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BACKGROUND: While a neoadjuvant chemotherapy regimen using docetaxel, cisplatin, and 5-fluorouracil (NAC-DCF) is considered the standard treatment for locally advanced esophageal cancer (EC) in Japan, a reliable marker for early prediction of treatment efficacy remains unclear. We investigated the utility of the tumor response after a first course of NAC-DCF as a post-surgery survival predictor in patients with EC. METHODS: We enrolled 150 consecutive patients who underwent NAC-DCF followed by surgery for EC between September 2009 and January 2019. The initial tumor reduction (ITR), defined as the percentage decrease in the shorter diameter of the tumor after the first course of NAC-DCF, was evaluated using computed tomography. We analyzed the relationship between ITR, clinicopathological parameters, and survival. RESULTS: The median ITR was 21.07% (range -11.45 to 50.13%). The optimal cut-off value for ITR for predicting prognosis was 10% (hazard ratio [HR] 3.30, 95% confidence interval [CI] 1.98-5.51), based on univariate logistic regression analyses for recurrence-free survival (RFS). Compared with patients with ITR <10%, patients with ITR ≥10% showed a significantly higher proportion of ypM0 (80.0% vs. 92.5%) and responders in terms of overall clinical response (50.0% vs. 80.8%). Multivariate analysis for RFS revealed that ypN2-3 (HR 2.78, 95% CI 1.67-4.62), non-response in terms of overall clinical response (HR 1.87, 95% CI 1.10-3.18), and ITR <10% (HR 2.48, 95% CI 1.42-4.32) were independent prognostic factors. CONCLUSIONS: Tumor response after the first course of NAC-DCF may be a good predictor of survival in patients with EC who underwent NAC-DCF plus surgery.
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Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Docetaxel , Neoplasias Esofágicas , Esofagectomia , Fluoruracila , Terapia Neoadjuvante , Humanos , Masculino , Feminino , Terapia Neoadjuvante/mortalidade , Estudos Retrospectivos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Taxa de Sobrevida , Cisplatino/administração & dosagem , Idoso , Docetaxel/administração & dosagem , Esofagectomia/mortalidade , Prognóstico , Fluoruracila/administração & dosagem , Seguimentos , Adulto , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/mortalidade , Idoso de 80 Anos ou maisRESUMO
We aimed to determine the frequency and prognosis of supraclavicular (#104) lymph node (LN) metastasis compared with other LN stations in patients with advanced thoracic esophageal cancer and to identify risk factors for metastasis to delineate the indications for three-field lymphadenectomy (3FL). The study cohort of 567 eligible patients with esophageal cancer had undergone subtotal esophagectomy from 2003 to 2020. LN metastasis was defined as pathologically proven metastasis or positron emission tomography-positive LNs. The efficacy index (EI), calculated from the frequency of LN metastases and survival rates, was used as prognostic value of each LN station dissection for patient survival. Risk factors for #104 LN metastasis were determined by multivariable logistic regression. The frequency of #104 LN metastasis was 11.6% overall, 31.7% in upper and 8.3% in middle/lower third lesion. Neoadjuvant chemotherapy was administered to 71% of patients and chemo-radiation to 11%. The 5-year overall survival was 45.8%. The EI for #104 LNs (5.3) was similar to that for #101 LNs. Risk factors were age < 65 years, upper third lesion, clinical N2-3, #101/106rec LN metastasis and poorly differentiated carcinoma. The 5-year overall survival of patients with middle/lower lesions was 38% (EI 3.1), similar to that for #101 and #8/9/11 LNs. The prognosis of patients with #104 LN metastases is similar to that of patients with metastases in other regional LN stations. Therefore, we recommend 3FL exclusively for patients at a high risk of #104 LN metastasis due to the overall metastatic rate not being high.
