Protein kinase Cγ in cerebellar Purkinje cells regulates Ca2+-activated large-conductance K+ channels and motor coordination.

The cerebellum, the site where protein kinase C (PKC) was first discovered, contains the highest amount of PKC in the central nervous system, with PKCγ being the major isoform. Systemic PKCγ-knockout (KO) mice showed impaired motor coordination and deficient pruning of surplus climbing fibers (CFs) from developing cerebellar Purkinje cells (PCs). However, the physiological significance of PKCγ in the mature cerebellum and the cause of motor incoordination remain unknown. Using adeno-associated virus vectors targeting PCs, we showed that impaired motor coordination was restored by re-expression of PKCγ in mature PKCγ-KO mouse PCs in a kinase activity-dependent manner, while normal motor coordination in mature Prkcgfl/fl mice was impaired by the Cre-dependent removal of PKCγ from PCs. Notably, the rescue or removal of PKCγ from mature PKCγ-KO or Prkcgfl/fl mice, respectively, did not affect the CF innervation profile of PCs, suggesting the presence of a mechanism distinct from multiple CF innervation of PCs for the motor defects in PKCγ-deficient mice. We found marked potentiation of Ca2+-activated large-conductance K+ (BK) channel currents in PKCγ-deficient mice, as compared to wild-type mice, which decreased the membrane resistance, resulting in attenuation of the electrical signal during the propagation and significant alterations of the complex spike waveform. These changes in PKCγ-deficient mice were restored by the rescue of PKCγ or pharmacological suppression of BK channels. Our results suggest that PKCγ is a critical regulator that negatively modulates BK currents in PCs, which significantly influences PC output from the cerebellar cortex and, eventually, motor coordination.

High cost of chemotherapy for gynecologic malignancies.

BACKGROUND: The prognosis of gynecological malignancies has improved with the recent advent of molecularly targeted drugs and immune checkpoint inhibitors. However, these drugs are expensive and contribute to the increasing costs of medical care. METHODS: The Japanese Clinical Oncology Group (JCOG) Health Economics Committee conducted a questionnaire survey of JCOG-affiliated facilities from July 2021 to June 2022 to assess the prevalence of high-cost regimens. RESULTS: A total of 57 affiliated facilities were surveyed regarding standard regimens for advanced ovarian and cervical cancers for gynecological malignancies. Responses were obtained from 39 facilities (68.4%) regarding ovarian cancer and 37 (64.9%) concerning cervical cancer, with respective case counts of 854 and 163. For ovarian cancer, 505 of 854 patients (59.1%) were treated with regimens that included PARP inhibitors, costing >500 000 Japanese yen monthly, while 111 patients (13.0%) received treatments that included bevacizumab, with costs exceeding 200 000 Japanese yen monthly. These costs are ~20 and ~10 times higher than those of the conventional regimens, respectively. For cervical cancer, 79 patients (48.4%) were treated with bevacizumab regimens costing >200 000 Japanese yen per month, ~10 times the cost of conventional treatments. CONCLUSIONS: In this survey, >70% of patients with ovarian cancer were treated with regimens that included poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or bevacizumab; ~50% of patients with cervical cancer were treated with regimens containing bevacizumab. These treatments were ~10 and ~20 times more expensive than conventional regimens, respectively. These findings can inform future health economics studies, particularly in assessing cost-effectiveness and related matters.

Current trends in chemotherapy for advanced ovarian cancer.

Chemotherapy for advanced ovarian cancer has progressed over the past several decades with the introduction of cytotoxic agents. Various methods, including single agents, combination therapy and changes in the method of administration, have been validated in many clinical trials and have been combined in an attempt to improve the prognosis of advanced ovarian cancer. In recent years, molecular-targeted agents have been added to cytotoxic agents as a treatment option for maintenance therapy; however, their efficacy has been limited, and further development of treatment options is expected. The advent of poly(ADP-ribose) polymerase inhibitors has considerably improved prognosis and has affected treatment strategies for advanced ovarian cancer over the past few years. With the addition of the recently introduced immune checkpoint inhibitors, future treatment strategies for advanced ovarian cancer may become more complex. In this review, we introduce the latest advances in chemotherapy for advanced ovarian cancer and discuss future perspectives.

