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.

症例 1 は 67 歳,男性。当科初診 5 年前に骨髄異形成症候群に対し同種造血幹細胞移植をし,ボリコナゾール(VRCZ)を内服していた。4 カ 月前から頭頂部に生じた有棘細胞癌(SCC)に腫瘍切除と分層植皮,術後放射線照射を行ったが,右頚部リンパ節転移及び局所再発した。5 カ 月後に頭蓋骨外板含めた拡大切除,右側頚部リンパ節郭清と耳下腺を摘出し,皮弁形成と全層植皮で再建した。再手術 25 日後に SCC の肝転移が判明し,1 年 5 カ 月後に SCC で死亡した。症例 2 は 77 歳, 男性。当科初診 13 年前に急性リンパ性白血病で臍帯血移植後,8 年前より肺アスペルギルス症で VRCZ を内服していた。1 年前より頭頂部に生じた疣贅状皮疹から転じた SCC で,腫瘍切除と人工真皮植皮を行った。術後は創部感染を繰り返し,6 ~7 カ 月後に頭蓋骨外板を含めた拡大切除と分層植皮を行ったが,術後は次第に体力が低下し,10 カ 月後に急性腎不全,基礎疾患により死亡した。VRCZ による光線過敏症と SCC 発症の本邦報告は未だ少ないが,SCC の侵襲度が高く予後不良例も多い傾向である。VRCZ 長期内服患者は基礎疾患も多彩で,高齢,免疫抑制状態など発癌リスク・予後不良因子を併せ持つ患者が多く,遮光指導,定期的な皮膚観察に加え,SCC の病期進行前の早期発見が重要と思われる。今回 VRCZ の長期内服中に生じ,予後不良であった SCC の 2 症例を本邦既報例と併せ報告する。

Background We evaluated the efficacy of intraperitoneal (IP) carboplatin in combination with dose-dense paclitaxel (ddTCip) for suboptimal residual ovarian cancer. Methods This was a phase 2 study to evaluate ddTCip. Patients with stage II–IV ovarian carcinoma, who underwent primary cytoreductive surgery and had radiologically evaluable disease after surgery, were eligible to participate in this study. IP carboplatin (AUC = 6) was administered on day 1, and intravenous paclitaxel (80 mg/m 2 ) was administered on days 1, 8 and 15. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Interval- debulking surgery followed by the same regimen was allowed when indicated. Results A total of 117 patients were considered eligible for this study prior to surgery and temporarily registered. Of the 117 patients, 76 patients met the inclusion criteria and were enrolled in this study. Fifty-nine (83.1%) patients had objective clinical responses. Median PFS and OS were 18.3 and 55.5 months, respectively. Sixty-four (84.2%) patients had grade 3/4 neutropenia, 43 (56.5%) patients had anaemia and 17 (22.4%) patients had thrombocytopenia. Port-related adverse events occurred in nine (11.8%) patients. Conclusions Front-line chemotherapy with ddTCip therapy appears safe and effective, even for patients with suboptimal residual ovarian cancer. Trial registration UMIN Clinical Trials Registry (ID: UMIN000001713) on February 16th, 2009.

Objective: Concurrent chemoradiotherapy using cisplatin was thought to be standard treatment for squamous cell carcinoma of cervix,but it had not been effective for adenocarcinoma.Concurrent chemoradiotherapy using irinotecan hydrochloride (CPT-11) had been effective for colorectal cancer,thus,we chose CPT-11 as a candidate for gynecologic adenocarcinoma.To evaluate the maximum tolerated dose (MTD) of weekly CPT-11 with external pelvic radiotherapy,a phase 1/2 study was conducted according to modified Fibonacci method.Methods: Eligible patients were advanced uterine cancer with measurable diseases[performance score (PS): 0-2].Study period was from August 1st,2002 to December 31st,2008.The starting dose level (DL) of CPT-11 was 30 mg/m2 (DL1) given weekly for 4 weeks.Subsequently,dose escalation was scheduled in 10 mg/m2 increments to 60 mg/m2 (DL4).The fixed radiotherapy consisted of whole pelvic 1.8 Gy/d,once a day in weekday for five weeks and it amounted to 45 Gy (25 fractions) in total.Results: Seventeen patients were enrolled.As for toxicities,one (1/17: 5.9％) grade (G) 4 neutropenia lasting 7 days had been seen in DL4.G2 diarrhea was identified in 35.3％ (6/17) of the patients,and 11.8％ (2/17) G3 diarrhea was observed in DL3 and DL4.Thus,the MTD of CPT-11 was defined as dose of 60 mg/m2.The recommended dose was decided as 50 mg/m2.The response rate was 88.2％[9 complete response (CR),3 partial response (PR),3 stable disease (SD),2 not evaluable (NE)].Disease control rate at 1 month after treatment completion was 100％ but distant metastases were found in 24％ (4/17) in longer outcome.Conclusions: MTD was 60 mg/m2 and recommended dose was set as 50 mg/m2.This concurrent chemoradiation using weekly CPT-11 was feasible at 50 mg/m2,and it might be effective even in adenocarcinoma of the uterus.