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PURPOSE: Gastric cancer patients with peritoneal metastasis (PM) are generally treated with systemic chemotherapy. When PM has disappeared because of chemotherapy, radical gastrectomy (so-called conversion surgery) is usually performed. We have previously reported the efficacy of conversion surgery, but there are no reports examining the efficacy of palliative gastrectomy for patients with residual PM after chemotherapy. The purpose of this study was to investigate the efficacy of palliative surgery for gastric cancer patients with PM who still have residual peritoneal dissemination after chemotherapy. METHODS: Twenty-five gastric cancer patients with PM confirmed by laparoscopy and who had received chemotherapy but who still had residual PM were included in this study. Among the 25 patients, palliative surgery was performed in 20 patients (PS group) and chemotherapy was continued in 5 patients (CTx group), and their therapeutic outcomes were compared. RESULTS: In the PS group, total and distal gastrectomies were performed. Clavien-Dindo grade I postoperative complications occurred in two patients (10%). There were no treatment-related deaths. Postoperative chemotherapy was performed all cases. In the PS group, the median survival time (MST) reached 22.5 months, with 1- and 2-year overall survival (OS) rates of 95% and 45%, respectively, whereas in the CTx group, the MST was 15.8 months, and the 1- and 2-year OS rates were 60% and 0%, respectively. The PS group had significantly longer OS than the CTx group (P=0.044). CONCLUSIONS: Palliative surgery is safe and may prolong survival in gastric cancer patients with residual PM after chemotherapy.
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Laparoscopia , Neoplasias Peritoneais , Neoplasias Gástricas , Humanos , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/cirurgia , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Cuidados Paliativos , Peritônio , Gastrectomia/efeitos adversos , Estudos RetrospectivosRESUMO
OBJECTIVE: To evaluate pathological response to NAC in metastatic LNs, and assess its clinical prognostic significance in patients with EC. SUMMARY OF BACKGROUND DATA: The pathological response to preoperative treatment is commonly evaluated in the PT. However, LN metastases strongly correlate with systemic micro-metastases. Thus, pathological evaluation of LN response could more accurately predict prognosis in EC patients undergoing NAC before surgery. METHODS: We enrolled 371 consecutive patients who underwent triplet NAC followed by surgery for EC between January 2010 and December 2016. Pathological LN regression grade was defined by the proportion of viable tumor area within the whole tumor bed area for all metastatic LNs: grade I, >50%; II, 10%-50%; III, <10%; and IV, 0%. We analyzed the correlation of grade with clinico-pathological parameters. RESULTS: Among 319 patients with clinically positive LNs, pathological LN regression grades were I/II/III/IV in 115/51/58/95 patients, and 191 patients (59.9%) showed discordance between the PT and LN pathological regression grades. LN regression grade significantly correlated with cN positive number, ypTNM, lymphovascular invasion, and clinical/pathological PT response. Multivariate analysis for recurrence-free survival revealed that LN regression grade [hazard ratio (HR) = 2.25, P < 0.001], ypT (HR = 1.65, P = 0.005), and ypT (HR = 1.62, P = 0.004) were independent prognostic factors, but not pathological PT regression grade (P = 0.67). CONCLUSIONS: Compared to PT response, pathological LN response better predicted long-term survival in EC patients who received NAC plus curative surgery.
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Neoplasias Esofágicas , Terapia Neoadjuvante , Quimioterapia Adjuvante , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/cirurgia , Humanos , Linfonodos/patologia , Metástase Linfática/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos RetrospectivosRESUMO
Background: To improve the diagnostic accuracy of preoperative T staging in gastric cancer, the authors evaluated tumor-related factors that might affect the diagnosis. Materials & methods: The authors analyzed the data of cT2-4b gastric cancer patients enrolled in the prospective, multicenter JCOG1302A study. They used contrast-enhanced computed tomography to analyze the association between tumor-related factors and the diagnostic accuracy of T3-4b staging for gastric cancer. Results: Among 876 cT3-4b tumors, the diagnostic accuracy was relatively low in the lower third of the stomach compared with those in the upper or middle. A multivariable analysis revealed that accuracy was higher in the lesser curvature or entire circumference region than in other areas (p < 0.001), in macroscopic types 3/5 than in types 0/1/2 (p = 0.003) and in the undifferentiated histological type than in the differentiated type (p = 0.011). Conclusion: The authors found tumor-related factors affecting preoperative T staging by enhanced computed tomography.