Activation of oxidative phosphorylation in TP53-inactive endometrial carcinomas with a poor prognosis.

OBJECTIVE: We aimed to identify pathways for potential therapeutic targets by conducting molecular profiling of endometrial carcinomas in patients with poor prognosis. METHODS: The classification of endometrial carcinomas has undergone a paradigm shift with the advent of next generation sequencing based molecular profiling. Although this emerging classification reflects poor prognosis in patients with endometrial carcinoma, knowledge of affected biological pathways is still lacking. In this study, 85 patients with endometrial carcinomas at the Shizuoka Cancer Center were evaluated from January 2014 to March 2019 and classified based on The Cancer Genome Atlas subgroups. The accumulation of germline and somatic mutations was determined using next generation sequencing. Gene expression profiling was used to determine the effect of TP53 inactivation on the recurrence of endometrial carcinoma. Additionally, the biological pathways associated with TP53 inactivation were estimated by pathway analysis based on gene expression. RESULTS: Based on The Cancer Genome Atlas classification, the ratio of polymerase-epsilon to copy number-high subgroups and the frequency of PTEN and TP53 mutations differed in patients, and mutations of ARHGAP35 observed in normal endometrium were accumulated in the polymerase-epsilon and microsatellite instability subgroups. We revealed that copy number-high reflects TP53 inactivation in endometrial carcinomas, and that TP53-inactive tumors with or without TP53 mutations have poor prognosis. Furthermore, overexpression of aurora kinase A and activation of oxidative phosphorylation were found in TP53-inactivated endometrial carcinomas, suggesting that the PI3K/mTOR and autophagy pathways are potential drug targets. CONCLUSION: Our analysis revealed a relationship between pathways involved in oxidative phosphorylation and poor prognosis and provides insight into potential drug targets.

Regulatory connection between the expression level of classical protein kinase C and pruning of climbing fibers from cerebellar Purkinje cells.

Cerebellar Purkinje cells (PCs) express two members of the classical protein kinase C (cPKC) subfamily, namely, PKCα and PKCγ. Previous studies on PKCγ knockout (KO) mice have revealed a critical role of PKCγ in the pruning of climbing fibers (CFs) from PCs during development. The question remains as to why only PKCγ and not PKCα is involved in CF synapse elimination from PCs. To address this question, we assessed the expression levels of PKCγ and PKCα in wild-type (WT) and PKCγ KO PCs using PC-specific quantitative real-time reverse transcription-polymerase chain reaction, western blotting, and immunohistochemical analysis. The results revealed that the vast majority of cPKCs in PCs were PKCγ, whereas PKCα accounted for the remaining minimal fraction. The amount of PKCα was not up-regulated in PKCγ KO PCs. Lentiviral expression of PKCα in PKCγ KO PCs resulted in a 10-times increase in the amount of PKCα mRNA in the PKCγ KO PCs, compared to that in WT PCs. Our quantification showed that the expression levels of cPKC mRNA in PKCγ KO PCs increased roughly from 1% to 22% of that in WT PCs solely through PKCα expression. The up-regulation of PKCα in PKCγ KO PCs significantly rescued the impaired CF synapse elimination. Although both PKCα and PKCγ are capable of pruning supernumerary CF synapses from developing PCs, these results suggest that the expression levels of cPKCs in PKCγ KO PCs are too low for CF pruning.

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer.

