A single-institution retrospective exploratory analysis on the effectiveness and safety of lenvatinib plus pembrolizumab for advanced endometrial cancer: insights from ProMisE molecular classification system.

BACKGROUND: The Proactive Molecular Risk Classifier for Endometrial Cancer has identified four risk groups for the prognosis of endometrial cancer. Lenvatinib plus pembrolizumab was recently approved as a second-line treatment for unresectable endometrial cancer, but reports in clinical practice are lacking. The relationship between the efficacy of lenvatinib/pembrolizumab and Proactive Molecular Risk Classifier for Endometrial Cancer classification is unclear. METHODS: This single-centre retrospective study included patients who underwent lenvatinib/pembrolizumab therapy at Iwate Medical University Hospital between January 2022 and March 2023. Formalin-fixed paraffin-embedded specimens obtained from patients before treatment were collected and classified into the mismatch repair-deficient, p53 abnormal and no specific molecular profile subtypes using immunohistochemistry. The response rate, progression-free survival and adverse events were evaluated using electronic medical records. The study was approved by the hospital's ethics committee (approval number: MH2022-093). RESULTS: This study enrolled 20 patients, who underwent a median follow-up of 17.8 months (95% confidence interval: 16.6-18.9). The best overall response rate was 60.0% (36.1-80.9), and the median progression-free survival was 11.6 months (2.9-20.3). The median progression-free survival in the p53 abnormal group (n = 9) was 3.4 months (3.0-3.8); however, progression-free survival did not reach the median (P < 0.001) in the mismatch repair-deficient/no specific molecular profile group (n = 11). Symptomatic immune-related adverse events (except hypothyroidism) occurred in 4/20 (25.0%) patients, and partial responses were observed in all cases. No treatment-related deaths occurred. CONCLUSION: The p53abn group in the Proactive Molecular Risk Classifier for Endometrial Cancer classification has a poor prognosis even after treatment with lenvatinib/pembrolizumab.

A Phase II Study of S-1 plus Oxaliplatin for Patients with Recurrent Non-Squamous Cell Carcinoma of the Uterine Cervix (Tohoku Gynecologic Cancer Unit: TGCU206 Study).

Recurrent non-squamous cell carcinoma (non-SCC) of the uterine cervix is resistant to treatment and has a poor prognosis. The efficacy and safety of S-1/oxaliplatin (SOX) therapy in patients with recurrent non-SCC was examined in a phase II study. Fifteen patients were enrolled between August 2013 and March 2023. S-1 was administered orally at a daily dose of 80-120 mg for 14 days, and oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. Each treatment cycle lasted 21 days. The anti-tumor effects, adverse events, progression-free survival (PFS), and overall survival (OS) were investigated. The median patient age was 54 (41-74) years. The anti-tumor effect was rated as a partial response in five patients, stable disease in four, and progressive disease in 6. The overall response rate was 33% and the disease control rate was 60%. Regarding hematologic toxicities of grade 3 or more severity, leukopenia, neutropenia, anemia, and thrombocytopenia occurred in 26.6-40.0%. None of the patients discontinued the treatment because of adverse events. The median PFS and OS were 6 months (95% confidence interval [CI]: 2-11 months) and 22 months (95% CI: 11-23 months), respectively. No treatment-related deaths occurred. These results suggest that SOX therapy is useful for the treatment of recurrent non-SCC with promising anti-tumor effects and minimal adverse events.

Efficacy and Safety of Platinum-based Chemotherapy With Bevacizumab Followed by Bevacizumab Maintenance for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer During PARP Inhibitor Therapy: A Multicenter Retrospective Study.

