imaging as defined by protocol. Evaluations were obtained at least every 6 months for year 1, every 6 months for year 2, and then annually for the remainder of the 5-year study. Time to tumor progression, sites of recurrence, and the method of relapse detection were identified. RESULTS: The patient cohort consisted of 115 stage II patients, 328 stage III patients, and 23 patients with resected stage IV melanoma. The medium time to progression for the 225 patients who developed tumor progression was 7 months. Tumor progression was detected by patients, physician examination or routine labs, or by CT imaging alone in 27, 14, and 59% of cases respectively. Melanoma recurrences were noted to be locoregional in 36% of cases and systemic in 64% of cases. Thirty percent of patients with locoregional relapse and 75% of patients with systemic relapse were detected solely by CT imaging. CONCLUSIONS: CT imaging alone detected the majority of sites of disease progression in our patients with high-risk cutaneous melanoma. This disease was not heralded by symptoms, physical examination, or blood work. Although the benefit of the early detection of advanced melanoma is unknown, this experience is relevant because of the rapid development and availability of potentially curative immunotherapies.
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Melanoma/diagnóstico , Melanoma/secundário , Recidiva Local de Neoplasia/diagnóstico , Vigilância da População/métodos , Autoexame , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Doenças Assintomáticas , Análise Química do Sangue , Ensaios Clínicos como Assunto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Exame Físico , Adulto JovemRESUMO
BACKGROUND & AIMS: Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. METHODS: We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. RESULTS: Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. CONCLUSIONS: We found that small intestinal carcinoids can occur as an inherited autosomal-dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.
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Tumor Carcinoide/genética , Mutação em Linhagem Germinativa , Neoplasias Intestinais/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/patologia , Família , Feminino , Humanos , Neoplasias Intestinais/diagnóstico , Neoplasias Intestinais/patologia , Laparotomia , Masculino , Pessoa de Meia-Idade , Linhagem , Estudos Prospectivos , Adulto JovemRESUMO
PURPOSE: There is no consensus for the treatment of melanoma metastatic to the liver. Percutaneous hepatic perfusion with melphalan (PHP-Mel) is a method of delivering regional chemotherapy selectively to the liver. In this study, we report the results of a multicenter, randomized controlled trial comparing PHP-Mel with best alternative care (BAC) for patients with ocular or cutaneous melanoma metastatic to the liver. PATIENTS AND METHODS: A total of 93 patients were randomized to PHP-Mel (n = 44) or BAC (n = 49). On the PHP-Mel arm, melphalan was delivered via the hepatic artery, and the hepatic effluent captured and filtered extracorporeally prior to return to the systemic circulation via a venovenous bypass circuit. PHP-Mel was repeatable every 4-8 weeks. The primary endpoint was hepatic progression-free survival (hPFS), and secondary endpoints included overall PFS (oPFS), overall survival (OS), hepatic objective response (hOR), and safety. RESULTS: hPFS was 7.0 months for PHP-Mel and 1.6 months for BAC (p < 0.0001), while oPFS was 5.4 months for PHP-Mel and 1.6 months for BAC (p < 0.0001). Median OS was not significantly different (PHP-Mel 10.6 months vs. BAC 10.0 months), likely due to crossover to PHP-Mel treatment (57.1 %) from the BAC arm, and the hOR was 36.4 % for PHP-Mel and 2.0 % for BAC (p < 0.001). The majority of adverse events were related to bone marrow suppression. Four deaths were attributed to PHP-Mel, three in the primary PHP-Mel group, and one post-crossover to PHP-Mel from BAC. CONCLUSION: This randomized, phase III study demonstrated the efficacy of the PHP-Mel procedure. hPFS, oPFS, and hOR were significantly improved with PHP-Mel. PHP with melphalan should provide a new treatment option for unresectable metastatic melanoma in the liver.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Oculares/secundário , Artéria Hepática , Neoplasias Hepáticas/secundário , Melanoma/patologia , Neoplasias Cutâneas/secundário , Adulto , Idoso , Quimioterapia do Câncer por Perfusão Regional , Embolização Terapêutica , Neoplasias Oculares/tratamento farmacológico , Feminino , Seguimentos , Humanos , Infusões Intra-Arteriais , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Perfusão , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Taxa de SobrevidaRESUMO