Additional chemotherapy before surgery is expected to have potentially beneficial effects on prognosis compared with chemotherapy only after surgery for advanced gastric cancer. The consideration of chemotherapy before surgery depends on preoperative diagnosis of the depth of tumor invasion in the stomach wall. Overdiagnosis of the depth of tumor invasion may lead to unnecessary administration of chemotherapy that is harmful to the patient. Tumor-related factors such as tumor location, macroscopic type and histological type may affect the diagnosis. Therefore, these factors should be considered with special care for the diagnosis, which may lead to higher accuracy in diagnosing the depth of tumor invasion in gastric cancer.
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Neoplasias Gástricas , Humanos , Estadiamento de Neoplasias , Estudos Prospectivos , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE: Microfocus computed tomography (micro-CT) has not been widely used at high radiation intensity (industrial micro-CT) in life science fields. In this preliminary study, we investigated its potential value in the detection of micro-hepatic tumors in a mouse model. METHODS: The liver with micro-hepatic tumors was surgically resected en-bloc from mice, and examined with industrial micro-CT and lower intensity micro-CT (small animal micro-CT). The number of hepatic tumors was manually counted on serial images. Then, the accuracy of each technique was determined by preparing matching liver sections and comparing the number of tumors identified in a conventional pathological examination. RESULTS: The number of hepatic tumors evaluated with industrial micro-CT showed high concordance with the results of the pathological examinations (intraclass correlation coefficient [ICC]: 0.984; 95% confidence interval [CI] 0.959-0.994). On the other hand, the number of hepatic tumors evaluated with the small animal micro-CT showed low concordance with the number identified in the pathological examinations (ICC: 0.533; 95% CI 0.181-0.815). CONCLUSION: Industrial micro-CT improved the detection of small structures in resected specimens, and might be a promising solution for life science research.
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Disciplinas das Ciências Biológicas , Neoplasias Hepáticas , Animais , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Camundongos , Tomografia Computadorizada por Raios X/métodosRESUMO
PURPOSE: To investigate the relationship between changes in taste due to surgical procedures and other clinical factors, we performed a detailed investigation of taste alteration in patients who underwent gastrectomy. METHODS: Questionnaires on taste alteration were distributed to patients who visited our outpatient clinic from July 2018 to January 2019 for the postoperative evaluation of gastric cancer. Associations of clinical characteristics with changes in sensitivity to the four major taste types (sweet, sour, salty, and bitter) were examined. RESULTS: Of the 243 eligible patients, 42 (17.3%) experienced taste alteration after gastrectomy; taste sensitivity decreased in 21 (8.6%) patients and increased in 31 (12.7%) patients. The frequency of a decreased sensitivity to sweet was significantly higher in patients who underwent total gastrectomy than in those who underwent distal gastrectomy (18.8% vs. 3.3%, P = 0.001). Patients who underwent total gastrectomy were significantly more likely than those who received distal gastrectomy to experience increased sensitivity to sour (12.5% vs. 2.2%, respectively; P = 0.004) and bitter (15.6% vs. 3.8%, respectively; P = 0.007) tastes. A multivariate analysis revealed that total gastrectomy was an independent risk factor for total taste alteration. CONCLUSIONS: Patients who underwent total gastrectomy showed a high likelihood of both loss and gain of taste sensitivity.
