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Cancer genome profiling has revealed important genetic alterations that serve as prognostic indicators and guides for treatment decisions, enabling precision medicine. The shift to molecular diagnosis of brain tumors, as reflected in the 2021 World Health Organization Classification of Tumors of the Central Nervous System, is a crucial role for treatment decision-making. This review discusses the significance and role of cancer genome profiling in precision medicine for malignant brain tumors, particularly gliomas. Furthermore, we explore the progress in cancer genome analysis, focusing on cancer gene panel testing, integration of genomic information in brain tumor classification, and hereditary tumors. Additionally, we discuss the transformative effect of genomic medicine on early detection, risk assessment, and precision medicine strategies. The tumor mutational burden in brain tumors is considered low, but the application of molecular targeted drugs, such as isocitrate dehydrogenase inhibitors, v-raf murine sarcoma viral oncogene homolog B1 inhibitors, fibroblast growth factor receptor inhibitors, neurotrophic tyrosine receptor kinase, mechanistic target of rapamycin inhibitors, and anti-programmed death receptor-1 antibody drugs are promising for glioma treatment. We also discuss the future prospects of molecular targeted drugs., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: Platinum/taxane (TC) chemotherapy with debulking surgery stays the mainstay of the treatment in ovarian cancer patients with peritoneal metastasis, and recently its novel modality, intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip), was shown to have greater therapeutic impact. Nevertheless, the response varies among patients and consequent recurrence, or relapse often occurs. Discovery of therapeutic response predictor to ddTCip and/or TC therapy is eagerly awaited to improve the treatment outcome., Methods: Using datasets in 76 participants in our ddTCip study and published databases on patients received TC therapy, we first validated a total of 75 previously suggested markers, sought out more active biomarkers through the association analyses of genome-wide transcriptome and genotyping data with progression-free survival (PFS) and adverse events, and then developed multiplex statistical prediction models for PFS and toxicity by mainly using multiple regression analysis and the classification and regression tree (CART) algorithm., Results: The association analyses revealed that SPINK1 could be a possible biomarker of ddTCip efficacy, while ABCB1 rs1045642 and ERCC1 rs11615 would be a predictor of hematologic toxicity and peripheral neuropathy, respectively. Multiple regression analyses and CART algorithm finally provided a potent efficacy prediction model using 5 gene expression data and robust multiplex toxicity prediction models-CART models using a total of 4 genotype combinations and multiple regression models using 15 polymorphisms on 12 genes., Conclusion: Biomarkers and multiplex models composed here could work well in the response prediction of ddTCip and/or TC therapy, which might contribute to realize optimal selection of the key therapy., (© 2024. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Background: We proposed a novel treatment strategy, consisting of triweekly cisplatin plus dose-dense weekly paclitaxel before and after radical hysterectomy without adjuvant radiation therapy to treat locally advanced cervical cancer. However, cisplatin-related severe non-hematologic toxicities were frequent during this strategy. This study aimed to assess the applicability of replacing cisplatin with carboplatin in our proposed strategy., Methods: Women with International Federation of Gynecology and Obstetrics (FIGO) 2008 stage IB2, IIA2, or IIB cervical cancer received three cycles of carboplatin (based on an area under the curve of six), each 21 days apart, starting on day 1, and 80 mg/m 2 of paclitaxel on days 1, 8, and 15 of each 21-day cycle before undergoing radical hysterectomy. Patients with one or more high-risk factors, including lymph vascular invasion, parametrial invasion, lymph-node metastasis, or positive margins, received three additional cycles of chemotherapy after hysterectomy. Concurrent chemoradiation therapy was only applied to those patients who failed to respond to neoadjuvant chemotherapy., Results: Between September 2014 and July 2016, 50 women (13 women with FIGO stage IB2, 5 with stage IIA2, and 32 with stage IIB) were enrolled in this study. The overall response rate to chemotherapy was 92%, including 22% with pathological complete response. Forty-nine women (98%) completed the planned radical hysterectomy, and 11 (22%) women with one or more high-risk factors received three additional cycles of chemotherapy. Only four women (8%) received concurrent chemoradiation therapy after surgery. The 2- and 3-year progression-free survival rates were 88.0% and 83.8%, respectively, and the 2- and 3-year overall survival rates were 98.0% and 95.4%, respectively. Only two patients reported grade 3 or higher non-hematologic toxicities including grade 3 nausea in one patient and grade 3 liver dysfunction in one patient., Conclusions: Replacement the platinum agent resulted in equivalent efficacy, with reduced toxicity, in women with locally advanced cervical cancer. This strategy could considerably diminish the application of radiation therapy without reduced survival. A study to identify those patients who will benefit from this new multidisciplinary strategy is warranted.