BACKGROUND: Complete cytoreduction with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been shown to improve survival in patients with low-grade mucinous adenocarcinoma (LGMA). However, incomplete cytoreduction exposes patients to significant morbidity without a similar survival benefit. Preoperative assessment of the ability to achieve CRS is therefore a critical step in selecting patients for CRS/HIPEC. OBJECTIVE: The aim of this study was to develop and validate a preoperative scoring system to accurately predict the ability to achieve complete cytoreduction in patients with LGMA of the appendix. METHODS: A simplified preoperative assessment for appendix tumor (SPAAT) score was developed based on computed tomography scan findings thought to predict incomplete cytoreduction. We applied the SPAAT score to patients with LGMA to determine the ability of the score to predict complete cytoreduction. This scoring system was then applied to a separate cohort of patients from a different institution. Sensitivity and specificity were determined for the SPAAT score. Survival was calculated and correlated with the SPAAT score and the completeness of cytoreduction score. RESULTS: A SPAAT score of <3 is a significant predictor of complete cytoreduction in the derivation cohort. In the validation cohort, 40 of 42 patients with a SPAAT score <3 achieved a complete cytoreduction, for a positive predictive value of 95.2 % and a negative predictive value of 100 %. Additionally, the SPAAT score was a significant predictor of disease-free survival. CONCLUSIONS: The SPAAT score is a useful tool in the preoperative assessment of patients with LGMA who are under consideration for cytoreductive surgery. Prospective analysis of this scoring system is warranted to appropriately select patients who will benefit from CRS/HIPEC.
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Adenocarcinoma Mucinoso/diagnóstico por imagem , Neoplasias do Apêndice/diagnóstico por imagem , Hipertermia Induzida , Seleção de Pacientes , Neoplasias Peritoneais/diagnóstico por imagem , Pseudomixoma Peritoneal/diagnóstico por imagem , Adenocarcinoma Mucinoso/secundário , Adenocarcinoma Mucinoso/cirurgia , Antineoplásicos/administração & dosagem , Neoplasias do Apêndice/patologia , Neoplasias do Apêndice/cirurgia , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Doença , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasia Residual , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Valor Preditivo dos Testes , Período Pré-Operatório , Pseudomixoma Peritoneal/etiologia , Pseudomixoma Peritoneal/terapia , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients. Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFNγ and TNF. The severity of acute toxicities experienced by the patients correlated with serum IFNγ and TNF levels. The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFNγ ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions. Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+) cells in vivo; however, reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions.
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Linfócitos B/imunologia , Citocinas/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma de Células B/terapia , Linfócitos T/imunologia , Antígenos CD19/imunologia , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma de Células B/imunologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Indução de Remissão , Linfócitos T/transplante , Transdução GenéticaRESUMO
BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare disease treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Estimation of personalized survival times can potentially guide treatment and surveillance. METHODS: We analyzed 104 patients who underwent CRS and cisplatin-based HIPEC for MPM. By means of 25 demographic, laboratory, operative, and histopathological variables, we developed a novel nomogram using machine-learned Bayesian belief networks with stepwise training, testing, and cross-validation. RESULTS: The mean peritoneal carcinomatosis index (PCI) was 15, and 66 % of patients had a completeness of cytoreduction (CC) score of 0 or 1. Eighty-seven percent of patients had epithelioid histology. The median follow-up time was 49 (1-195) months. The 3- and 5-year overall survivals (OS) were 58 and 46 %, respectively. The histological subtype, pre-CRS PCI, and preoperative serum CA-125 had the greatest impact on OS and were included in the nomogram. The mean areas under the receiver operating characteristic curve for the 10-fold cross-validation of the 3- and 5-year models were 0.77 and 0.74, respectively. The graphical calculator or nomogram uses color coding to assist the clinician in quickly estimating individualized patient-specific survival before surgery. CONCLUSIONS: Machine-learned Bayesian belief network analysis generated a novel nomogram predicting 3- and 5-year OS in patients treated with CRS and HIPEC for MPM. Pre-CRS estimation of survival times may potentially individualize patient care by influencing the use of systemic therapy and frequency of diagnostic imaging, and might prevent CRS in patients unlikely to achieve favorable outcomes despite surgical intervention.
