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OBJECTIVE: To examine the efficacy and safety of minimally invasive surgery (MIS) and conventional abdominal surgery for epithelial ovarian cancer (EOC), stratified by treatment type. METHODS: A systematic review and meta-analysis were conducted by an Expert Panel of the Japan Society of Gynecologic Oncology Ovarian Cancer Committee. Several academic databases, including PubMed/MEDLINE, Cochrane Database, and Ichushi were searched by the Japan Medical Library Association on November 11, 2023, using the keywords "epithelial ovarian cancer", "minimally invasive surgery", "laparoscopic", and "robot-assisted". Articles describing MIS treatment for EOC compared with conventional abdominal surgery were independently assessed by two authors. The primary outcomes were survival and perioperative adverse events. RESULTS: After screening 1114 studies, 35 articles were identified, including primary staging surgery (PSS) for early-stage EOC EOC (n = 20) and neoadjuvant chemotherapy following interval debulking surgery (NACT-IDS; n = 10) and upfront primary debulking surgery (PDS; n = 5) for advanced-stage EOC. These studies included 29,888 patients (7661 undergoing MIS and 22,227 undergoing abdominal surgery). Patients receiving MIS and abdominal surgery had similar overall survival (PSS: odds ratio [OR] 1.02, 95% confidence interval [CI] 0.75-1.37; NACT-IDS: OR 0.93, 95%CI 0.25-3.44 and PDS: OR 0.66, 95%CI 0.36-1.22, all P > 0.05). MIS showed perioperative complication rates comparable to those of abdominal surgery (intraoperative and postoperative, all treatment types P ≥ 0.05). However, the rate of lymph node dissection in early-stage EOC (PSS: OR 0.49, 95%CI0.26-0.91) and multivisceral resections in advanced-stage EOC (NACT-IDS: OR 0.27 95%CI 0.16-0.44 and PDS: OR 0.27, 95%CI 0.16-0.44) was lower in MIS than in abdominal surgery (all P < 0.05). CONCLUSION: MIS did not negatively impact the survival and perioperative complications of patients with EOC compared to abdominal surgery. While MIS is a viable option, varied case selection and surgical procedures suggest potential bias, requiring further validation studies.
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BACKGROUND: Outcomes with and without bevacizumab as first-line chemotherapy in Japanese-only ovarian cancer patients have not been reported. In this study, we report a retrospective study conducted at the Tohoku Gynecologic Cancer Unit. PATIENTS AND METHODS: The study included 453 patients with stage III/IV ovarian, fallopian tube, and primary peritoneal cancer who received first-line platinum-based chemotherapy. The patients were divided into two groups: bevacizumab (168 patients) and without bevacizumab (285 patients). The primary endpoint was the rate of platinum-resistant recurrence and the secondary endpoints were the antitumor response, progression-free survival, overall survival, and adverse events. RESULTS: The objective response rates for patients with measurable diseases treated with and without bevacizumab were 84.5% and 73.0%, respectively (P = 0.0066). Platinum-resistant recurrence in the groups treated with and without bevacizumab was noted in 31 (18.4%) and 111 (38.6%) patients, respectively (P < 0.0001). The median progression-free survival for the bevacizumab and without bevacizumab groups was 23 and 15 months, respectively (P = 0.0002), and the median overall survival was not reached and 49 months, respectively (P = 0.0005). Hypertension of grade 3 or higher was observed in 21 patients (12.5%) in the bevacizumab group (P < 0.001), and proteinuria was observed in 18 patients (10.7%) and 1 patient (0.3%) in the bevacizumab and without bevacizumab groups, respectively (P < 0.001). Intestinal perforation was observed in only one patient (0.6%) in the bevacizumab group. CONCLUSION: Combination and maintenance with bevacizumab in primary chemotherapy for advanced ovarian, fallopian tube, and primary peritoneal cancer was effective in reducing platinum-resistant recurrence rates and prolonging progression-free and overall survival.