This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1-21 with carboplatin (area under the concentration-time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8 and 15 every 3 weeks for up to 6 21-day cycles. Dose escalation followed a 3 + 3 design to determine dose-limiting toxicities, maximum tolerated dose and the recommended phase 2 dose. Nine patients (median age 62 [range 27-72] years) received a median of 5 (range 3-6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose-limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer.

Tetraalkoxyphenanthrene-Fused Hexadecadehydro[20]- and Tetracosadehydro[30]annulenes: Syntheses, Aromaticity/Antiaromaticity, Electronic Properties, and Self-Assembly.

Tetraalkoxyphenanthrene-fused hexadecadehydro[20]- and tetracosadehydro[30]annulenes possessing octatetrayne linkages were synthesized and their properties together with those of phenanthrene-fused octadehydro[12]- and dodecadehydro[18]annulenes have been investigated. Various spectroscopic and electrochemical measurements as well as quantum chemical calculations support that planar [20]- and [30]annulenes are weakly antiaromatic and nonaromatic, respectively. The detailed concentration- and temperature-dependent 1H NMR and UV-vis data of present dehydroannulenes provided evidence for the enhancement of π-π stacking interactions by extension of the acetylenic linkages. Dehydroannulenes formed self-assembled clusters and their morphology and crystallinity proved to depend on the length of acetylenic linkages, the shape of dehydroannulene core, and the bulkiness of alkoxy groups appended to the phenanthrene moieties.

The issues regarding postoperative adjuvant therapy and prognostic risk factors for patients with stage I-II cervical cancer: A review.

The treatment for most patients with early-stage cervical cancer involves radical hysterectomy and pelvic lymph node dissection, and indications for postoperative adjuvant therapy have been determined by evaluating the prognostic risk factors for recurrence in each case. The aim of this review is to raise and discuss the various issues that have not yet been resolved regarding the prognostic risk factors and postoperative adjuvant therapy. Several clinicopathological factors, such as tumor size, lymphovascular space involvement, deep stromal invasion, parametrial involvement and lymph node metastasis, have been identified to have prognostic significance in early-stage cervical cancer. However, this remains controversial because there is suggested to be substantial heterogeneity among patients after radical hysterectomy and lymphadenectomy and it would be difficult to define the risk groups clearly. This indicates the need to develop more convenient and accurate criteria to define risk groups. According to the currently available evidence, patients in the high-risk group should receive adjuvant concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) and fluolouracil. However, CCRT with CDDP administered weekly (CCRT-P) has instead been applied in a clinical context worldwide. Whether CCRT-P has a survival benefit compared with radiotherapy (RT) alone is unknown because no randomized phase III trials have been performed for patients in the high-risk group after radical surgery. Patients with high-risk factors have a high incidence of distant metastasis, for whom systemic chemotherapy might be a key to improving overall survival. The pivotal study that investigated the role of RT alone for patients with intermediate-risk factors after hysterectomy is the GOG092 trial. This trial showed a 47% reduction in the risk of recurrence after RT compared with no further treatment (NFT). However, the improvement in overall survival with RT did not reach statistical significance, while patients allocated to the RT group did experience an increase in severe toxicities compared with the NFT group. This could be why many physicians are reluctant to treat patients with this approach, although guidelines recommend RT for patients with intermediate-risk factors. With regard to toxicities, postoperative RT would be problematic because the organs in the pelvis targeted by RT have already been damaged by radical surgery. To reduce the toxicities, intensity-modulated radiotherapy would best be used worldwide. Further improvement in adjuvant therapy will come from enhanced definition of prognostic risk factors, better patient selection, and refinements in both local and systematic therapies.

Benzo- and Naphthopentalenes: Syntheses, Structures, and Properties.

Benzo- and naphthopentalene derivatives were synthesized, and the effects of structural variations on their antiaromaticity and optoelectronic and electrochemical properties were examined experimentally and theoretically in detail. The results unveiled that with increasing the bond order of the carbon-carbon bond ([5,6] junction) shared by the pentalene and aromatic moieties, the 8π antiaromatic character of pentalene is enhanced and the HOMO-LUMO gap is decreased, which accompanies both the elevation of the HOMO level and the lowering of the LUMO level. The ethynylene units between the pentalene skeleton and the phenyl groups proved to extend π-conjugation sufficiently.

Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial.

PURPOSE: Olanzapine is effective in chemotherapy-induced nausea and vomiting (CINV). In patients receiving highly emetogenic chemotherapy (HEC), its efficacy was reported as rescue therapy for breakthrough emesis refractory to triplet therapy (palonosetron, aprepitant, and dexamethasone). However, its preventive effects with triplet therapy for CINV are unknown. This study aimed to investigate efficacy and safety of preventive use of olanzapine with triplet therapy for CINV of HEC. METHODS: This study is a prospective multicenter study conducted by Kansai Clinical Oncology Group. Forty chemo-naïve gynecological cancer patients receiving HEC with cisplatin (≥50 mg/m(2)) were enrolled. Oral olanzapine (5 mg) was administered with triplet therapy a day prior to cisplatin administration and on days 1-5. The primary endpoint was complete response (no vomiting and no rescue) rate for the overall phase (0-120 h post-chemotherapy). Secondary endpoints were complete response rate for acute phase (0-24 h post-chemotherapy) and delayed phase (24-120 h post-chemotherapy) and complete control (no vomiting, no rescue, and no significant nausea) rate and total control (no vomiting, no rescue, and no nausea) rate for each phase. These endpoints were evaluated during the first cycle of chemotherapy. RESULTS: Complete response rates for acute, delayed, and overall phases were 97.5, 95.0, and 92.5 %, respectively. Complete control rates were 92.5, 87.5, and 82.5 %, respectively. Total control rates were 87.5, 67.5, and 67.5 %, respectively. There were no grade 3 or 4 adverse events. CONCLUSIONS: Preventive use of olanzapine combined with triplet therapy gives better results than those from previously reported studies of triplet therapy.

Adjuvant chemotherapy versus concurrent chemoradiotherapy for high-risk cervical cancer after radical hysterectomy and systematic lymphadenectomy.

BACKGROUND: The aims of this study were to evaluate the efficacy and toxicity of chemotherapy (CT) compared with concurrent chemoradiotherapy (CCRT) after radical hysterectomy and lymphadenectomy in high-risk patients with early-stage cervical cancer and to evaluate whether the radicality of the lymphadenectomy would affect the outcome and toxicity of postoperative adjuvant therapy. METHODS: The cases of all patients (n = 393) with FIGO IB1-IIB cervical cancer who were treated by radical surgery at Shizuoka Cancer Center between January 2002 and December 2013 were reviewed. Of these, 111 patients met the inclusion criteria for this retrospective study: (1) high risk for occurrence due to pathologically confirmed parametrial invasion and/or pelvic lymph node metastasis; (2) postoperative treatment with adjuvant CT or CCRT. The clinical data of these patients were reviewed. RESULTS: Of the 111 patients, 37 and 74 patients underwent CT and CCRT, respectively. The 4-year progression-free survival rate [PFS; 71.7 (CT) vs. 68.3 % (CCRT)] and overall survival rate [76.0 (CT) vs. 82.7 % (CCRT)] did not differ significantly between the two groups. The CT group contained significantly more patients with severe neutropenia than the CCRT group (66.7 vs. 23.0 %, respectively; p < 0.001), and the CCRT group contained significantly more patients with diarrhea than the CT group (10.8 vs. 0 %, respectively; p = 0.04). The patients who had ≥40 lymph nodes dissected (≥40 group) had higher PFS than the patients who had <40 lymph nodes dissected (<40 group) (73.2 vs. 64.2 %, respectively), although the difference was not significant. In the CT group, there was no significant association between the number of dissected lymph nodes and severe toxicities. However, in the CCRT group, significantly more vomiting (p = 0.046) and edema (p = 0.046) occurred in the ≥40 group than in the <40 group. CONCLUSIONS: Chemotherapy after surgery for high-risk patients had similar efficacy and a different toxicity profile compared with CCRT, and a more radical surgical procedure would improve the survival outcome. However, CCRT was associated with worse toxicity than CT. We advocate a prospective randomized study to compare CT with CCRT for patients with high-risk factors for recurrence.