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Gastrectomia/efeitos adversos , Gastrectomia/métodos , Neoplasias Gástricas/fisiopatologia , Neoplasias Gástricas/cirurgia , Distúrbios do Paladar/etiologia , Distúrbios do Paladar/fisiopatologia , Paladar , Feminino , Humanos , Masculino , Fatores de Risco , Limiar Sensorial , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Predictive factors of nivolumab treatment response in patients with gastric cancer (GC) remain unclear. METHODS: In this retrospective cohort study, tissue specimens of patients with unresectable or recurrent GC and prior or scheduled treatment with nivolumab as third-line or higher therapy between September 2017 and February 2019 were collected from 23 institutions. The tumour-positive score (TPS) and combined positive score (CPS) of PD-L1 expression and mismatch repair (MMR) were analysed by immunohistochemistry. Associations between clinicopathological factors and tumour-response rate, hyperprogressive disease (HPD) rate and survival were assessed. RESULTS: Of 200 eligible patients, 143 had measurable lesions. The response and HPD rates were 17.5% and 22.1%, respectively. The response rate was significantly higher in patients with performance status (PS) 0-1 (P = 0.026), non-peritoneal metastasis (P = 0.021), PD-L1 TPS ≥ 1 (P = 0.012), CPS ≥ 5 (P = 0.007) or ≥ 10 (P < 0.001) or MMR deficiency (P < 0.001). The HPD rate was significantly higher in patients with PS 2-3 (P = 0.026), liver metastasis (P < 0.001) and CPS < 10 (P = 0.048). Multivariate analysis revealed that CPS (P = 0.001) and MMR (P = 0.002) were independent prognostic factors of progression-free survival, as well as liver metastasis (P < 0.001), peritoneal metastasis (P = 0.004) and CRP (P < 0.001). CONCLUSIONS: PD-L1 CPS and MMR could be useful biomarkers for nivolumab treatment efficacy in GC. CLINICAL TRIAL REGISTRATION: UMIN000032164.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Nivolumabe/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Biomarcadores Tumorais , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologiaRESUMO
INTRODUCTION: Next-generation sequencing (NGS) with molecular barcodes (MB) is a novel method that enables the highly sensitive detection of circulating tumor DNA (ctDNA) in a relatively wide range of genes. OBJECTIVE: The aim of this study was to examine the utility of NGS with MB for detecting ctDNA in patients with esophageal squamous cell carcinoma (ESCC). METHODS: Five patients with ESCC who underwent preoperative treatment followed by esophagectomy were examined. The frequency of TP53 mutations in DNA extracted from tumor tissue and plasma at each time point during the treatment course was analyzed using NGS without MB. In 1 patient, additional analysis using NGS with MB was conducted to compare the sensitivities and to evaluate the clinical utility of this novel method. RESULTS: TP53 mutations in tumor tissue were identified in 3 of 5 patients with ESCC. In 1 patient, the mutational allele frequency in plasma was 1.97% before preoperative treatment, and decreased to 0.09% after preoperative treatment. As the maximum frequency of background errors were 3.22% using NGS without MB and 0.08% with MB, which indicated that the sensitivity of ctDNA detection using NGS with MB was much higher than without MB. In 1 patient who had recurrence half a year after surgery, only NGS with MB could detect ctDNA even at 4 weeks after surgery, at a frequency of 0.20%. CONCLUSIONS: NGS with MB enabled comprehensive and highly sensitive detection of ctDNA in a patient with ESCC. This novel method may be useful for the clinical diagnosis of ESCC.