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Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Neoplasias Peritoneais , Humanos , Feminino , Bevacizumab/efeitos adversos , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/patologia , Neoplasias Peritoneais/patologia , Tubas Uterinas/patologia , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Platina/efeitos adversos , Recidiva Local de Neoplasia/patologiaRESUMO
Hereditary cancer syndromes, which are characterized by onset at an early age and an increased risk of developing certain tumors, are caused by germline pathogenic variants in tumor suppressor genes and are mostly inherited in an autosomal dominant manner. Therefore, hereditary cancer syndromes have been used as powerful models to identify and characterize susceptibility genes associated with cancer. Furthermore, clarification of the association between genotypes and phenotypes in one disease has provided insights into the etiology of other seemingly different diseases. Molecular genetic discoveries from the study of hereditary cancer syndrome have not only changed the methods of diagnosis and management, but have also shed light on the molecular regulatory pathways that are important in the development and treatment of sporadic tumors. The main cancer susceptibility syndromes that involve gynecologic cancers include hereditary breast and ovarian cancer syndrome as well as Lynch syndrome. However, in addition to these two hereditary cancer syndromes, there are several other hereditary syndromes associated with gynecologic cancers. In the present review, we provide an overview of the clinical features, and discuss the molecular genetics, of four rare hereditary gynecological cancer syndromes; Cowden syndrome, Peutz-Jeghers syndrome, DICER1 syndrome and rhabdoid tumor predisposition syndrome 2.
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Neoplasias dos Genitais Femininos/patologia , Síndromes Neoplásicas Hereditárias/patologia , Feminino , Predisposição Genética para Doença , Neoplasias dos Genitais Femininos/genética , Humanos , Biologia Molecular , Síndromes Neoplásicas Hereditárias/genéticaRESUMO
BACKGROUND: Ovarian abscesses, which occur mostly in sexually active women via recurrent salpingitis, occur rarely in virginal adolescent girls. Here, we present a case of an ovarian abscess in a virginal adolescent girl who was diagnosed and treated by laparoscopy. CASE PRESENTATION: A 13-year-old healthy girl presented with fever lasting for a month without abdominal pain. Computed tomography scan and magnetic resonance imaging indicated a right ovarian abscess. Laparoscopic surgery revealed a right ovarian abscess with intact uterus and fallopian tubes. The abscess was caused by Staphylococcus aureus. The patient recovered completely after excision of the abscess, followed by antibiotic treatment. CONCLUSIONS: Ovarian abscess may occur in virginal adolescent girls; Staphylococcus aureus, an uncommon species causing ovarian abscess, may cause the infection.
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Laparoscopia , Doenças Ovarianas , Salpingite , Abscesso/diagnóstico por imagem , Abscesso/tratamento farmacológico , Abscesso/cirurgia , Adolescente , Antibacterianos/uso terapêutico , Feminino , Humanos , Doenças Ovarianas/diagnóstico por imagem , Doenças Ovarianas/cirurgia , Salpingite/tratamento farmacológico , Staphylococcus aureusRESUMO
BACKGROUND: Within the claudin (CLDN) family, CLDN12 mRNA expression is altered in various types of cancer, but its clinicopathological relevance has yet to be established due to the absence of specific antibodies (Abs) with broad applications. METHODS: We generated a monoclonal Ab (mAb) against human/mouse CLDN12 and verified its specificity. By performing immunohistochemical staining and semiquantification, we evaluated the relationship between CLDN12 expression and clinicopathological parameters in tissues from 138 cases of cervical cancer. RESULTS: Western blot and immunohistochemical analyses revealed that the established mAb selectively recognized the CLDN12 protein. Twenty six of the 138 cases (18.8%) showed low CLDN12 expression, and the disease-specific survival (DSS) and recurrence-free survival rates were significantly decreased compared with those in the high CLDN12 expression group. We also demonstrated, via univariable and multivariable analyses, that the low CLDN12 expression represents a significant prognostic factor for the DSS of cervical cancer patients (HR 3.412, p = 0.002 and HR 2.615, p = 0.029, respectively). CONCLUSIONS: It can be concluded that a reduced CLDN12 expression predicts a poor outcome for cervical cancer. The novel anti-CLDN12 mAb could be a valuable tool to evaluate the biological relevance of the CLDN12 expression in diverse cancer types and other diseases.