Reconsideration of postoperative concurrent chemoradiotherapy with fluorouracil and cisplatin for uterine cervical cancer.

AIM: The aim of this retrospective study was to analyze data for patients with stage IB-IIB uterine cervical cancer who were treated with concurrent chemoradiotherapy with fluorouracil (5-FU) and cisplatin (CCRT-FP) as postoperative adjuvant therapy and to re-examine these issues and further treatment. METHODS: Patients with high risk for recurrence underwent CCRT-FP as postoperative adjuvant therapy. A total of 73 patients who met these criteria were included in this study. Data related to survival, toxicity, and treatment feasibility were analyzed, and the question of whether there were differences in survival and toxicity according to the number of dissected lymph nodes at surgery was evaluated. RESULTS: Median patient age was 45 years (range, 24-67 years). Two-thirds of patients had squamous cell histologic type, 41 patients (56.2%) had parametrial invasion, and 60 patients (82.2%) had lymph node metastases. Estimated 4-year progression-free survival, overall survival, and local control rates were 71.8%, 84.1%, and 88.5%, respectively. Sixteen patients (21.9%) had grade 3-4 neutropenia and one of them died of septic shock. Non-hematological toxicities were also common: 13 (17.8%) experienced grade 3-4 nausea, and nine (12.3%) experienced grade 3-4 diarrhea. Ileus occurred in 17 patients (23.3%), and seven of them (9.6%) were not yet cured. One patient experienced gastrointestinal perforation. CONCLUSIONS: CCRT-FP in the postoperative setting resulted in good survival outcome but toxicity remained problematic. Development of appropriate treatment for patients with high-risk prognostic factors after radical hysterectomy and lymphadenectomy is required.

Feasibility of extended-field irradiation and intracavitary brachytherapy combined with weekly cisplatin chemosensitization for IB2-IIIB cervical cancer with positive paraaortic or high common iliac lymph nodes: a retrospective review.

BACKGROUND: The aim of this retrospective study was to investigate the feasibility of primary treatment with extended-field irradiation and weekly cisplatin (extended-field concurrent chemoradiotherapy, EFCCRT) as initial therapy in patients with International Federation of Gynecology and Obstetrics IB1 to IIIB cervical cancer with paraaortic or high common iliac lymph node metastases. METHODS: Participants comprised patients with confirmed cervical cancer, showing paraaortic or high common iliac lymph node metastases on diagnostic imaging, treated with EFCCRT. Total external radiation doses were 50.4 Gy to the whole pelvis and 45.0 Gy to the lumbar paraaortic region. High-dose-rate intracavitary brachytherapy was performed to deliver a total dose of 18-24 Gy in 6-Gy fractions prescribed at point A. Weekly cisplatin (30-40 mg/m(2)) was given concurrently with radiotherapy. RESULTS: Twenty-four patients were treated. Median follow-up interval was 34 months. The dose of cisplatin was 30 mg/m(2) in 2 cases, 35 mg/m(2) in 8 cases, and 40 mg/m(2) in 14 cases. Twenty-two cases (92 %) received more than 160 mg/m(2) cisplatin. Ten cases (42 %) experienced acute grade 3/4 hematological toxicity, and 9 cases (38 %) experienced acute grade 3 nonhematological toxicity. No case presented late grade 3/4 toxicity. Three-year progression-free and overall survival rates were 54 % and 72 %, respectively. Eleven cases recurred during follow-up. Sites of recurrence were within the irradiation field in 4 cases, outside the field in 6 cases, and in both fields in 1 case. CONCLUSION: EFCCRT and high-dose-rate intracavitary brachytherapy for patients with paraaortic or high common iliac lymph node metastases from cervical cancer is feasible.