Background: There are few studies on serum vascular endothelial growth factors and receptors (VEGF/VEGFRs) in patients with uterine cervical cancer (CC). The aim of this study was to determine whether VEGF/VEGFRs could be used as prognostic biomarkers in patients with CC., Methods: A total of 107 patients with stage IB to IIB CC, who underwent radical hysterectomy at Tottori University Hospital between 2006 and 2015, were included in this study. Serum samples were collected prior to radical hysterectomy, and levels of VEGF-A, VEGF-C, VEGFR-1, and VEGFR-2 were analyzed by enzyme-linked immunosorbent assays. We evaluated the association between the levels of these angiogenic factors and clinicopathologic variables. Survival analysis of 93 patients treated between 2006 and 2013 was performed., Results: The levels of VEGF-A in patients with bulky tumor, pelvic lymph-node involvement (PLNI), and parametrial infiltration (PI) were significantly higher than those in patients without these factors (P = 0.022, P = 0.020, and P = 0.0013, respectively). The overall survival (OS) of patients with high VEGF-A and VEGFR-2 defined by median levels was significantly lower than the OS of patients with low levels of VEGF-A and VEGFR-2 (P = 0.014, P = 0.012, respectively). Multivariate analysis revealed that PLNI, serum VEGF-A levels, and serum VEGFR-2 levels were independent prognostic factors for OS (hazard ratio for VEGF-A 3.42, 95% CI 1.07-13.2; hazard ratio for VEGFR-2 6.37, 95% CI 1.59-43.5)., Conclusion: Our results suggest that serum VEGF-A and VEGFR-2 may be promising prognostic biomarkers for CC.

Background: To prepare for a future clinical trial for improving the long-term prognosis of patients with uterine leiomyosarcoma (ULMS), we conducted a multi-institutional survey in the Tohoku region of Japan., Methods: We conducted a retrospective cohort study between 2011 and 2014 in member institutions of the Tohoku Translational Research Center Development Network., Results: A total of 53 patients with ULMS were registered in 31 institutions for the present survey. The median patient age was 56 years, 67.9% of the patients were postmenopausal, 88.7% had a performance status of 0 or 1, and only 6 patients (11.3%) showed preoperative evidence of malignancy. Although retroperitoneal lymphadenectomy was performed in only 26.4% of patients, 64.2% patients were identified as having FIGO stage 1 disease; 73.6% were eligible to undergo complete surgery. Among 36 patients who were treated with postoperative chemotherapy, 28 (77.8%) received docetaxel and gemcitabine combination therapy. The most frequent recurrence site was the lungs, and the median progression-free survival of all enrolled patients was 11.7 months. However, the median progression-free survival and the median overall survival in patients with stages III and IV disease were 3.4 and 11.4 months, respectively., Conclusion: Although ULMS was associated with a high rate of complete or optimal surgery, the long-term prognosis was poor. Effective postoperative therapy should be developed to improve the long-term prognosis of patients with ULMS.

Background: The standard chemotherapeutic regimen for stage IVB, persistent, or recurrent uterine cervical cancer is platinum-based combination chemotherapy such as cisplatin (CDDP)/paclitaxel and CDDP/nogitecan hydrochloride (NGT, topotecan). Because it is unclear whether the CDDP/NGT combination chemotherapy is tolerable for Japanese patients, we conducted the present study to assess the feasibility of CDDP/NGT combination chemotherapy., Methods: Between June 2012 and April 2014, 15 patients with stage IVB, persistent, or recurrent uterine cervical cancer were enrolled in this study. Patients underwent six cycles of NGT at a dose of 0.75 mg/m 2 , followed immediately by CDDP at a dose of 50 mg/m 2 on day 1 by intravenous infusion, and then NGT at a dose of 0.75 mg/m 2 on days 2 and 3., Results: Of 15 patients, 9 patients underwent at least 6 cycles of NGT/CDDP combination chemotherapy. Of a total of 83 cycles, 70 cycles (84.3 %) of NGT/CDDP combination chemotherapy could be continued at the starting dose of NGT (0.75 mg/m 2 ). Grade 3/4 hematological toxicities included leukopenia in 10 patients (66.7 %), neutropenia in 15 (100 %), anemia in 6 (40.0 %), thrombocytopenia in 4 (26.7 %), and febrile neutropenia in 4 (26.7 %). The response rate according to RECIST was 27 % (3/11), with partial response in 3 patients., Conclusions: NGT/CDDP combination chemotherapy may be a tolerable and effective regimen for Japanese patients with stage IVB, persistent, or recurrent uterine cervical cancer. Based on the results of this study, NGT/CDDP combination chemotherapy was approved in Japan in November 2015.