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Claudinas/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/biossíntese , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/mortalidade , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Células HEK293 , Humanos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Taxa de Sobrevida , Neoplasias do Colo do Útero/patologiaRESUMO
Transcervical resection is widely used in the management of submucosal fibroids. However, uterine perforation and thermal bowel injuries are known complications associated with the procedure. This is a case report of a 44-year-old woman who presented with heavy menstrual bleeding and anemia. Magnetic resonance imaging and hysteroscopy revealed multiple fibroids, including a submucosal type 1 fibroid. She had previously undergone a total proctocolectomy with intestinal pouch-anal anastomosis for ulcerative colitis. Because there was a high risk of permanent colostomy in the event of a bowel injury, an electrode-free, operative hysteroscopy using the Intrauterine Bigatti Shaver (IBS), a hysteroscopic morcellator system, was employed to prevent thermal bowel injury. The fibroid was completely removed using the IBS system with no complications. Therefore, we recommend the electrode-free use of a hysteroscopic morcellator system in patients with a history of extensive pelvic surgery.
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Leiomioma , Menorragia , Proctocolectomia Restauradora , Neoplasias Uterinas , Adulto , Feminino , Humanos , Histeroscopia , Leiomioma/cirurgia , Gravidez , Neoplasias Uterinas/cirurgiaRESUMO
Stage IVA cervical cancer is a tumor that invades the mucosa of the bladder or rectum without distant metastasis and is difficult to treat, and concurrent chemoradiotherapy is recommended. Although radical surgery following neoadjuvant chemotherapy is a treatment option for stage IVA cervical cancer, the evidence is limited. A 51-year-old woman with bulky cervical cancer and rectal invasion was referred to our hospital. Paclitaxel and cisplatin were administered as neoadjuvant chemotherapies. After two cycles of chemotherapy, the tumor size decreased markedly. Total pelvic exenteration was performed, and a complete resection was achieved. Four cycles of paclitaxel and cisplatin were administered postoperatively. Thirty-three months after the completion of adjuvant chemotherapy, the patient was alive and free of disease. Radical surgery after neoadjuvant chemotherapy may be a treatment option for stage IVA cervical cancer with bulky tumors.
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BACKGROUND: Polyadenosine 5'-diphosphoribose polymerase inhibitors (PARP-Is) are novel, effective agents for treating newly diagnosed epithelial ovarian cancer (EOC). However, the effect of PARP-I on the progression of recurrent EOC has not yet been determined. In particular, there is limited evidence regarding retreatment with PARP-I for recurrent EOC that has progressed on PARP-I in the short term. CASE REPORT: A 69-year-old woman with a BRCA1 mutated EOC relapsed five months after starting olaparib maintenance following neoadjuvant chemotherapy and interval debulking surgery. Although the platinum-free interval was within six months, secondary cytoreductive surgery was performed because the tumor was locoregional. Following two cycles of weekly nedaplatin, niraparib induced a complete response, and the patient maintained a progression-free status for 15 months. CONCLUSION: Even with short-term progression on PARP-I, local control combined with different platinum agents and PARP-I can be used to achieve good responses.