Association between Brain White Matter Lesions and Disease Activity in HAM/TSP Patients.

Human T-cell leukemia virus type 1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients may have brain white matter (WM) lesions, but the association of these lesions with disease activity is poorly understood. We retrospectively evaluated the brain WM lesions of 22 HAM/TSP patients (male 4: female 18) including 5 rapid progressors, 16 slow progressors, and 1 very slow progressor. The severity of WM brain lesions on axial Fluid Attenuated Inversion Recovery images was evaluated utilizing the Fazekas scale, cerebrospinal fluid biomarkers, and proviral load in peripheral blood mononuclear cells. Imaging and biological data were compared at the first visit and a subsequent visit more than 4 years later. Patients with comorbidities including adult T-cell leukemia-lymphoma and cerebrovascular disease were excluded. The results revealed that brain WM lesions in the rapid progressors group were more pronounced than those in slow progressors. In patients with HAM/TSP, severe and persistent inflammation of the spinal cord may cause brain WM lesions.

Tetraalkoxyphenanthrene-fused dehydroannulenes: synthesis, self-assembly, and electronic, optical, and electrochemical properties.

Novel tetraalkoxyphenanthrene-fused dehydro[12]-, [18]-, and [24]annulenes 1-3 were synthesized by using Cu-mediated or Pd-catalyzed oxidative macrocyclization reactions as key steps, and their electronic, optical, and electrochemical properties have been investigated in detail. X-ray crystallographic analysis of a single crystal of 1 a demonstrated that the molecules were arranged longitudinally in a slipped π-stacked fashion to form a 1D column. (1)H NMR and UV/Vis spectroscopic and cyclic voltammetric analysis in conjugation with nucleus-independent chemical shift (NICS) calculations for 1-3 support that the annulation at the 9,10-positions of phenanthrene to the dehydroannulene ring enhances the tropicity and decreases the HOMO-LUMO gaps of the molecules relative to the benzannulation and that 1 possesses an antiaromatic character. Self-association behavior due to π-π stacking in CDCl3 was observed for 1 and 2 and was quantified by concentration-dependent (1)H NMR spectroscopic measurements. The self-assembly of 1 and 2 into well-defined 1D superstructures with high aspect ratios were obtained, and the morphology and crystallinity of these compounds were investigated by means of SEM and wide-angle X-ray diffraction (WAXD) measurements. Furthermore, it was shown that 1 b and 2 b display liquid-crystalline phases by means of differential scanning calorimetry, polarizing optical microscopy, and variable-temperature WAXD measurements.

Hexadecadehydrodibenzo[20]-, tetracosadehydrotribenzo[30]-, and dotriacontadehydrotetrabenzo[40]annulenes: syntheses, characterizations, electronic properties, and self-associations.

Hexadecadehydrodibenzo[20]-, tetracosadehydrotribenzo[30]-, and dotriacontadehydrotetrabenzo[40]annulene derivatives ([20]-, [30]-, and [40]DBAs) possessing tetrayne linkages were synthesized. X-ray diffraction analysis demonstrated that the molecules of [30]DBA and p-xylene form a 2D sheetlike structure. Planar [20]- and [30]DBAs show significantly weak or almost no tropicity. The extension of the acetylenic linkages from a diyne to a tetrayne unit narrows HOMO-LUMO gaps. The self-association behavior of [30]DBA in solution resulting from effective π-π stacking interactions was observed.

Characterization of rare histological subtypes of ovarian cancer based on molecular profiling.