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DNA Tumoral Circulante/sangue , Código de Barras de DNA Taxonômico/métodos , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Idoso , Genes p53 , Humanos , Masculino , Pessoa de Meia-Idade , MutaçãoAssuntos
Neoplasias Esofágicas , Terapia Neoadjuvante , Humanos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Neoplasias Esofágicas/terapia , Prognóstico , Taxa de Sobrevida , Esofagectomia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas do Esôfago/cirurgia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimioterapia AdjuvanteRESUMO
BACKGROUND: Dysphagia is a major symptom of esophageal cancer (EC) that significantly affects patient quality of life; however, little is known regarding its clinical impact on the treatment course in patients with EC. METHODS: This retrospective study included 434 consecutive patients with EC who received docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy as an initial treatment. We evaluated the relationships between the dysphagia score at diagnosis and clinicopathological factors, including DCF therapy-related adverse events, tumor response, and survival. RESULTS: The dysphagia scores were 0 in 208 patients (47.9%), 1 in 82 patients (18.9%), 2 in 52 patients (12.0%), 3 in 59 patients (13.6%), and 4 in 33 patients (7.6%). High (≥ 3) dysphagia scores were significantly associated with high incidences of grade 3/4 febrile neutropenia (FN) (79.3 vs. 35.7%, P < 0.001) and diarrhea (63.0 vs. 28.1%, P < 0.001) compared with low (≤ 2) scores. Logistic regression analysis further identified the dysphagia scores as an independent predictor of both FN and severe diarrhea during DCF chemotherapy. Furthermore, compared with low scores, high dysphagia scores were associated with a worse clinical response to chemotherapy (response rate 65.2 vs. 78.7%, P = 0.008) and worse 5-year overall survival (35.4 vs. 56.4%, P = 0.001). CONCLUSIONS: The dysphagia score at diagnosis was an independent predictor of FN and severe diarrhea. Furthermore, this score might be useful in predicting chemotherapy response and long-term survival in patients treated with DCF.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transtornos de Deglutição/diagnóstico , Transtornos de Deglutição/mortalidade , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Transtornos de Deglutição/etiologia , Docetaxel/administração & dosagem , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Surgery often introduce inflammatory response, which may promote tumor growth and metastasis of residual cancer cells. We investigated the impacts of methylprednisolone on the tumor growth and peritoneal seedings in mice treated with lipopolysaccharide (LPS), which mimics systemic inflammation induced by surgical stress and postoperative complications. METHODS: The serum interleukin-6 (IL-6) levels, tumor volume, tumor weight, and the number of peritoneal nodules were investigated in tumor growth model and peritoneal seeding model using BALB/c mice and murine CT26 cancer cell lines in vivo. We conducted functional analyses of IL-6 in Western blotting and proliferation assays in vitro. We also investigated whether preoperative administration of methylprednisolone decreased postoperative serum IL-6 levels in cancer patients in a randomized clinical study. RESULTS: In the in vivo study, methylprednisolone inhibited the LPS-induced increase of serum IL-6 levels (mean, 33,756 pg/ml vs. 5917 pg/ml; P < 0.001), tumor volume (mean, 397 mm3 vs. 274 mm3; P = 0.019), tumor weight (mean, 0.38 g vs. 0.15 g; P = 0.020), and the number of peritoneal nodules (mean, 112 vs. 47; P = 0.002). In the in vitro study, IL-6 enhanced JAK/STAT signaling and increased the cell proliferation, and IL-6R-neutralizing antibody attenuated these effects. In the clinical study, serum IL-6 levels were significantly decreased by methylprednisolone (median, 97.5 pg/ml vs. 18.0 pg/ml; P = 0.030). CONCLUSIONS: Surgical stress and postoperative complications may enhance tumor growth due to the increase of IL-6. However, methylprednisolone can decrease serum IL-6 levels, thus inhibiting tumor growth and peritoneal seeding.
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Metilprednisolona/farmacologia , Recidiva Local de Neoplasia/tratamento farmacológico , Inoculação de Neoplasia , Neoplasias Peritoneais/tratamento farmacológico , Complicações Pós-Operatórias , Neoplasias Gástricas/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Apoptose , Biomarcadores Tumorais/sangue , Proliferação de Células , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Neoplasias Peritoneais/metabolismo , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/cirurgia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A 58-year-old man was diagnosed with liver dysfunction during a health exam and subsequently visited a doctor. Abdominal ultrasonography revealed space-occupying lesions in the gall bladder and bile duct, and he was hospitalized for further examination and treatment. Computed tomography (CT), endoscopic retrograde cholangiopancreatography (ERCP), and magnetic resonance cholangiopancreatography (MRCP) revealed double cancer of the gall bladder and bile duct with pancreaticobiliary maljunction (PBM), and we performed a pancreatoduodenectomy. Pathological examination revealed gall bladder and bile duct cancer, and severe dysplasia of the papilla of Vater. We diagnosed synchronous triple cancer because none of the cancers had continuity or vascular invasion. Each cancer was at Stage I, and the patient has survived for 2 years and 6 months without recurrence and no additional treatment. PBM is a mutation of the junction of the pancreatic and bile ducts outside of the duodenal wall, and is a known complication of biliary tract cancer due to the reflux of pancreatic juice and bile. Because K-ras and p53 gene mutations occur in the biliary tract mucosal epithelium, PBM increases the risk of developing multicentric cancer. It is important to consider the existence of double cancer when biliary tract cancer is detected in a PBM patient.