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Procedimentos Cirúrgicos de Citorredução , Indazóis , Neoplasias Ovarianas , Ftalazinas , Piperazinas , Piperidinas , Humanos , Feminino , Idoso , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológicoRESUMO
Clear cell carcinoma (CCC) of the diaphragm is rare, with an origin that is reported to be associated with malignant transformation of extraperitoneal endometriosis. Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants in one of the DNA mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. Women with LS have a significantly increased lifetime risk of endometrial and ovarian cancer. CCC is a common histology of endometriosis- and LS-associated malignancy. The present study describes the case of a 51-year-old woman with an intra-abdominal mass found during a routine physical examination. The patient had undergone total hysterectomy and bilateral adnexectomy for atypical endometrial hyperplasia (AEH) and ovarian endometriosis, respectively, 3 years previously. Enhanced computed tomography showed a mass on the surface of the liver. Laparoscopic examination of the abdominal cavity revealed a tumor on the underside of the right diaphragm, which was then surgically excised. Pathological examination of the excised tumor, along with immunohistochemistry, led to a diagnosis of CCC. Since LS was suspected due to the genetic family history of the patient, microsatellite instability analysis was performed on the diaphragmatic tumor, and the results were positive. Immunohistochemistry was performed for MMR proteins in AEH and CCC cells, both of which revealed loss of MSH2 and MSH6 expression. Following detailed genetic counseling, genetic testing of MMR genes was performed, revealing a germline pathogenic variant in MSH2 (c.1000C>T, p.Gln344*), thus confirming the diagnosis of LS. To the best of our knowledge, this is the first case report of concurrent diaphragmatic CCC and LS. Patients with LS and endometriosis are at risk of developing ovarian cancer or intra-abdominal malignant tumors. In addition, immunohistochemistry screening for MMR proteins should be considered in patients with AEH and a family history of LS-related cancer, to enable early clinical intervention in cases of endometrial cancer.
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AIM: Ovarian serous carcinoma (OSC) and ovarian clear cell carcinoma (OCCC) are two major histological types of epithelial ovarian carcinoma (EOC), each with different biological features and clinical behaviors. Although immunostaining is commonly used for differential diagnosis between OSC and OCCC, correct identification of EOC with mixed-type histology is sometimes a diagnostic challenge. The aim of the present study was to explore candidate genes as potential diagnostic biomarkers that distinguish OSC from OCCC. METHODS: A total of 57 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery. Total RNAs were extracted from fresh-frozen tissues of EOC patients, and were used for comprehensive gene expression analysis using DNA microarray technology. RESULTS: Ten candidate genes, FXYD2, TMEM101, GABARAPL1, ARG2, GLRX, RBPMS, GDF15, PPP1R3B, TOB1, and GSTM3 were up-regulated in OCCC compared to OSC. All EOC patients were divided into two groups according to hierarchical clustering using a 10-gene signature. CONCLUSION: Our data suggest that the 10 candidate genes would be an excellent marker for distinguishing OSC from OCCC. Furthermore, the molecular signatures of the 10 genes may enlighten us on the differences in carcinogenesis, and provide a theoretical basis for OCCC's resistance to chemotherapy in the future.
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Adenocarcinoma de Células Claras , Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/patologia , Pessoa de Meia-Idade , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/patologia , Idoso , Diagnóstico Diferencial , Perfilação da Expressão Gênica , Adulto , Biomarcadores Tumorais/genéticaRESUMO
Paraovarian tumor of borderline malignancy is rare. Only 13 cases in Japan, including the present cases, and 40 cases overseas have been reported. We report two cases of paraovarian tumor of borderline malignancy. Case 1: A 38-year-old woman was found to have a right ovarian cyst. Transvaginal ultrasonography showed a unilocular cystic tumor and a solid part of 8 mm in diameter within the tumor. Malignancy could not be ruled out, therefore the laparotomy was performed. The tumor was paraovarian tumor. Intraoperative rapid histological diagnosis was made and the patient was diagnosed with a serous borderline tumor. There has been no recurrence 1 year after surgery. Case 2: A 30-year-old woman was found to have a right hydrosalpinx, or an ovarian cyst, with a solid part inside. Transvaginal ultrasonography showed the solid part within the tumor was 14 × 9 mm. Laparoscopic surgery was performed and we diagnosed the tumor as paraovarian cyst. Histological diagnosis was mucinous borderline tumor. There has been no recurrence 11 months after surgery.