Objective: To assess the relationship between pre- and postoperative high-risk human papillomavirus (hrHPV) genotypes and hrHPV type-specific persistence and reappearance of abnormal cytology after successful conization., Methods: A retrospective analysis was performed of 211 patients who were undergoing conization after hrHPV genotype testing at Tottori University Hospital between July 2009 and June 2013. Of the 211 women, 129 underwent pre- and postoperative hrHPV genotype testing and were diagnosed with cervical intraepithelial neoplasia (CIN) grades 1-3 with negative margins., Results: The postoperative pathological diagnosis was CIN 1 in 8 patients, CIN 2 in 12, CIN 3 in 108 and adenocarcinoma in situ in 1 patient. Before conization, the most frequent hrHPV genotypes were HPV16 (n = 52; 40.3 %), followed by HPV52 (n = 32; 24.8 %) and HPV58 (n = 28; 21.7 %), while HPV18 was detected in 6 cases (4.7 %). Of the 23 postoperative hrHPV-positive cases, the same genotypes were detected in 10 cases while a different genotype was detected in 11 cases; type did not affect the frequency of persistent postoperative infection. The 3-year cumulative risk for the reappearance of abnormal cytology was significantly higher in postoperative hrHPV-positive patients than in postoperative hrHPV-negative patients (31.6 vs 9.7 %, P = 0.0014). A high-grade squamous intraepithelial lesion (HSIL) was observed during the follow-up period in one patient with persistent HPV16 infection., Conclusions: Postoperative hrHPV infection was a significant positive predictor for the reappearance of abnormal cytology and HPV16 infection-induced HSIL after treatment. Therefore, our study suggests that hrHPV genotype testing may be useful to follow-up CIN patients.

Background: Recent studies have shown that somatic mutations in the AT-rich interactive domain 1A (SWI-like) gene (ARID1A) are the most common genetic changes in clear cell carcinoma of the ovary (CCC). A gene mutation of ARID1A was found in approximately half of CCC cases, and led to absence of the encoded protein and inactivation of the putative tumor suppressor. Here, we investigated whether ARID1A could be a prognostic biomarker for this disease., Methods: We analyzed the protein expression of ARID1A in CCC from 112 patients by immunohistochemical staining, and evaluated the association of these molecular parameters with clinical outcome., Results: The loss of ARID1A expression was found in 39 % (44/112) of CCC, and was not associated with patient age, FIGO stage, and status of residual tumor. The 5-year survival rate for FIGO stage I or II patients with negative tumor expression of ARID1A was lower than those with positive tumor expression of ARID1A (74 % vs 91 %), but this difference was not observed in FIGO stage III or IV patients. Multivariable analysis revealed that ARID1A expression was an independent prognostic factor in FIGO stage I or II CCC patients., Conclusion: ARID1A may be a biomarker that is predictive of the outcome of FIGO stage I and II CCC.

Background: Lower limb lymphedema (LLL) is one of the most frequent postoperative complications of retroperitoneal lymphadenectomy for gynecologic cancer. LLL often impairs quality of life, activities of daily living, sleep, and sex in patients with gynecologic cancer. We conducted this study to evaluate the incidence and risk factors for LLL after gynecologic cancer surgery in patients who received assessment and periodic complex decongestive physiotherapy (CDP)., Methods: We retrospectively reviewed 126 cases of gynecologic cancer that underwent surgery involving retroperitoneal lymphadenectomy at Tottori University Hospital between 2009 and 2012. All patients received physical examinations to detect LLL and underwent CDP by nurse specialists within several months after surgery. The International Society of Lymphology staging of lymphedema severity was used as the diagnostic criteria., Results: Of 126 patients, 57 (45.2%) had LLL, comprising 45 and 12 patients with stage 1 and stage 2 LLL, respectively. No patient had stage 3 LLL. LLL was present in 37 (29.4%) patients at the initial physical examination. Multivariate analysis revealed that adjuvant concurrent chemoradiotherapy and age ≥ 55 years were independent risk factors for ≥ stage 2 LLL., Conclusions: To minimize the incidence of ≥ stage 2 LLL, gynecologic oncologists should be vigilant for this condition in patients who are ≥ 55 years and in those who undergo adjuvant chemoradiotherapy. Patients should be advised to have a physical assessment for LLL and to receive education about CDP immediately after surgery involving retroperitoneal lymphadenectomy for gynecologic cancer.