Assuntos
Teorema de Bayes , Mesotelioma/mortalidade , Nomogramas , Neoplasias Peritoneais/mortalidade , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inteligência Artificial , Quimioterapia do Câncer por Perfusão Regional , Cisplatino/administração & dosagem , Terapia Combinada , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Hipertermia Induzida , Masculino , Mesotelioma/diagnóstico , Mesotelioma/terapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/terapia , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Chronic granulomatous disease is a rare immunodeficiency complicated by dysregulated inflammation and granulomatous complications of the GI tract. The management of chronic granulomatous disease colitis presents the dilemma of an immunocompromised host requiring immunosuppressive therapy which can potentiate fatal infections. OBJECTIVE: The aim of this study was to identify the types of GI surgery performed in patients and determine the role of surgery in the management of refractory colitis. DESIGN AND SETTINGS: A retrospective single-institution chart review was performed. PATIENTS: Of 268 patients with chronic granulomatous disease treated at the National Institutes of Health between 1985 and 2011, 98 (37%) were identified as having colitis; 27 (10%) had a history of GI luminal surgery. MAIN OUTCOME MEASURES: Patient characteristics, type of GI surgery, and clinical outcomes were documented. RESULTS: A total of 62 GI luminal surgeries were performed in 27 patients with chronic granulomatous disease and colitis. All 27 had a history of perineal disease requiring intervention. Four (15%) had additional surgery performed for reasons other than colitis. Otherwise, 12 (44%) had surgery limited to the perineum, 2 (7%) had a segmental resection, and 13 (48%) underwent fecal diversion with ileostomy or colostomy. Despite local procedures, 7 (58%) patients in the perineal-only group remained symptomatic. Both patients with a segmental resection had persistent perineal disease, and 1 had a recurrent colovesicular fistula. Of the 13 ostomy patients, 11 initially received a diverting ostomy. Eight (73%) of these ultimately required additional procedures for refractory disease, and 4 (36%) developed peristomal pyoderma gangrenosum. Four patients who underwent proctocolectomy with end ileostomy, either initially (2) or as a definitive procedure (2), experienced resolution of colitis and perineal disease. LIMITATIONS: This study is limited by its retrospective design, small sample size, and highly selected patient population. CONCLUSIONS: Proctocolectomy with end ileostomy may offer a definitive treatment in a patient with refractory chronic granulomatous disease colitis given current therapeutic limitations.
Assuntos
Colite/cirurgia , Doença Granulomatosa Crônica/complicações , Estudos de Coortes , Colectomia , Colite/etiologia , Colo/cirurgia , Colostomia , Feminino , Humanos , Ileostomia , Masculino , Períneo/cirurgia , Pioderma Gangrenoso/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Intraoperative parathyroid hormone monitoring (IOPTH) is a widely used adjunct for primary hyperparathyroidism (pHPT). However, the benefit of IOPTH in familial pHPT, such as in multiple endocrine neoplasia type I (MEN1), remains unclear. METHODS: We performed a retrospective analysis of 52 patients with MEN1-associated pHPT undergoing initial parathyroidectomy with IOPTH monitoring at our institution. Parathyroid hormone (PTH) levels were measured before skin incision and 10 min after resection of the last parathyroid gland. Variables analyzed included percent drop of PTH from baseline and the final PTH level compared to the normal reference range (RR). RESULTS: A total of 52 patients underwent initial subtotal parathyroidectomy with IOPTH. An IOPTH decrease cutoff of ≥75 % from baseline had the highest biochemical cure rate (87 %). In the remaining 13 % who met this cutoff, all had persistent pHPT, with ≥90 % drop of PTH from baseline. The remaining patients, who did not meet the ≥75 % cutoff, were cured. Follow-up was available for three of four patients with final IOPTH levels above the RR: one had persistent pHPT, two had hypoparathyroidism (50 %). When a postresection PTH level was within the RR, 88 % of patients were cured. While considered cured from pHPT, 7 % of patients in this group developed permanent hypoparathyroidism. When the final PTH level dropped below the RR, 28 % developed permanent hypoparathyroidism. CONCLUSIONS: A cutoff in IOPTH decrease of ≥75 % from baseline has the highest biochemically cure rate in patients with pHPT associated with MEN1. However, a 75 % cutoff in IOPTH decrease does not exclude persistent pHPT. The absolute IOPTH value does not accurately predict postoperative hypoparathyroidism.