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Cistos Ovarianos/cirurgia , Neoplasias Ovarianas/cirurgia , Adulto , Feminino , Humanos , Laparotomia , Cistos Ovarianos/patologia , Neoplasias Ovarianas/patologiaRESUMO
OBJECTIVE: Baroreflex is a regulatory mechanism that slows the fetal heart rate. This study aimed to investigate the effects of lipopolysaccharide (LPS)-induced endotoxemia on fetal baroreceptor sensitivity in preterm fetal sheep. METHODS: The changes in fetal baroreceptor sensitivity were measured in seven chronically instrumented preterm fetal sheep. Fetal baroreceptor sensitivity was measured in three phases: (A) control phase, defined as the 24 h before the first injection of LPS; (B) acute phase, defined as the 24 h between the first and second injections of LPS; and (C) fetal acidosis phase, defined as the time from the second LPS injection until intrauterine fetal death. Histological examinations of the fetal membrane and umbilical cord were also conducted. RESULTS: Each fetus developed metabolic acidosis after the second injection of LPS. The fetuses died 24.7 (SD = 6.1) hours after the second injection of LPS. Both the umbilical cord and fetal membranes showed histological evidence of severe inflammation. In total, 163 fetal baroreceptor measurements were performed in this experiment (A, n = 77 times; B, n = 60 times; C, n = 26 times). Fetal baroreceptor sensitivity showed significant differences in all three phases (A: 2.7 [SD = 0.2]; B: 2.5 [SD = 0.2]; and C: 1.5 [SD = 0.2]). Post hoc tests showed that baroreceptor sensitivity in the acidosis phase had decreased significantly compared to that in the control and acute phases (p<.001 and p=.002, respectively). CONCLUSIONS: Fetal baroreceptor sensitivity decreased during fetal acidosis induced by LPSs.
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Acidose , Doenças Fetais , Gravidez , Feminino , Humanos , Ovinos , Animais , Lipopolissacarídeos , Pressorreceptores/metabolismo , Pressorreceptores/patologia , Feto/patologia , Inflamação/induzido quimicamente , Inflamação/patologia , Frequência Cardíaca FetalRESUMO
BACKGROUND: Ovarian cancer has the worst outcome among gynecological malignancies; therefore, biomarkers that could contribute to the early diagnosis and/or prognosis prediction are urgently required. In the present study, we focused on the secreted protein spondin-1 (SPON1) and clarified the prognostic relevance in ovarian cancer. METHODS: We developed a monoclonal antibody (mAb) that selectively recognizes SPON1. Using this specific mAb, we determined the expression of SPON1 protein in the normal ovary, serous tubal intraepithelial carcinoma (STIC), and ovarian cancer tissues, as well as in various normal adult tissues by immunohistochemistry, and verified its clinicopathological significance in ovarian cancer. RESULTS: The normal ovarian tissue was barely positive for SPON1, and no immunoreactive signals were detected in other healthy tissues examined, which was in good agreement with data obtained from gene expression databases. By contrast, upon semi-quantification, 22 of 242 ovarian cancer cases (9.1%) exhibited high SPON1 expression, whereas 64 (26.4%), 87 (36.0%), and 69 (28.5%) cases, which were designated as SPON1-low, possessed the moderate, weak, and negative SPON1 expression, respectively. The STIC tissues also possessed SPON1-positive signals. The 5-year recurrence-free survival (RFS) rate in the SPON1-high group (13.6%) was significantly lower than that in the SPON1-low group (51.2%). In addition, high SPON1 expression was significantly associated with several clinicopathological variables. Multivariable analysis revealed that high SPON1 was an independent prognostic factor for RFS of ovarian cancer. CONCLUSIONS: SPON1 represents a prognostic biomarker for ovarian cancer, and the anti-SPON1 mAb could be valuable as an outcome predictor.
