Explore the vast range of titles available.

Neuroendocrine carcinoma (NEC) of the head and neck is a rare type of malignancy, accounting for only 0.3% of all head and neck cancers, and its clinicopathological and genomic features have not been fully characterized. We conducted a retrospective analysis of 27 patients with poorly differentiated NEC of the head and neck seen at our institution over a period of 15 years. Patient characteristics, adopted therapies, and clinical outcomes were reviewed based on the medical records. Pathological analysis and targeted sequencing of 523 cancer-related genes were performed using evaluable biopsied/resected specimens based on the clinical data. The most common tumor locations were the paranasal sinus (33%) and the oropharynx (19%). Eighty-one percent of the patients had locally advanced disease. The 3-year overall survival rates in all patients and in the 17 patients with locally advanced disease who received multimodal curative treatments were 39% and 53%, respectively. Histologically, large cell neuroendocrine carcinoma was the predominant subtype (58% of evaluable cases), and the Ki-67 labeling index ranged from 59 to 99% (median: 85%). Next-generation sequencing in 14 patients identified pathogenic/likely pathogenic variants in TP53, RB1, PIK3CA-related genes (PREX2, PIK3CA, and PTEN), NOTCH1, and SMARCA4 in six (43%), three (21%), two (14%), two (14%), and one (7%) patients, respectively. Sequencing also detected the FGFR3-TACC3 fusion gene in one patient. The median value of the total mutational burden (TMB) was 7.1/Mb, and three patients had TMB ≥ 10. Regardless of the aggressive pathological features, our data revealed favorable clinical characteristics in the patients with locally advanced disease who received curative treatment. The lower TP53 and RB1 mutation prevalence rates compared to those described for small cell lung cancer suggests the biological heterogeneity of NEC in different parts of the body. Furthermore, the FGFR3-TACC3 fusion gene and mutations in genes encoding the components of the NOTCH and PI3K/AKT/mTOR pathways found in our study may be promising targets for NEC of the head and neck.

BackgroundAdvanced relapsed ovarian cancer has a poor prognosis, and treatment options are limited.MethodsThis phase I trial investigated the dosage, safety, pharmacokinetics and efficacy of trabectedin plus pegylated liposomal doxorubicin (PLD) in Japanese patients with advanced relapsed ovarian, fallopian tube, or primary peritoneal cancer. Patients received trabectedin 0.9 or 1.1 mg/m2 immediately after PLD 30 mg/m2; both drugs were given by intravenous infusion. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) was determined in an initial dose escalation phase, and this was used in a subsequent safety assessment phase. Safety and tumor response were monitored throughout the trial, and drug concentrations for pharmacokinetic analysis were measured during cycle 1.ResultsEighteen patients were included. The MTD of trabectedin was determined as 1.1 mg/m2. Gastrointestinal adverse events were experienced by all patients, but were mostly grade 1 or 2 in intensity. Most patients had grade ≥ 3 elevations in transaminase levels or grade ≥ 3 reductions in neutrophil count, but these events were generally manageable through dose reduction and/or supportive therapies, as appropriate. There were no deaths during the trial. Trabectedin exposure increased in a dose-dependent manner. The overall response rate was 27.8%.ConclusionsTrabectedin, in combination with PLD, may have clinical benefits in Japanese patients with relapsed advanced ovarian cancer. The recommended dosage of trabectedin for further study in this population is 1.1 mg/m2 once every 21 days.Clinical trial registration number: JapicCTI-163164

Background The long-term outcomes and risk factors of paclitaxel-induced peripheral neuropathy (PIPN) have not yet been fully elucidated. Methods We identified 219 breast cancer patients who received paclitaxel as adjuvant chemotherapy between 2002 and 2009. We retrospectively analyzed the incidence, time to onset, duration, and risk factors for PIPN by chart review. Results Of the 219 patients, 212 developed PIPN (97%) during a median follow-up time of 57 months (range 5.3–95.5). Median time to PIPN onset was 21 days (range 11–101) for the entire patient population: 35 days (range 14–77) for weekly administration and 21 days (range 11–101) for tri-weekly administration. PIPN caused termination of paclitaxel treatment in 7 patients (4%). Median duration of PIPN was 727 days (range 14–2621 days). PIPN persisted in 64 and 41% of patients at 1 and 3 years after initiating paclitaxel, respectively. Age ≥60 years and severity of PIPN were significantly associated with PIPN duration. Conclusions PIPN persists longer in older patients and in those who experience severe neuropathy. Further studies to identify the risk factors for PIPN are warranted.

Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression‐free survival (PFS) and overall survival (OS) versus chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3, randomized, double‐blind, placebo‐controlled KEYNOTE‐826 study. We report outcomes in patients enrolled in Japan. Patients received pembrolizumab 200 mg or placebo Q3W for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5) with or without bevacizumab 15 mg/kg. Dual primary endpoints were PFS per RECIST v1.1 by investigator assessment and OS in the global population; these were evaluated in patients with tumors with PD‐L1 combined positive score (CPS) ≥1, all‐comers, and PD‐L1 CPS ≥10. Fifty‐seven patients from Japan were randomized (pembrolizumab plus chemotherapy, n = 35; placebo plus chemotherapy, n = 22). Pembrolizumab plus chemotherapy improved PFS versus placebo plus chemotherapy in patients with PD‐L1 CPS ≥1 (n = 51; hazard ratio [HR; 95% CI], 0.36 [0.16–0.77]), all‐comers (n = 57; 0.45 [0.22–0.90]), and patients with PD‐L1 CPS ≥10 (n = 25; 0.36 [0.12–1.07]). HRs (95% CI) for OS were 0.38 (0.14–1.01), 0.41 (0.17–1.00), and 0.37 (0.10–1.30), respectively. Incidence of grade 3–5 AEs was 94% in the pembrolizumab group and 100% in the placebo group. Consistent with findings in the global KEYNOTE‐826 study, pembrolizumab plus chemotherapy with or without bevacizumab may prolong survival versus placebo plus chemotherapy with or without bevacizumab and had a manageable safety profile in Japanese patients with persistent, recurrent, or metastatic cervical cancer. Pembrolizumab plus chemotherapy with or without bevacizumab demonstrated prolonged progression‐free survival and overall survival compared with chemotherapy in patients with persistent, recurrent, or metastatic cervical cancer in the phase 3 KEYNOTE‐826 study. In this subset analysis of patients enrolled in Japan in the KEYNOTE‐826 study, pembrolizumab plus chemotherapy with or without bevacizumab was associated with prolonged progression‐free survival and overall survival in this setting.

ObjectiveOptimal adjuvant chemotherapy for nonsquamous cervical carcinoma has not yet been established. This study investigated the efficacy and safety of docetaxel/carboplatin (DC) for early-stage nonsquamous cell cervical carcinoma after radical hysterectomy (RH).MethodsWe evaluated 157 patients with stage IB-IIB nonsquamous cervical carcinoma with intermediate risk and high risk treated at our institution with DC after type II or III RH from 2007 to 2021. Patients received docetaxel (60–70 mg/m2) and carboplatin (area under the curve 5–6) every 3 weeks for six cycles. The primary endpoint was 2 year recurrence-free survival (RFS) and the secondary endpoint was adverse events (AEs).ResultsThere were 106 intermediate-risk and 51 high-risk patients. The high-risk patients included 11 with positive parametrial involvement, 20 with pelvic lymph node metastases, and 20 with both parametrial involvement and pelvic lymph node metastases. The 2 year RFS rates for intermediate-risk, high-risk, and positive pelvic lymph nodes were 94.8% (95% confidence interval [CI], 87.9–97.8), 80.1% (95% CI, 64.1–89.5), and 74.5% (95% CI, 55.4–86.4), respectively. Sixteen patients had recurrence, including local recurrence (n = 6), distant metastasis (n = 9), and local and distant metastasis (n = 1). Hematologic toxicity was the most frequent AE, especially leukopenia and neutropenia. Nausea and constipation were the most frequent nonhematologic toxicities.ConclusionDC therapy at our institution showed good 2 year RFS, and postoperative adjuvant therapy with DC therapy is suggested as a useful strategy for patients with nonsquamous cervical carcinoma.