Assuntos
Hiperparatireoidismo Primário/sangue , Hiperparatireoidismo Primário/etiologia , Monitorização Intraoperatória/métodos , Neoplasia Endócrina Múltipla Tipo 1/complicações , Hormônio Paratireóideo/sangue , Paratireoidectomia , Adolescente , Adulto , Idoso , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract. Despite this, they rarely occur, accounting for only 1% to 3% of all gastrointestinal tumors. This report describes a 53-year-old female patient with surgical history of Roux-en-Y gastric bypass (RYGB) who presented with right upper quadrant abdominal pain. CT imaging revealed a large 20 × 12 × 16 cm mass in the excluded stomach remnant. Ultrasound-guided biopsy confirmed this mass to be a GIST. The patient was treated surgically with exploratory laparotomy with distal pancreatectomy, partial colectomy, partial gastrectomy, and splenectomy. There are currently only 3 known reported cases of GISTs after RYGB.
Assuntos
Derivação Gástrica , Coto Gástrico , Tumores do Estroma Gastrointestinal , Obesidade Mórbida , Feminino , Humanos , Pessoa de Meia-Idade , Derivação Gástrica/efeitos adversos , Derivação Gástrica/métodos , Tumores do Estroma Gastrointestinal/cirurgia , Tumores do Estroma Gastrointestinal/patologia , Coto Gástrico/patologia , Coto Gástrico/cirurgia , Gastrectomia/métodos , Esplenectomia , Obesidade Mórbida/cirurgia , Obesidade Mórbida/patologia , Anastomose em-Y de RouxRESUMO
Melanoma is most associated with cancer of the skin. However, a small subset of these melanomas can be a primary malignancy of other mucosal membranes. A 55-year-old male presented to the gastroenterologist with 1 year of symptoms typical of colon cancer including bloating, abdominal pain and weight loss. He underwent colonoscopy and a mass was seen in the transverse colon that was later proven melanoma. A PET CT scan showed this was his only focus of disease. He then underwent a laparoscopic-assisted extended right hemicolectomy. He had an uneventful postoperative course. He was thoroughly examined for other sources of melanoma such as cutaneous, anal and uveal sources. He has recovered well at home and is receiving adjuvant pembrolizumab immunotherapy. Mucosal primary melanomas have a worse 5-year survival than primary cutaneous melanomas. A multi-disciplinary approach is necessary to treat and properly diagnose these malignancies.
RESUMO
Background and Aims: Early-stage small intestinal neuroendocrine tumors (SI-NETs) are generally asymptomatic and difficult to diagnose. As a result, patients often present with late-stage incurable disease. SI-NETs originate from enterochromaffin (EC) cells, which develop enteroendocrine cell (EEC) clusters consisting of a subset of EC cells at the crypt bottom at an early stage of tumor progression. In a familial form of SI-NET, EEC clusters arise in a multifocal and polyclonal fashion. We sought to determine whether early detection and analysis of cryptal EEC clusters could provide insight into the development of SI-NETs and allow successful pre-symptomatic screening for at risk family members of patients with SI-NETs. Methods: Isolated crypts from endoscopic ileal biopsies or surgically removed specimens from 43 patients with familial SI-NET and 20 controls were formalin-fixed, immunostained for chromogranin A, and examined by confocal three-dimensional analysis for the presence of EEC cluster formations. Results: Examination of multiple areas of macroscopic tumor-free mucosa in surgically resected specimens from patients with familial SI-NET revealed widely distributed, independent, multifocal EEC micro-tumor formations of varying sizes. Consistent with this finding, randomly sampled ileal biopsy specimens identified aberrant crypt containing endocrine cell clusters (ACECs) in patients. ACECs were found exclusively in patients (23/43, 53%) and not in controls (0/20). Furthermore, analysis of positions and numbers of EECs in crypts and ACECs indicated significant increases in EECs at the crypt bottom, predominantly at positions 0 and 1' (p < 0.0001 compared to controls), suggesting the progression of EEC accumulation below +4 position as the early process of ACEC formation. These findings also suggested that ACECs were precursors in the development of micro-tumors and subsequent macro-tumors. Conclusion: This study indicates that SI-NETs develop from deep crypt EC cells to become ACECs, micro-tumors, and ultimately gross tumors. This process occurs widely throughout the distal small intestine in patients with familial SI-NETs consistent with but not exclusively explained by germline disease. Finally, analysis of crypts from ileal biopsies could contribute in part to earlier diagnostic screening processes avoiding late-stage presentation of incurable disease.