Background: We performed a retrospective study to clarify the outcome of stage IB2-IIB patients with bulky cervical cancer who underwent neoadjuvant chemotherapy (NAC) followed by radical hysterectomy and adjuvant treatment., Methods: Sixty-five patients with bulky stage IB2-IIB cervical cancer, treated at Tottori University Hospital between 2001 and 2011, were examined retrospectively. The indication for adjuvant treatment was limited to the following pathological high-risk factors: pelvic lymph node (PLN) involvement, parametrial infiltration (PI), and a compromised surgical margin., Results: Fifty-one patients had squamous cell carcinoma (SCC) and 14 non-SCC. Three patients were ineligible for radical hysterectomy after NAC, and underwent concurrent chemoradiotherapy. In 62 patients who underwent radical hysterectomy, 13 had only PLN involvement and 6 only PI, and 10 had both PLN involvement and PI. In 33 patients who had no adjuvant treatment, 6 recurred, and only one underwent salvage chemotherapy. In 29 patients who underwent adjuvant treatment, 15 recurred and 11 died. Multivariate Cox proportional analysis revealed that PLN involvement was an independent prognostic factor., Conclusions: Even if the indication for adjuvant treatment is limited to only high-risk patients, about 70 % of stage IB2-IIB patients with bulky cervical cancer could be cured by NAC followed by radical hysterectomy. Additionally, about 40 % of those patients could be cured without adjuvant treatment. In contrast, the strategy for patients with PLN involvement, who account for about 35 % of stage IB2-IIB bulky cervical cancer after NAC, should be carefully reconsidered based on quality of life and cost-effectiveness.

Malignant mixed müllerian tumors (MMMT) of the fallopian tube are extremely rare, and optimal therapy for them is unknown. A 71-year-old woman presented to us with symptoms of abdominal distension and nausea. A right salpingo-oophorectomy was performed. Pathological examination determined International Federation of Gynecology and Obstetrics (FIGO) stage IIIc MMMT of the right fallopian tube. Of note, multiple tumoral nodules were attached to the sigmoid colon. The patient received three courses of chemotherapy, consisting of 175 mg/m(2) paclitaxel and AUC=5 carboplatin (TC therapy), administered at 3-week intervals. A second, debulking, surgery was then performed, consisting of total abdominal hysterectomy, left salpingo-oophorectomy, and pelvic and paraaortic lymphadenectomy. The tumor attached to the sigmoid colon had shrunk by 60% after chemotherapy. The patient received an additional five courses of adjuvant TC therapy. The patient is alive and free of disease 28 months after the debulking surgery. TC therapy may be effective for MMMT of the fallopian tube.

We report on a 45-year-old patient with stage IIIc ovarian cancer, multiple brain metastases, and meningitis carcinomatosa. After three courses of initial chemotherapy, consisting of docetaxel and carboplatin, the patient underwent interval cytoreductive surgery, consisting of hyster-ectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy, and retroperitoneal lymphadenectomy. Then five courses of the same chemotherapy were given as adjuvant treatment. At the completion of the primary therapy, she achieved a complete remission. Ten months after the completion of the initial treatment, multiple brain metastases with meningitis carcinomatosa were detected. After four courses of the same chemotherapy, she again had a complete response, confirmed by cranial enhanced magnetic resonance imaging (MRI), and she felt well, with relief from the debilitating neurologic symptoms for 4 months. After this 4 months, her disease recurred, with meningitis carcinomatosa, and she requested supportive care only. She died 4 months after this recurrence. Chemotherapy can help to prolong life for some patients with multiple brain metastases and meningitis carcinomatosa from ovarian cancer.