We had conducted phase 1/2 studies of cancer vaccination therapy using neo-tumor antigens in patients with refractory/persistent cervical cancer (CC) and ovarian cancer (OC) to assess the feasibility and efficacy. Enrollees must be refractory/persistent disease for usual treatments with Human Leukocyte Antigen-A*0201 or A*2402. The targets were epitope peptides obtained from driver genes in surviving pathways as follows: for CC A*0201, peptides from Up Regulating Lung Cancer 10 gene (URLC10) and Hypoxia-inducible gene 2 (HIG-2) and for OC A*0201, HIG2, VEGFR (vascular epithelial growth factor receptor) 1 and 2 were used. For CC A*2402, Forkhead Box M1 (FOXM1), Maternal Embryonic Leucine zipper Kinase (MELK), and Holliday Junction Recognition Protein (HJURP) were used. For OC A*2402, cocktails of peptides from FOXM1, MELK, HJURP, VEGFR1, and VEGFR2 were used. Subcutaneous administration was performed with adjuvant weekly. The toxicity profiles and tumor-response were analyzed in eight-week interval. Sixty-six patients were accrued, and 64 were evaluable for adverse events (AEs), and 35 for response. AEs of G2/3 dermatologic reaction (DR) of injection site had been identified in 15.6% and no other severe AEs were detected. Response rate in OC and CC were 22.9% and 20%, respectively. Median overall survival showed longer in performance status (PS) 0 (versus PS1/2), in CRP negative (versus positive) and in DR positive (versus negative) such as 8.7 m versus 1.2 m (p < .001), 8.8 m versus 3.0 m (p < .05) and 10.2 m versus 1.2 m (p < .001), respectively. In conclusion, our vaccination therapy was feasible and effective in this cohort of patients.

Background We sometimes encounter difficulties in assessing the severity of pediatric atopic dermatitis (AD) using currently available biomarkers such as thymus and activation-regulated chemokine (TARC) due to the higher baseline values in non-AD children. Recent case control studies have indicated the usefulness of squamous cell carcinoma antigens (SCCAs) in pediatric and adult AD. Notably, SCCAs are induced by IL-4 and IL-13, vital Th2 cytokines that play important roles in AD etiology. Objectives Relatively low prevalence and mild disease severity of pediatric AD are observed in our Ishigaki cohort presumably due to the moisturising subtropical climate, which could conversely mean possible higher allergic potential of non-AD subjects towards AD. Thus, the purpose of this study was to further investigate the feasibility of using SCCAs together with TARC and periostin as biomarkers for pediatric AD even in the Ishigaki cohort. Methods We enrolled 1459 nursery school children and identified 96 as having AD through 2009–2011. As statistical analyses, we performed Student's t-test, correlation analysis, and receiver and operating characteristic (ROC) analysis. Results Serum SCCA1, SCCA2, periostin and TARC levels were all significantly increased in AD compared with those in non-AD, but only serum SCCA2 showed a significant increase in AD when assessed in each age group or in subgroup analysis. Among the biomarkers tested, serum SCCA2 also showed the best correlations with clinical AD severity and TARC and showed the best diagnosability for AD in ROC analysis. Conclusions SCCA2 is a potent biomarker for pediatric AD in the Ishigaki cohort.