This study evaluated the influence of positive peritoneal cytology (PPC) on the prognosis of patients with stage IA endometrial cancer, and the usefulness of adjuvant chemotherapy in their treatment. We retrospectively analyzed the data of patients with stage IA endometrial cancer admitted in our hospital between 2005 and 2015. Among 989 patients who underwent peritoneal cytology, 135 (13.7%) had PPC. Multivariate analysis extracted several independent risk factors for recurrence in stage IA patients, including those with PPC. Adjuvant chemotherapy did not cause a significant difference in the 5-year relapse-free survival rate in patients with PPC (p = 0.78). Similarly, the 5-year recurrence-free survival rate with or without chemotherapy was not different among type II cancer patients (p = 0.11). However, the baseline risk of 5-year relapse-free survival without chemotherapy in patients with PPC and type II was very low (66.7%). While PPC was an independent risk factor for recurrence in stage IA endometrial cancer, adjuvant chemotherapy did not influence the survival rate in patients with PPC. While it is controversial whether adjuvant chemotherapy should be administered in stage IA uterine cancer with only PPC as a prognostic factor, it should be considered for early-stage patients who have multiple risk factors for recurrence.

Patients with triple‐negative breast cancers (TNBCs) typically have a poor prognosis because such cancers have no effective therapeutic targets, such as estrogen receptors for endocrine therapy or human epidermal growth factor receptor 2 (HER2) receptors for anti‐HER2 therapy. As the phosphatidylinositol 3′ kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) cascade is activated in TNBCs, mTOR is a potential molecular target for anticancer therapy. In this study, we investigated the antitumor activities of everolimus, an oral mTOR inhibitor, in nine TNBC cell lines. Everolimus effectively inhibited cell growth at concentrations under 100 nM (IC50) in five cell lines and even in the 1‐nM range in three of the five cell lines. To identify specific characteristics that could be used as predictive markers of efficacy, we evaluated the expressions of proteins in the mTOR cascade, basal markers, and cancer stem cell markers using western blotting, fluorescent in situ hybridization (FISH), or immunohistochemistry. All five of the sensitive cell lines were categorized as a basal‐like subtype positive for either epidermal growth factor receptor (EGFR) or CK5/6, although resistant cell lines were not of this subtype and tended to exhibit the characteristics of cancer stem cells, with decreased E‐cadherin and the increased expression of Snail or Twist. In vivo assays demonstrated antitumor activity in a mouse xenograft model of basal‐like breast cancer, rather than non‐basal breast cancer. These results suggest that everolimus has favorable activity against basal‐like subtypes of TNBCs. Epidermal growth factor receptor and CK5/6 are positive predictive markers of the TNBC response to everolimus, while cancer stem cell markers are negative predictive markers.

Study 309/KEYNOTE‐775 is a phase 3 open‐label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician's choice (TPC) in patients with advanced endometrial cancer with progression after platinum‐based therapy. Primary endpoints of superiority for lenvatinib plus pembrolizumab were met for progression‐free survival (PFS) and overall survival (OS) in all‐comers (ie, regardless of mismatch repair [MMR] status) and patients with MMR proficiency (pMMR). We present results for the Japanese subset. Patients were randomized to oral lenvatinib 20 mg/day plus intravenous pembrolizumab 200 mg every 3 weeks (Q3W; up to 35 cycles of pembrolizumab) or TPC (intravenous doxorubicin 60 mg/m2 Q3W or paclitaxel 80 mg/m2 QW [3 weeks on/1 week off]). Primary endpoints were PFS by blinded independent central review per RECIST version 1.1 and OS. One hundred four patients were randomized in Japan (data cutoff, October 26, 2020; median follow‐up, 11.8 [range, 1.1–26.9] months). Hazard ratios (HRs) for PFS with lenvatinib plus pembrolizumab versus TPC were 1.04 (95% CI, 0.63–1.73) in patients with pMMR and 0.81 (0.50–1.31) in all‐comers. Hazard ratios for OS were 0.74 (0.41–1.34) with pMMR and 0.59 (0.33–1.04) for all‐comers. Adverse events were manageable and led to discontinuation of one/both study drugs in 36.5% of patients in the lenvatinib plus pembrolizumab group versus 7.8% in the TPC group. Similar to the global Study 309/KEYNOTE‐775 results, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum‐based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population. Study 309/KEYNOTE‐775 is a phase 3 open‐label, randomized trial of lenvatinib plus pembrolizumab versus treatment of physician’s choice in patients with advanced endometrial cancer with progression after platinum‐based therapy. We present results for the Japanese subset of this clinical trial. Similar to results from the global study, this analysis suggested favorable efficacy and manageable safety with lenvatinib plus pembrolizumab after platinum‐based chemotherapy in Japanese patients with advanced endometrial cancer and supports this combination as a new standard of care in this population.