OBJECTIVE: Pan-cancer analysis across The Cancer Genome Atlas has revealed the molecular profiles of major types of carcinomas. High-grade serous carcinomas (HGSCs) have been characterized; however, in ovarian cancer, the profile of carcinoma with minor histopathological changes remains unclear. This study aimed to perform the molecular profiling of rare malignant ovarian tumors, including non-epithelial tumors (NETs; germ cell tumors and sex cord tumors) and clear cell carcinoma (CCC), to determine how they differ from the major HGSCs. METHODS: Sixty-nine malignant ovarian tumors surgically resected at the Shizuoka Cancer Center between January 2014 and March 2019 were classified based on their histopathological types. The germline and somatic mutations in these carcinomas, including NETs, were determined using next-generation sequencing. Gene expression analysis was performed to investigate the major pathways of drug resistance, which is a characteristic of CCC. RESULTS: NETs harbored copy-neutral loss of heterozygosity, accompanied by a high homologous recombination deficiency score; germline mutations of PALB2 and BARD1 were identified in two patients with NET. In chemoresistant CCC, the epithelial-mesenchymal transition pathway was activated regardless of ABC transporter expression. CONCLUSION: This study revealed some genomic characteristics of rare malignant ovarian tumors, including NETs and CCC.

Siblings with Cockayne Syndrome B Type III Presenting with Slowly Progressive Cerebellar Ataxia.

Two patients, 48- and 50-year-old sisters, presented with a characteristic facial appearance with slowly progressive deafness and cerebellar ataxia starting in their 30s. Genetic testing identified compound heterozygous pathogenic variants in the ERCC6 gene: c.1583G>A (p.G528E) and c.1873T>G (p.Y625D). A diagnosis of Cockayne syndrome (CS) B type III was made. CS is usually diagnosed in childhood with well-defined facial characteristics and photosensitivity. This case report describes rare cases of adulthood CS with a primary presentation of slowly progressing deafness and cerebellar ataxia. CS should be considered in adults with characteristic facial and skin findings, deafness, and cerebellar ataxia.

Is there a need for a technical certification system for gynecological robotic surgery? Questionnaire survey of members of the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy.

The Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy (JSGOE) introduced a system for the certification of laparoscopic surgeons in 2002 and a system for the certification of facilities in 2014. We examined the opinions of the members of the Japan Society of Gynecologic and Obstetric Endoscopy and Minimally Invasive Therapy (JSGOE) regarding the necessity of a certification training system and a technical certification system for robotic surgery skills in Japan. Members of the JSGOE were surveyed with two questionnaires. Overall, 870 and 519 participants responded to the first and second questionnaires, respectively. Half of the respondents indicated that both systems were necessary. The breakdown by age and qualifications showed that this was especially true for the younger generation and respondents with more experience with robotic surgery. Overall, 40% of the respondents judged that a certification system for robotic surgery alone (with or without certification in laparoscopic surgery but with a requirement of experience in laparoscopic surgery) would be necessary. The opinions of the JSGOE members on making a certification system for robotic surgery were split into two clear-cut camps. Thus, we must further seek the extent of public demand for using a public survey so that a final decision can be made on whether to establish this system.

Polymyalgia Rheumatica Following COVID-19 Vaccination.

We herein report a 71-year-old woman presented with a fever, arthralgia, general malaise and leg muscle stiffness following administration of the COVID-19 mRNA vaccine (Comirnaty, Pfizer-BioNTech). Laboratory findings showed an elevated C-reactive protein level and erythrocyte sedimentation rate. In addition, Gallium-67 scintigraphy demonstrated an increased uptake in multiple joints. Typing of human leukocyte antigen (HLA) revealed the presence of the DRB1*0404/*0803 allele. These findings met the diagnostic criteria for polymyalgia rheumatica (PMR), and when we started steroid treatment, her symptoms improved rapidly. This patient developed PMR after receiving a COVID-19 mRNA vaccine (Comirnaty, Pfizer-BioNTech). This case is considered to be valuable, as the HLA-DRB1 allele was also confirmed.