Purpose: In 2007, Ministry of Health, Labour and Welfare (MHLW) warned to refrain from prescribing oseltamivir for teenagers when two Japanese teenagers with influenza fell from a high-rise building after taking oseltamivir. Revisions of the warning texts of anti-influenza drugs were discussed by the Subcommittee of Pharmaceutical Affairs and Food Sanitation Council, MHLW, based on the studies and trends of anti-influenza medication over the last 10 years. Method: The research group led by Dr Nobuhiko Okabe conducted nationwide survey since the 2007/2008 influenza season. The results of Japanese and foreign epidemiological and non-clinical studies of abnormal behaviors in influenza patients since 2009 were reviewed. Result: Severe abnormal behaviors have been reported in influenza patients taking all types of anti-influenza drugs, as well as in untreated patients. There are some risks to patients whether treated with any anti-influenza drug, or non-treated though it is still not possible to rule out a potential causal relationship between abnormal behaviors and anti-influenza drugs. 70% of abnormal behaviors occurred within two days after the onset of fever. No difference was found between anti-influenza drugs treated and non-treated patients. In patients receiving oseltamivir and other anti-influenza drugs, the frequency of abnormal behaviors is not clearly different between teenagers and patients under 10 years old. Conclusion: The specific "boxed warning" and the restriction only for oseltamivir that should not be used for teenagers was lifted. Therefore, the labeling of all anti-influenza drugs carry a consistent warning about the potential for abnormal behaviors in Japan.

Despite the improvement of treatments, refractory or chemotherapy resistant ovarian and cervical cancers have been still incurable. In such tumors, the actionable salvage gene-pathways of up-regulating lung cancer 10 (URLC10), hypoxia inducible factor (HIF) and its core protein HIG2- tumor growth factor beta (TGF beta)- the Caenorhabditis elegans SMA ("small" worm phenotype) and Drosophila Mothers Against Decapentaplegic (SMAD), maternal embryonic leucine zipper kinase (MELK)- forkhead box M1 (FOXM1) which induces and stimulates stathmin concerning cell (vascular endothelial cell and tumor cell) migration and counter pathway of P53, and holliday junction recognition protein (HJURP)-histone H3-like centromeric protein A (CEMPA)-Histone, which play important roles in tumor proliferation, metastasis and cell cycling. They had been shifted from original driver gene such as Ras-MAPK or PIK3CA-mTOR. Furthermore, tumor specific micro-environmental factors such as vascular endothelial growth factor (VEGF) receptors facilitate tumor new-angiogenesis, invasion and metastasis, as well. We found human leukocyte antigen (HLA)-A*2402 and 0201 restricted epitope neo-antigens or, epitope peptides of VEGF receptor 1 and 2, using micro-cDNA assay form clinical samples. The peptides consisted in nine to eleven mer peptides, which were presented by HLA (major histocompatibility 1) on cell membrane. We administered the multiple peptides subcutaneously as vaccination and it activated intrinsic cell immune system of cytotoxic T cell (CTL). We conducted a phase 1/2 study of those peptides vaccine (PV) cocktails to elucidate their toxicity profiles and efficacy from 4 June 2010 to Jan 2013 for phase 1 studies, and subsequently continued phase 2 studies at outpatient’s clinic of our hospital. PV were administered at a dose of 1mg of each peptide with MONTANIDE*ISA51 (SEPPIC Co. Ltd, France). Enrollees were obtained written informed consent after our IRB approval on 3 June 2010. In results, no major adverse events were seen except dermatologic reactions at injection site. One patient showed complete response, two showed partial response and 10 showed stable disease out of 22 evaluable patients. Median overall survival was 5 months and 9 months in HLA-A2402 and 0201 group, respectively. In conclusion, these findings suggest the peptides cocktail vaccines were safe and applicable for advanced/recurrent OC.

Objective: To examine clinico-pathological characteristics and outcomes of uterine carcinosarcoma (UCS) in women aged >= 80 years. Methods: This is a secondary analysis of a previous multicenter retrospective study examining 906 women with stage I-IV UCS who underwent primary hysterectomy. Patient demographics, treatment types, tumor characteristics, and survival were examined across aged >= 80 (n = 82 [9.1%]), aged 60-79, (n = 526 [58.1%]), and aged < 60 (n = 298 [32.9%]). Results: Women in the aged >= 80 group were more likely to be Caucasian, undergo simple hysterectomy without lymphadenectomy, and receive no postoperative therapy (all, P < 0.05). Tumors in the aged >= 80 group were more likely to have high-grade carcinoma, heterologous sarcoma, and sarcoma dominance but less likely to have lympho-vascular space invasion (all, P < 0.05). Lymphadenectomy did not improve survival in the aged >= 80 group (P > 0.05), whereas lymphadenectomy was protective for survival in the younger groups (both, P < 0.05). Postoperative chemotherapy was associated with improved progression-free survival (PFS) in the aged >= 80 group (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.22-0.89, P = 0.021). With chemotherapy treatment, women in the aged >= 80 group had PFS similar to those in the aged 60-79 group (HR 0.97, 95%CI 0.51-1.83, P = 0.92). In contrast, without chemotherapy treatment, women in the aged 80 group had significantly decreased PFS compared to the aged 60-79 group (HR 1.62, 95%CI 1.09-2.40, P = 0.016). Similar associations were observed for postoperative radiotherapy. Conclusion: Nearly 10% of women with UCS are aged >= 80 that are characterized by aggressive tumor factors. Postoperative therapy but not extensive surgery may improve survival in this age group.