Background/objectiveElderly patients with cancer are often at risk for undertreatment because of frailty, an aging-specific problem. However, current real-world conditions of recurrent ovarian cancer treatment in elderly patients remain unclear. This study aimed to clarify treatment patterns in elderly patients with recurrent ovarian cancer.Patients and methodsWe used an ovarian cancer database containing the diagnosis and initial therapy of all patients at the National Cancer Center Hospital in Japan from 2007 to 2014. Patients were stratified into the platinum-sensitive group and the platinum-resistant group. We retrospectively assessed chemotherapy use in patients aged ≤ 64, 65–69, 70–74, 75–79, and ≥ 80 years.ResultsAmong 253 patients (sensitive group: 135; resistant group: 118), by age group 91%, 95%, 100%, 100%, and 100% received chemotherapy in the sensitive group, and 79%, 67%, 50%, 29%, 0% received chemotherapy in the resistant group, respectively. In the resistant group, the percentage of patients aged 70–74 or 75–79 years who received chemotherapy was significantly lower than the percentage among patients aged ≤ 64 years, respectively (p = 0.01, p = 0.01). In multivariate analysis, age ≥ 70 years (odds ratio [OR], 4.412; 95% confidence interval (CI), 1.628–11.959; p = 0.004) and platinum-free interval < 3 months (OR, 3.434; 95% CI, 1.401–8.399; p = 0.007) were inversely associated with chemotherapy use.ConclusionsDoctors and patients did not consider chemotherapy in patients aged ≥ 70 years with platinum-resistant disease. Older age was independently and inversely associated with chemotherapy use in platinum-resistant ovarian cancer. Our results highlight the importance of demographic information in clinical decision-making for elderly patients.

PIK3CA mutations are common activating mutations associated with breast cancer (occurring in 20–30% of all cases) and are potent predictive markers for responses to PI3K inhibitors. Thus, it is important to develop sensitive methods to detect these mutations. We established a novel detection method using a quenching probe (QP) system to identify PIK3CA mutations, using DNA from 309 breast cancer tissues. In a developmental cohort, we determined the optimal detection threshold of the QP system with human tumor DNA from 119 freshly frozen tumor samples. We found a 96% concordance rate with the QP system between DNA from 26 matching fresh‐frozen specimens and formalin‐fixed paraffin‐embedded (FFPE) specimens from the same patients, and known PIK3CA mutation status in the developmental cohort. In a validation cohort, we evaluated whether the threshold for judging mutations using the QP system with frozen specimen‐derived DNA was applicable with FFPE‐derived DNA. In the validation cohort, 30 DNA samples from 190 FFPE‐derived DNA samples with known PIK3CA mutation status were analyzed by direct sequencing (DS) and droplet digital PCR, in a blinded manner. The sensitivity and specificity of the droplet digital PCR results were 100% and 100% (QP system), and 60% and 100% (DS), respectively. We also analyzed the relationship between clinical outcomes and the PIK3CA mutational status of 309 breast cancer samples, including the developmental cohort and validation cohort samples. Multivariate analysis suggested that PIK3CA mutations, especially H1047R, were prognostic factors of relapse‐free survival. Our novel detection system could be more useful than DS for detecting clinical PIK3CA mutations. We could detect PIK3CA mutations in 309 breast cancer by using a novel method, the quenching probe system. In our cohort, PIK3CA mutations, especially H1047R, were prognostic factors of relapse‐free survival.