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Neoplasias dos Ductos Biliares/patologia , Ducto Colédoco/patologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Pancreáticas/patologia , Neoplasias dos Ductos Biliares/cirurgia , Colangiopancreatografia Retrógrada Endoscópica , Ducto Colédoco/cirurgia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/cirurgia , Neoplasias Pancreáticas/cirurgia , PancreaticoduodenectomiaRESUMO
A 68 -year-old man underwent a pancreaticoduodenectomy after being diagnosed with primary duodenal cancer. The postoperative pathological diagnosis was tub2, SE, ly1, v1, panc3, pn+, N0. Although adjuvant chemotherapy was administered, local recurrence in the portal region was detected 18 months later. The recurrent tumor pressed against the region of the bile duct anastomosis, which caused obstructive jaundice. After serum bilirubin levels were reduced, resection of the recurrent tumors was performed. This required resection of the transverse colon, parts of the portal vein, and the inferior vena cava. The bile duct anastomotic region, which had been infiltrated by the tumor, was excised and rebuilt. The postoperative pathological diagnosis was tub2. The patient continued to receive adjuvant chemotherapy and showed no signs of recurrence 9 months after surgery. Extended resection for local recurrences of primary duodenal cancer may be an effective means of disease control.
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Neoplasias dos Ductos Biliares/cirurgia , Neoplasias Duodenais/cirurgia , Neoplasias do Jejuno/cirurgia , Idoso , Neoplasias dos Ductos Biliares/secundário , Neoplasias Duodenais/patologia , Hepatectomia , Humanos , Neoplasias do Jejuno/secundário , Masculino , Pancreaticoduodenectomia , Veia Porta/patologia , Recidiva , Veia Cava Inferior/patologiaRESUMO
Here, we present the case of a 60-year-old man in whom abdominal computed tomography showed a solid abdominal tumor (11 cm in diameter) in the pelvic space, with widely disseminated nodular lesions. Emergency surgery was performed following the rapid onset of intense abdominal pain. Peritoneal disseminations were widespread and the tumor was confirmed to be in the pelvic space. The tumor was not connected to any segment of the intestinal tract but rather to the retroperitoneum. Immunohistochemical staining was positive for c-kit (exon 11 mutation) and CD34 but negative for S-100 protein. Careful postoperative examination did not reveal any lesions in the upper or lower alimentary tract. On the basis of these findings we diagnosed the tumor as an extragastrointestinal stromal tumor (EGIST) originating from the retroperitoneum. After surgery, intravenous infusion of imatinib was started at a full dose of 400mg/day; however, owing to strong adverse effects, the dose was reduced to 200mg/day. Despite halving the dose, the patient has remained lesion-free according to computed tomography for 36 months after the operation. Low-dose imatinib chemotherapy remained efficacious in controlling progression in this case.