The aim of this study was to examine the significance of lymphovascular space invasion (LVSI) with a sarcomatous component on the tumor characteristics and clinical outcomes of women with uterine carcinosarcoma (UCS).

Purpose To propose a categorization model of uterine carcinosarcoma (UCS) based on tumor cell types (carcinoma and sarcoma) and sarcoma dominance. Methods This secondary analysis of a prior multicenter retrospective study examined 889 cases of UCS with available histologic evaluation. Based on survival outcome, cases were clustered into three groups: low-grade carcinoma with nondominant homologous sarcoma [type A, n = 96 (10.8%)], (1) low-grade carcinoma with heterologous sarcoma or any sarcoma dominance and (2) high-grade carcinoma with nondominant homologous sarcoma [type B, n = 412 (46.3%)], and high-grade carcinoma with heterologous sarcoma or any sarcoma dominance [type C, n = 381 (42.9%)]. Tumor characteristics and outcome were examined based on the categorization. Results Women in type C category were more likely to be older, obese, and Caucasian, whereas those in type A category were younger, less obese, Asian, and nulligravid (all P < 0.01). Type C tumors were more likely to have metastatic implants, large tumor size, lymphovascular space invasion with sarcoma cells, and higher lymph node ratio, whereas type A tumors were more likely to be early-stage disease and small (all P < 0.05). On multivariate analysis, tumor categorization was independently associated with progression-free survival (5-year rates: 70.1% for type A, 48.3% for type B, and 35.9% for type C, adjusted P < 0.01) and cause-specific survival (5-year rates: 82.8% for type A, 63.0% for type B, and 47.1% for type C, adjusted P < 0.01). Conclusion Characteristic differences in clinicopathological factors and outcomes in UCS imply that different underlying etiologies and biological behaviors may be present, supporting a new classification system.

Objective: To examine significance of sarcoma dominance (SD) patterns in uterine carcinosarcoma (UCS). Methods: This is a secondary analysis of multicenter retrospective study examining women with stages [IV UCS who underwent primary surgery. SD was defined as >50% of sarcoma component in uterine tumor. SD patterns were grouped as homologous sarcoma without SD (homo/non-dominance, n = 351), heterologous sarcoma without SD (hetero/non-dominance, n = 174), homologous sarcoma with SD (homo/dominance, n = 175), and heterologous sarcoma with SD (hetero/dominance, n = 189), and correlated to tumor characteristics and survival. Results: SD patterns were significantly associated with age, body habitus, carcinoma type, tumor size, depth of myometrial invasion, and nodal metastasis (all, P < 0.05). On univariate analysis, SD was associated with decreased progression-free survival (PFS) and cause-specific survival (CSS) in homologous cases (both, P< 0.05) but not in heterologous cases. On multivariate models, both homologous and heterologous SD patterns remained independent prognostic factors for decreased PFS (adjusted-hazard ratio [HR] ranges: homo/dominance 1.35-1.69, and hetero/dominance 1.47-1.64) and CSS (adjusted-HR ranges: 1.52-1.84 and 1.66-1.81, respectively) compared to homo/non-dominance (all, P <0.05). Among stage I-III disease, when tumors had SD, adding radiotherapy to chemotherapy was significantly associated with improved PFS (adjusted-HR: homo/dominance 0.49, and hetero/dominance 0.45) and CSS (0.36 and 0.31, respectively) compared to chemotherapy alone (all, P < 0.05); contrary, this association was not observed with absence of SD (all, P> 0.05). Conclusion: In UCS, SD impacts survival in homologous but not in heterologous type. Regardless of sarcoma types, SD was associated with decreased survival in UCS; adding radiotherapy to chemotherapy may be an effective postoperative strategy. (C) 2018 Elsevier Ltd. All rights reserved.