BACKGROUND/AIM: In recent years, the usefulness of poly ADP-ribose polymerase (PARP) inhibitors as subsequent maintenance therapy with poly ADP-ribose polymerase (PARP) inhibitors has been reported. However, it has been reported shown that platinum-based chemotherapy has a low response rate and short progression-free survival for recurrent platinum-sensitive ovarian cancer during treatment with PARP inhibitor therapy. This retrospective study evaluated platinum-based chemotherapy with bevacizumab (BEV) followed by BEV maintenance in these recurrent patients. PATIENTS AND METHODS: Efficacy and safety were evaluated in 23 patients with ovarian, fallopian tube, or primary peritoneal cancer diagnosed with platinum-sensitive recurrence during PARP inhibitor treatment (administered from April 2019 to December 2022). Platinum-based chemotherapy included either paclitaxel with carboplatin, paclitaxel with cisplatin, docetaxel with carboplatin, or doxorubicin with carboplatin. BEV was administered in combination with any of these chemotherapies agents. Chemotherapy was administered for 6 cycles and BEV was administered up to 21 cycles. RESULTS: The median numbers of cycles of platinum-based chemotherapy and BEV administration were 6 and 8, respectively. Complete response was observed in four patients (17.4%), partial response in 15 (65.2%), stable disease in two (8.7%), and progressive disease in two (8.7%). Objective response and disease control rates were 82.6% and 91.3%, respectively. Grade 3 or higher hematological toxicity occurred in 8 patients, with leukopenia, neutropenia in 14, anemia in 5, and thrombocytopenia in 4. On the other hand, non-hematological toxicities included hypertension in three patients, proteinuria in two, constipation in one, and carboplatin hypersensitivity in four. Only one patient discontinued chemotherapy due to an adverse event of proteinuria. No treatment-related deaths occurred. CONCLUSION: Platinum-based chemotherapy with BEV followed by BEV maintenance for platinum-sensitive recurrence during PARP inhibitor treatment was shown to be efficacious and safe. This combination should be further evaluated in larger randomized clinical trials.

Efficacy and Safety of Platinum Rechallenge in Patients With Platinum-resistant Ovarian, Fallopian Tube or Primary Peritoneal Cancer: A Multicenter Retrospective Study.

BACKGROUND/AIM: Ovarian cancer diagnosed with platinum-resistant recurrence has very poor prognosis and single-agent chemotherapy with no cross-resistance to prior chemotherapy is recommended for its treatment. In this study, we retrospectively evaluated the efficacy and safety of platinum rechallenge therapy for once diagnosed with platinum-resistant ovarian cancer who had a platinum-free interval (PFI) of at least 6 months. PATIENTS AND METHODS: The study included 49 patients who received platinum rechallenge therapy for ovarian, fallopian tube or primary peritoneal cancer who were once diagnosed with platinum-resistant recurrence between January 2010 and March 2021 and evaluated the efficacy and safety of this treatment. In addition, patient background factors were identified, and independent prognostic factors for progression-free survival (PFS) and overall survival (OS) were investigated. RESULTS: A complete response was noted in 7 cases, partial response in 21, stable disease in 9, and progressive disease in 10. The response and disease control rates were 55% and 76%, respectively. The median PFS and OS were 8.5 months and 35.8 months, respectively. The independent prognostic factor was PFI for OS, and there was no independent prognostic factor for PFS. Seven patients discontinued chemotherapy owing to serious adverse events, including one patient with treatment-related death. CONCLUSION: Platinum rechallenge therapy for patients with platinum-resistant recurrence did not cause previously unreported adverse events, and the adverse events were manageable. In addition, high response and disease control rates were observed, as well as long-term OS. Platinum rechallenge therapy for platinum-resistant ovarian cancer may be a viable treatment option.

Novel Therapeutic Strategies for Refractory Ovarian Cancers: Clear Cell and Mucinous Carcinomas.

Ovarian cancer has the worst prognosis among gynecological cancers. In particular, clear cell and mucinous carcinomas are less sensitive to chemotherapy. The establishment of new therapies is necessary to improve the treatment outcomes for these carcinomas. In previous clinical studies, chemotherapy with cytotoxic anticancer drugs has failed to demonstrate better treatment outcomes than paclitaxel + carboplatin therapy. In recent years, attention has been focused on treatment with molecular target drugs and immune checkpoint inhibitors that target newly identified biomarkers. The issues that need to be addressed include the most appropriate combination of therapies, identifying patients who may benefit from each therapy, and how results should be incorporated into the standard of care for ovarian clear cell and mucinous carcinomas. In this article, we have reviewed the most promising therapies for ovarian clear cell and mucinous carcinomas, which are regarded as intractable, with an emphasis on therapies currently being investigated in clinical studies.

Comparison of Postoperative Adjuvant Chemotherapy and Concurrent Chemoradiotherapy for FIGO2018 Stage IIIC1 Cervical Cancer: A Retrospective Study.