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Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Adulto , Feminino , Humanos , Neoplasias Ovarianas/genética , Prognóstico , Cistadenocarcinoma Seroso/patologia , Neoplasias das Tubas Uterinas/patologia , Biomarcadores , Biomarcadores Tumorais/metabolismoRESUMO
Arteriovenous malformation (AVM) can arise in various organs, particularly the brain, but it is rare in the uterus. Uterine AVM is potentially lethal and is generally associated with uterine trauma, such as dilatation and curettage, therapeutic abortion or uterine surgery. On the other hand, uterine myoma is the most common benign gynecological tumor, but uterine cervical myoma is rare and grows in the extraperitoneal space, with development of complex capillary networks within the tumor. Cervical myoma surgery is therefore a difficult operation with a risk of massive bleeding. We report herein a patient with uterine AVM formed within a large cervical myoma in a postmenopausal woman. The patient was a 55-year-old Japanese woman who complained of lower abdominal distension. Ultrasonography, computed tomography and magnetic resonance imaging showed an 18 × 20-cm uterine cervical tumor with dilatation of numerous vessels. Pelvic angiography was scheduled to provide accurate diagnosis and to minimize intraoperative blood loss. In fact, preoperative pelvic angiography allowed us to identify the true feeding artery and drainage veins. Occlusion of the feeding artery with a balloon device is effective in decreasing intraoperative bleeding. Abdominal total hysterectomy was performed as the surgical management of this uterine AVM. Prophylactic endovascular balloon occlusion of the ipsilateral internal iliac artery reduced the amount of hemorrhage during surgery, although blood transfusion was needed in our patient. In conclusion, preoperative embolosclerotherapy should be considered as a treatment option in patients with AVM present in a large uterine cervical myoma.
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Malformações Arteriovenosas/complicações , Mioma/complicações , Neoplasias do Colo do Útero/complicações , Útero/irrigação sanguínea , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/cirurgia , Feminino , Humanos , Histerossalpingografia , Artéria Ilíaca/anormalidades , Artéria Ilíaca/diagnóstico por imagem , Artéria Ilíaca/cirurgia , Angiografia por Ressonância Magnética , Pessoa de Meia-Idade , Mioma/diagnóstico por imagem , Mioma/cirurgia , Tomografia Computadorizada por Raios X , Ultrassonografia , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/cirurgia , Útero/diagnóstico por imagem , Útero/cirurgiaRESUMO
Surgery can be curative treatment for pelvic locoregional recurrence of endometrial cancer; however, a cure is contingent on complete resection. Here, we report the case of a patient in whom recurrent endometrial tumor remained in the pelvis after resection; long-term control was achieved with postoperative administration of pembrolizumab.The patient had recurrent endometrial cancer of stage IA and was treated with chemotherapy and radiation, but tumor persisted in the pelvic cavity. We therefore attempted total pelvic exenteration, but the tumor was adherent to the pelvic wall and complete resection could not be achieved. However, postoperative administration of pembrolizumab controlled the residual tumor for more than two years without regrowth. We believe that since the resected tumor was MSI-High, the residual tumor responded well to pembrolizumab. It is not known whether cytoreductive surgery contributes to a long-term response to pembrolizumab, but at least in our patient, pembrolizumab appeared to be a very effective drug therapy for MSI-High endometrial cancer that was refractory to chemotherapy and radiotherapy.