Koji Matsuo ,1 Malcolm S. Ross ,2 Mayu Yunokawa ,3 Marian S. Johnson,4 Hiroko Machida ,1 Kohei Omatsu,5 Merieme M. Klobocista,6,* Dwight D. Im,7 Shinya Satoh ,8 Tsukasa Baba,9 Yuji Ikeda,10 Stephen H. Bush,11 Kosei Hasegawa,12 Erin A. Blake ,13 Munetaka Takekuma ,14 Masako Shida,15 Masato Nishimura,16 Sosuke Adachi,17 Tanja Pejovic,18 Satoshi Takeuchi ,19 Takuhei Yokoyama ,20 Yutaka Ueda,21 Keita Iwasaki,22 Takahito M. Miyake,23 Shiori Yanai,24 Tadayoshi Nagano,25 Tadao Takano,26 Mian MK Shahzad,11 Frederick R. Ueland,4 Joseph L. Kelley,2 Lynda D. Roman 1

Primary ovarian leiomyosarcoma (POLMS) is extremely rare, and optimal therapy for this disease is unknown. A 40-year-old woman presented at a local hospital with abdominal pain. Tumor resection of the left ovary was performed. The pathological diagnosis was leiomyoma of the left ovary. Nine months after surgery, she developed of severe back pain and a subcutaneous tumor on her left shoulder. Magnetic resonance imaging and computed tomography revealed left ovarian tumor recurrence, pelvic bone metastasis, and multiple liver masses. Biopsy of the subcutaneous tumor on her left shoulder demonstrated metastatic leiomyosarcoma. The previously resected left ovarian tumor was re-examined, and the tumor was found to be a leiomyosarcoma. The patient received gemcitabine 800 mg/m2 and docetaxel 60 mg/m2 (GD therapy), administered at 3-week intervals. After three cycles of GD therapy, the patient experienced dyspnea and was diagnosed with mild interstitial pneumonia. Oral corticosteroid therapy resulted in complete symptom improvement. Thereafter, the dosage of GD was decreased, and after 13 cycles of GD therapy, radiofrequency ablation was performed twice for liver metastases. The tumors have shrunk by 65.5% after 23 cycles of GD. She remains alive after undergoing 24 cycles of GD. GD therapy may be effective for POLMS.

Objective. To identify risk factors for venous thromboembolism (VTE) and to examine the association of VTE and survival in women with uterine carcinosarcoma. Methods. This multicenter retrospective study examined 906 women who underwent primary surgical treatment for stage I-IV uterine carcinosarcoma. Time-dependent analyses were performed for cumulative incidence of VTE after surgery on multivariate models. Results. There were 72 (7.9%) women who developed VTE after surgery with 1-, 2-, and 5-year cumulative incidences being 5.1%, 73%, and 10.2%, respectively. On multivariate analysis, older age (hazard ratio [HR] per year 1.03, P = 0.012), non-Asian race (HR 6.28, P < 0.001), large body habitus (HR per kg/m(2) 1.04, P = 0.014), residual disease at surgery (HR 3.04, P = 0.003), tumor size >= 5 cm (HR 2.73, P = 0.003), and stage IV disease (HR 2.12, P = 0.025) were independently associated with increased risk of developing VTE. A risk pattern analysis identified that obese Non-Asian women with large tumors (13.7% of population) had the highest incidence of VTE (2 year cumulative rate, 26.1%) whereas Asian women with no residual disease (47.1% of population) had the lowest (2-year cumulative rate, 1.6%) (P < 0.001). Presence of carcinoma/sarcoma in metastatic sites was significantly associated with increased risk of VTE compared to carcinoma alone (2-year rates, 31.2% versus 8.4%, P = 0.049). VTE was independently associated with decreased progression-free survival on multivariate models (5-year rates, 24.9% versus 47.2%, HR 1.46, 95%Cl 1.05-2.04, P = 0.026). Conclusion. Our study suggests that VTE represents a surrogate marker of aggressive tumor behavior and diminished patient condition in uterine carcinosarcoma; obese Non-Asian women with large tumors carry a disproportionally high risk of VTE, suggesting that long-term prophylaxis may benefit this population. (C) 2017 Elsevier Inc. All rights reserved.