Background and Objectives: In October 2018, the International Federation of Gynecology and Obstetrics (FIGO) revised its classification of advanced stages of cervical cancer. The main points of the classification are as follows: stage IIIC is newly established; pelvic lymph node metastasis is stage IIIC1; and para-aortic lymph node metastasis is stage IIIC2. Currently, in Japan, radical hysterectomy is performed in advanced stages IA2 to IIB of FIGO2014, and concurrent chemoradiotherapy (CCRT) is recommended for patients with positive lymph nodes. However, the efficacy of CCRT is not always satisfactory. The aim of this study was to compare postoperative adjuvant chemotherapy (CT) and postoperative CCRT in stage IIIC1 patients. Materials and Methods: Of the 40 patients who had undergone a radical hysterectomy at Iwate Medical University between January 2011 and December 2016 and were pathologically diagnosed as having positive pelvic lymph nodes, 21 patients in the adjuvant CT group and 19 patients in the postoperative CCRT group were compared. Results: The 5 year survival rates were 77.9% in the CT group and 74.7% in the CCRT group, with no significant difference. There was no significant difference in overall survival or progression-free survival between the two groups. There was no significant difference between CT and CCRT in postoperative adjuvant therapy in the new classification IIIC1 stage. Conclusions: The results of the prospective Japanese Gynecologic Oncology Group (JGOG) 1082 study are pending, but the present results suggest that CT may be a treatment option in rural areas where radiotherapy facilities are limited.

Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer.

The incidence of ovarian cancer, which has had a poor prognosis, is increasing annually. Currently, the prognosis is expected to improve with the use of molecular-targeted drugs and immune checkpoint inhibitors as maintenance therapies after the first-line chemotherapy. The GOG218 and ICON7 studies reported the usefulness of bevacizumab and the SOLO-1 and PRIMA (A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy) studies have reported the usefulness of olaparib and niraparib, respectively. The ATHENA study investigating the usefulness of rucaparib is currently ongoing. Although clinical studies of immune checkpoint inhibitors are lagging in the field of gynecology, many clinical studies using programmed death cell-1 (PD-1) and PD-1 ligand 1 (PD-L1) antibodies are currently ongoing. Some biomarkers have been identified for molecular-targeted drugs, but none have been identified for immune checkpoint inhibitors, which is a challenge that should be addressed in the future.

A case of ovarian adenosquamous carcinoma arising from endometrioid adenocarcinoma: a case report and systematic review.

BACKGROUND: The aims of this report were to describe a case of ovarian adenosquamous carcinoma and to systematically review the pertinent literature. METHODS: We describe a case in which a 57-year-old woman had stage IC ovarian cancer histologically diagnosed as adenosquamous carcinoma. We also systematically reviewed the literature using the PubMed database. CASE PRESENTATION: Preoperative computed tomography and magnetic resonance imaging showed a tumor measuring 14 cm in diameter and containing solid areas. Tumor marker levels were as follows: CA125, 42.6 U/mL; CA 19-9, 134.1 U/mL; CEA, 0.9 ng/mL; and SCC, 1.6 ng/mL. The patient underwent multiple surgeries including total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, para-aortic lymph node biopsy, and total omentectomy. Based on the cytological features of the ascitic fluid, the tumor was diagnosed as a squamous cell carcinoma. Histological examination of an excised specimen showed the transition of an endometrioid adenocarcinoma to a squamous cell carcinoma. There was no evidence of any teratomas or endometriosis-related features. We considered the tumor to be an adenosquamous carcinoma, with the squamous cell carcinoma component arising from the endometrioid adenocarcinoma component. After surgery, the patient underwent 6 cycles of paclitaxel and carboplatin chemotherapy. There has been no recurrence to date, 66 months after the initial treatment. RESULTS: Histologically, the 8 adenosquamous carcinomas reported in the literature either arose from the mature cystic teratoma (4 cases) or endometriosis (3 cases) or were pure adenosquamous carcinomas (1 case). Our literature search uncovered no cases of ovarian adenosquamous carcinomas originating from endometrioid adenocarcinomas. CONCLUSIONS: This is the first reported case of an adenosquamous carcinoma arising from an endometrioid adenocarcinoma. Because such tumors are rare, their standard management is unclear.

A phase I study of irinotecan and pegylated liposomal doxorubicin in recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study).