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Neoplasias do Endométrio , Exenteração Pélvica , Feminino , Humanos , Neoplasia Residual/cirurgia , Pelve/patologia , Pelve/cirurgia , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/patologia , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
The tightjunction protein claudin9 (CLDN9) is barely distributed in normal adult tissues but is ectopically expressed in various cancer types. Although multiple databases indicated upregulation of CLDN9 in endometrial cancers at the mRNA level, its protein expression and biological roles remain obscure. In the present study, the prognostic significance of CLDN9 expression in endometrial cancer was evaluated by immunohistochemical staining and semiquantification using formalinfixed paraffinembedded specimens obtained from 248 endometrial carcinoma cases. A total of 43 cases (17.3%) had high CLDN9 expression, whereas 205 cases (82.7%) exhibited low CLDN9 expression. The 5year diseasespecific survival rates in the high and low CLDN9 expression groups were 62.8 and 87.8% (P<0.001), respectively. In addition, multivariate analysis revealed that high CLDN9 expression was an independent prognostic factor (hazard ratio, 4.99; 95% CI, 1.9612.70; P<0.001). Furthermore, CLDN9 expression was significantly correlated with the expression of CLDN6 (P<0.001), which is the closest CLDN member to CLDN9 and a poor prognostic factor for endometrial carcinoma. The 5year diseasespecific survival rate of cases with CLDN6high/CLDN9high, CLDN6high/CLDN9low and CLDN6low/CLDN9high status was 30.0, 37.5 and 72.7%, respectively, whereas that of CLDN6low/CLDN9low was 89.8% (P=0.004). In conclusion, aberrant CLDN9 expression is a predictor of poor prognosis for endometrial cancer and may be utilized in combination with CLDN6 to achieve higher sensitivity.
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Claudinas , Neoplasias do Endométrio , Biomarcadores , Claudinas/genética , Claudinas/metabolismo , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Formaldeído , Humanos , Prognóstico , RNA Mensageiro/metabolismoRESUMO
NTRK gene fusion is rare in gynecological cancer. Entrectinib is a novel targeted drug, which is a potent inhibitor of TRK A, B and C. The present case report described a case of recurrent ovarian cancer with TPM3-NTRK1 rearrangement, which was detected by next-generation sequencing (NGS) and treated with entrectinib. A 56-year-old woman was diagnosed as having stage IV ovarian cancer with positive pleural fluid cytology. Neoadjuvant chemotherapy and interval debulking surgery, followed by chemotherapy, were performed. A total of 10 months after completion of chemotherapy, the disease recurred and the patient was treated with multimodal therapy for recurrence. DNA-based NGS detected TPM3-NTRK1 rearrangement and entrectinib therapy was initiated; however, the disease progressed despite 6 weeks of entrectinib administration, and 1 month after discontinuation of entrectinib, the patient died. After their death, immunohistochemistry with a pan-Trk monoclonal antibody was performed to determine the expression levels of TRK; however, immunohistochemistry was negative for TRK. In conclusion, the present case report described a rare case of recurrent ovarian cancer with TPM3-NTRK1 gene fusion, in which entrectinib was not effective. While NTRK gene fusion was detected by DNA-based NGS, immunohistochemistry was negative for TRK. These findings indicated that immunohistochemistry may be required for confirmation of TRK protein expression prior to entrectinib administration.
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OBJECTIVE: Epithelial ovarian cancer (EOC) is a heterogeneous disease with diverse clinicopathological features and behaviors, and its heterogeneity may be concerned with the accumulation of multiple somatic oncogenic mutations. The major goals of this study are to systematically perform the comprehensive mutational profiling in EOC patients, and investigate the associations between somatic mutations and clinicopathological characteristics. METHODS: A total of 80 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery, and genomic DNAs were extracted from fresh-frozen tissues. We investigated mutational status in hot spot regions of 50 cancer-related genes by targeted next-generation sequencing using an Ion AmpliSeq Cancer Hotspot Panel v2 Kit. RESULTS: Validated mutations were detected in 66 of the 80 tumors (82.5%). The five most frequently mutated genes were TP53 (43.8%), PIK3CA (27.5%), KRAS (23.8%), PTEN (10%) and CTNNB1 (10%). PTEN and CTNNB1 mutations were associated with younger age. PIK3CA1, KRAS and CTNNB1 mutations were observed in early-stage, whereas TP53 mutations were more common in advanced stage. Significant associations were observed between TP53 mutation and serous carcinoma, and between KRAS mutation and mucinous carcinoma. Both PIK3CA mutation and CTNNB1 mutation were also significantly associated with endometrioid and clear cell carcinoma. The patients with PIK3CA and KRAS mutations were significantly associated with favorable progression free survival (PFS). In particular, PIK3CA mutations had more significant associations with favorable PFS than PIK3CA wild-type in the endometrioid subtype (P = 0.012). Patients with mutations only in TP53 were significantly associated with worse PFS. CONCLUSION: EOCs were heterogeneous at the genomic level and harbored somatic oncogenic mutations. Our molecular profiling may have the potential for becoming a novel stratification within histological subtypes of EOC. Further studies are needed to define molecular classification for improved clinical outcomes and treatment of EOC patients in future.