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Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Tumores do Estroma Gastrointestinal/secundário , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Mesilato de Imatinib , Neoplasias Intestinais/tratamento farmacológico , Neoplasias Intestinais/patologia , Neoplasias Intestinais/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Recent reports have described the practicality of laparoscopic intragastric surgery (l-IGS) as an alternative for resecting submucosal tumors (SMTs) near the esophagogastric junction (EGJ), where excision using an exogastric approach would be difficult. However, even using IGS to perform a full-thickness resection of SMTs that are in or extremely close to the EGJ is very difficult to do safely and avoid disrupting or causing stenosis of the EGJ, without advanced experience. This study retrospectively examined the usefulness of l-IGS for gastric SMTs located in or extremely close to the EGJ. Fourteen patients with gastric SMTs < 2 cm of the EGJ and underwent l-IGS were eligible for this study. We examined the tumor location, operative time, intraoperative hemorrhage, degree of deformation, gastroesophageal reflux disease, perioperative complications, and recurrence. Furthermore, we compared patients with tumors in the EGJ with those with tumors near the EGJ and patients in whom three-port l-IGS was performed with those who underwent single-incision laparoscopic surgery. The average tumor size, operative time, intraoperative hemorrhage, and postoperative hospitalization of the 14 patients were 30.9 ± 21.3 mm, 125.2 ± 31.1 min, 30.7 ± 103.3 mL, and 9.2 ± 3.1 d, respectively. No differences in these parameters according to the type of l-IGS or tumor location were observed. All patients underwent l-IGS without complications and were free from EGJ deformation or esophagitis. We believe that l-IGS is useful for gastric SMTs located < 2 cm of the EGJ as it can be safely performed for difficult tumor locations and does not cause deformation of the EGJ.
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Cancer selective apoptosis remains a therapeutic challenge and off-target toxicity has limited enthusiasm for this target clinically. Sigma-2 ligands (S2) have been shown to enhance the cancer selectivity of small molecule drug candidates by improving internalization. Here, we report the synthesis of a novel drug conjugate, which was created by linking a clinically underperforming SMAC mimetic (second mitochondria-derived activator of caspases; LCL161), an inhibitor (antagonist) of inhibitor of apoptosis proteins (IAPinh) with the sigma-2 ligand SW43, resulting in the new chemical entity S2/IAPinh. Drug potency was assessed via cell viability assays across several pancreatic and ovarian cancer cell lines in comparison with the individual components (S2 and IAPinh) as well as their equimolar mixtures (S2 + IAPinh) both in vitro and in preclinical models of pancreatic and ovarian cancer. Mechanistic studies of S2/IAPinh-mediated cell death were investigated in vitro and in vivo using syngeneic and xenograft mouse models of murine pancreatic and human ovarian cancer, respectively. S2/IAPinh demonstrated markedly improved pharmacological activity in cancer cell lines and primary organoid cultures when compared to the controls. In vivo testing demonstrated a marked reduction in tumor growth rates and increased survival rates when compared to the respective control groups. The predicted mechanism of action of S2/IAPinh was confirmed through assessment of apoptosis pathways and demonstrated strong target degradation (cellular inhibitor of apoptosis proteins-1 [cIAP-1]) and activation of caspases 3 and 8. Taken together, S2/IAPinh demonstrated efficacy in models of pancreatic and ovarian cancer, two challenging malignancies in need of novel treatment concepts. Our data support an in-depth investigation into utilizing S2/IAPinh for the treatment of cancer.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Animais , Camundongos , Feminino , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Apoptose , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Caspases/metabolismo , Linhagem Celular TumoralRESUMO
Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol esters, suggestive of unaltered intracellular cholesterol trafficking. Cytotoxicity was caused by cholesterol excess, a phenomenon that contrasts the effects of NPC1 inhibition. RNA-sequencing revealed gene clusters involved in cholesterol homeostasis and ER stress response exclusively by cytotoxic S2L. ER stress markers were confirmed by qPCR and their targeted modulation inhibited or enhanced cytotoxicity of C10 in a predicted manner. Moreover, C10 increased sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR), both found to be pro-survival factors activated by ER stress. Furthermore, inhibition of downstream processes of the adaptive response to S2L with simvastatin resulted in synergistic treatment outcomes in combination with C10. Of note, the S2L conjugates retained the ER stress response of the parental ligands, indicative of cholesterol homeostasis being involved in the overall cytotoxicity of the drug conjugates. Based on these findings, we conclude that S2L-mediated cell death is due to free cholesterol accumulation that leads to ER stress. Consequently, the cytotoxic profiles of S2L drug conjugates are proposed to be enhanced via concurrent ER stress inducers or simvastatin, strategies that could be instrumental on the path toward tumor eradication.