PURPOSE: A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan hydrochloride (CPT-11) in CPT-11/pegylated liposomal doxorubicin (PLD) combination therapy, a novel treatment regimen for platinum- and taxane-resistant recurrent ovarian cancer. METHODS: Pegylated liposomal doxorubicin was administered intravenously on day 3 at a fixed dose of 30 mg/m(2). CPT-11 was administered intravenously on days 1 and 15, at a dose of 50 mg/m(2) on both days. One course of chemotherapy was 28 days, and patients were given a maximum of six courses, with the CPT-11 dose being increased in increments of 10 mg/m(2) (level 1, 50 mg/m(2); level 2, 60 mg/m(2); level 3, 70 mg/m(2); level 4, 80 mg/m(2)) to determine MTD and RD. RESULTS: During the period from April 2010 to March 2013, three patients were enrolled for each level. In the first course, no dose-limiting toxicity occurred in any of the patients. Grade 4 neutropenia was observed in two of three patients at level 4. At level 4, the antitumor effect was a partial response (PR) in two of the three patients and stable disease (SD) in one. At level 3, one of the three patients showed PR and two had SD. At level 4, the start of the next course was postponed in two of three patients. In addition, one patient at level 4 experienced hemotoxicity that met the criteria for dose reduction in the next course. The above results suggested that administration of CPT-11 at dose level 5 (90 mg/m(2)) would result in more patients with severe neutropenia and in more patients requiring postponement of the next course or a dose reduction. Based on the above, the RD of CPT-11 was determined to be 80 mg/m(2). CONCLUSIONS: The results suggest that CPT-11/PLD combination therapy for recurrent ovarian cancer is a useful treatment method with a high response rate and manageable adverse reactions. In the future phase II study, the safety and efficacy of this therapy will be assessed at 80 mg/m(2) of CPT-11 and 30 mg/m(2) of PLD.

A pilot study of oxaliplatin with oral S-1 as second-line chemotherapy for patients with recurrent adenocarcimona of the uterine cervix.

BACKGROUND: The efficacy and safety of S-1/oxaliplatin (SOX) therapy in patients with recurrent adenocarcinoma of the uterine cervix were examined in a pilot study. PATIENTS AND METHODS: S-1 was orally administered for 14 days at a dose of 80-120 mg/body/day to 7 patients with recurrent adenocarcinoma of the uterine cervix, with oxaliplatin being administered intravenously at a dose of 100 mg/m(2) on day 1. Each therapy cycle was 21 days, and the patients received 6 cycles at most. The antitumor effect, adverse events, progression-free survival (PFS), and overall survival (OS) were investigated. RESULTS: The median age of the patients was 49 years. The antitumor effect was rated as a complete response in 2 patients, partial response in 2, and stable disease in 3. The overall response rate was 57.1 %, and the disease control rate was 100 %. Regarding hematological toxicities of grade 3 or more, leukopenia, neutropenia and thrombocytopenia occurred in 42.9, 28.6 and 14.3 %, respectively; regarding non-hematological toxicities, grade 3 rectovaginal fistula occurred in 14.3 %, as well as grade 2 fatigue in 14.3 % of the patients. The median PFS and OS were 5 months (range 3-9 months) and 7 months (range 4-43 months), respectively. CONCLUSIONS: These results suggest that SOX therapy is useful for the treatment of recurrent adenocarcinoma of the uterine cervix, having a promising antitumor effect and minimal adverse effects. It was also suggested that SOX therapy may contribute to improving the prognosis for patients with adenocarcinoma of the uterine cervix.

Unusual markedly-dilated chorionic vessels with placentomegaly.

We reported a very rare case with placentomegaly and markedly-dilated chorionic vessels. A 23-year-old Japanese pregnant woman was referred to our hospital at 32 weeks of gestation because of suspected dilatation of the umbilical vein. Ultrasound revealed fetal growth restriction with no fetal anomalies. The placenta was thick. The umbilical cord had two arteries and one vein, and marginal insertion of the umbilical cord in the placenta was suspected. A lot of remarkably tortuous tubular structures were observed on the surface of the placenta. Slow blood flow, indemonstrable with color Doppler, was observed within them. Labor started suddenly and progressed very rapidly at 33 weeks of gestation. A female infant weighing 1524 g was delivered. The infant had no malformations. However, she showed hypotension, anemia and DIC and required blood transfusion. The placenta was very large, weighing 1416 g. On the fetal surface, numerous dilated and tortuous vessels were observed, arising from a vein that was connected to the umbilical vein. These venous channels were dilated and tortuous and led into the placenta. In conclusion, prenatal diagnosis of placentomegaly and markedly-dilated chorionic vessels requires assessment of growth, anemia and DIC of the fetus and the newborn infant.

Acute abdomen due to ovarian congestion: a fallopian tube accompanied by a paratubal cyst, coiling tightly round the ovary.