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Carcinoma Epitelial do Ovário/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Pessoa de Meia-Idade , MutaçãoRESUMO
PURPOSE: Endometrial carcinoma (EC) is a clinically heterogeneous disease characterized by a number of different histological subtypes, and its heterogeneity may be involved in the accumulation of multiple genetic alterations. The aim of this work was to investigate the comprehensive mutational profile of EC tumors, and examine the associations between somatic mutations and clinicopathological features or survival in EC patients. METHODS: A total of 100 surgical tumors were obtained from EC patients who had previously undergone surgery. Genomic DNA samples extracted from fresh-frozen tissues were analyzed using the Ion AmpliSeq Cancer Hotspot Panel v2 Kit, covering 50 tumor-related genes. RESULTS: Validated mutations were detected in 91 of the 100 tumors (91%) and identified in eight of the most frequently mutated genes, namely PTEN (57%), PIK3CA (51%), TP53 (30%), KRAS (23%), CTNNB1 (21%), FBFR2 (13%), FBXW7(10%) and RB1 (9%). PTEN mutations were found to associated with young age (< 60), early-stage, endometrioid histology, non-recurrence and better overall survival (OS). CTNNB1 mutations were associated with young age, endometrioid histology and better OS. On the other hands, TP53 mutations were associated with late-stage, non-endometrioid histology, high-grade, recurrence and worse OS. FBWX7 mutations were associated with late-stage, vascular invasion and lymph node metastasis. FGFR2 mutations correlated with deep (≥ 1/2) myometrial invasion. CONCLUSION: Our comprehensive mutational profile will be useful for understanding and evaluating the molecular characteristics of EC tumors, and may lead to the establishment of novel treatment strategies that improve the survival of patients with EC in the future.
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BACKGROUND: Immune-related adverse events associated with immune checkpoint therapy cause autoimmune disease-like symptoms. People who carry specific genotypes or haplotypes of human leucocyte antigen (HLA) are known to be predisposed to develop autoimmune diseases including narcolepsy. Immunotherapy could be a trigger to develop narcolepsy in predisposing HLA positive patients. CASE PRESENTATION: A 66-year-old woman with stage IVB endometrial carcinosarcoma experienced daytime sleepiness and temporary muscle weakness 14 days after the administration of an immune checkpoint inhibitor, pembrolizumab. These were consistent with the main symptoms of narcolepsy with cataplexy. This patient carried a highly predisposing HLA haplotype for narcolepsy; HLA-DQB1*06:02, DRB1*15:01, DQA1*01:02 and DRB5*01:01:01. A hypocretin-1/orexin-A concentration in the patient's cerebrospinal fluid was low at 9.6 pg/mL in ELISA, and 155.5 pg/mL in radioimmunoassay that was below the normal level of 200 pg/mL. Therefore, she was diagnosed with narcolepsy tentatively according to the International Classification of Sleep Disorders, third edition diagnostic criteria for narcolepsy. The onset of narcolepsy in the 60s is very rare, and narcoleptic symptoms in our patient were likely to be caused by pembrolizumab. CONCLUSIONS: This case suggests that treatment with immune checkpoint inhibitors potentially causes narcolepsy in genetically predisposed patients.