We experienced an unreported rare case with an adnexal mass causing severe acute abdomen during pregnancy. A 30-year-old Japanese pregnant woman was transported to our hospital for her right lower abdominal pain at 30 weeks of gestation. Magnetic resonance imaging and ultrasound demonstrated a cyst measuring 3-4 cm in diameter adjacent to the right ovary, and a parovarian cyst was considered to be the most probable diagnosis. We strongly suspected torsion of the ovarian pedicle or fallopian tube in conjunction with her clinical symptoms. Laparotomy revealed that the elongated right fallopian tube accompanied by a paratubal cyst was coiling tightly 2.5 times round the right ovary, causing apparent congestion and enlargement of the right ovary. Soon after we released the congested right ovary from the coiling of the fallopian tube, the congestion subsided. The postoperative course was favorable, and pregnancy and delivery were uneventful.

Prenatal ultrasound and magnetic resonance imaging findings of a hypovascular epignathus with a favorable prognosis.

Epignathus of a fetus is an extremely rare type of an oropharyngeal teratoma that commonly arises from the palate and often grows in the prenatal period, leading to polyhydramnios due to difficulty in swallowing before birth and a high mortality due to the airway obstruction after birth. We report here a very rare case of a fetus with an epignathus decreasing in size naturally in the prenatal period with a favorable prognosis. In contrast to previously reported cases of epignathus that grew rapidly in the prenatal period, color Doppler fetal ultrasound showed a hypovascular tumor in our case. Moreover, histopathologic examination revealed an epignathus with necrotic areas inside. Based on our experience, a hypovascular epignathus demonstrated by color Doppler fetal ultrasound may be an indicator of a favorable prognosis.

[Results of neoadjuvant chemotherapy using tri-weekly CDDP/CPT-11 for locally advanced cervical cancer].

OBJECTIVE: We assessed the antitumor response and safety of neoadjuvant chemotherapy (NAC) using cisplatin (CDDP) and irinotecan(CPT-11)given every three weeks for locally advanced cervical cancer with a bulky mass. SUBJECTS AND METHODS: Nineteen patients with cervical squamous cell cancer in FIGO stage of Ib2 to IIb were enrolled in this study. The FIGO stages were Ib2 in 5 patients, IIa in 2 patients, and IIb in 12 patients. One course of the chemotherapy regimen consisted of intravenous administrations of CDDP at a dose of 70 mg/m 2(day 1)and CPT-11 at 70 mg/m 2 (days 1 and 8) for 21 days, and two courses were administered. This chemotherapy was assessed for antitumor response, adverse events, complete surgical removal rate, progression-free survival time, and overall survival time. RECIST and NCI-CTCAE were used to determine antitumor response and adverse events, respectively. RESULTS: The results of assessment of the antitumor response showed CR in 3 patients(15. 8%), PR in 14(73. 7%), SD in 1 (5. 3%), and PD in 1(5. 3%). Neutropenia of grade 3 or higher occurred in 13 patients(68. 4%). Anemia occurred in 2 patients(10. 5%), and thrombocytopenia in 1 patient(5. 3%). Nausea and vomiting were observed in 2 patients(10. 5%). All patients underwent a chemotherapy regimen consisting of two courses, and the rate of complete surgical removal was 94. 7%. The median observation period was 27 months; the progression-free survival time was 18 months, and survival time was 27 months. CONCLUSION: Adverse drug reactions to NAC with the CDDP/CPT-11 combination administered every three weeks were controllable. The antitumor response rate for this chemotherapy was high. These assessment results indicate that NAC with a CDDP/CPT-11 combination was useful for local advanced cervical cancer.

Usefulness of desensitization protocol for a carboplatin hypersensitivity reaction during docetaxel-carboplatin therapy for recurrent ovarian cancer: Case report.

We report a case of recurrent ovarian cancer in which desensitization for a carboplatin hypersensitivity reaction proved useful. The patient was a 65-year-old woman who presented with a recurrence of stage IIIc ovarian cancer. The initial chemotherapy consisted of 6 courses of paclitaxel and carboplatin. Recurrence in the pelvis, splenic hilum and para-aortic lymph nodes was detected 19 months after the final day of treatment. The patient was treated with docetaxel-carboplatin therapy for the recurrence, but a Grade 3 hypersensitivity reaction to carboplatin was observed during the second course. Carboplatin desensitization was commenced with the third course and 6 courses were completed with no evidence of hypersensitivity reaction. The antitumor effect showed a complete response and the patient has had a disease-free survival thus far. Desensitization for patients diagnosed with a carboplatin hypersensitivity reaction appeared to be a key method of treatment for prolonging the survival time of patients with recurrent ovarian cancer.