Primary Small Bowel Adenocarcinoma with Metastatic Ovarian Tumor in a Pregnant Woman.

Introduction: Primary small bowel carcinoma in pregnant women is extremely rare. Small bowel cancer is difficult to diagnose because of its rarity, lack of specific clinical symptoms, and particular anatomical features. We experienced a case of primary small bowel adenocarcinoma with ovarian metastasis during pregnancy. This is the first reported case of a patient with small bowel adenocarcinoma whose pregnancy continued to term and ended in delivery. Case Presentation: A 32-year-old pregnant woman developed abdominal pain, and imaging examination revealed an ovarian tumor at 29 weeks of gestation. We performed laparotomy and resected the ovarian tumor, which was initially suspected to be primary ovarian cancer. The patient continued the pregnancy to term. A detailed examination of the abdominal cavity during cesarean delivery at 37 weeks revealed that the primary lesion was located in the small bowel. Conclusion: It is important to recognize that the small bowel may be the primary site of metastatic ovarian cancer. Detailed and careful examination is necessary to diagnose small bowel cancer during pregnancy.

Sarcopenia shortens overall survival of patients with platinum-resistant recurrent ovarian cancer: inverse probability of treatment-weighting analysis.

OBJECTIVE: The association between sarcopenia and prognosis in patients with platinum-resistant recurrent ovarian cancer remains unclear. This study investigated whether sarcopenia is a prognostic factor in patients with platinum-resistant recurrent ovarian cancer. METHODS: A total of 52 patients diagnosed with platinum-resistant recurrent ovarian cancer who had undergone non-platinum chemotherapy at our institution formed our study population. Body composition and clinicopathological data of these patients were collected retrospectively. Abdominal computed tomography (CT) scans obtained at the time of platinum-resistant recurrent ovarian cancer diagnosis were used to measure the cross-sectional area of skeletal muscles at L3 level. These values were corrected for height to calculate the skeletal muscle index, and accordingly sarcopenia was defined. Overall survival was defined as the primary outcome of the study. The impact of sarcopenia on overall survival was assessed using Cox proportional hazards regression models with inverse probability weighting of treatment based on propensity scores and log-rank tests. RESULTS: The median patient age was 63 years (IQR: 53-71). The most common International Federation of Gynecology and Obstetrics (FIGO) 2018 stage was stage III (50%) and the most common histology was serous or adenocarcinoma (67.3%). The optimal cut-off value of skeletal muscle index was 35.6 cm2/m2, which was calculated using the data of 21 patients with sarcopenia and 31 without sarcopenia. Sarcopenia was significantly associated with shorter overall survival (HR 1.93; 95% CI 1.06-3.49; p=0.03). Subgroup analysis based on patient attributes and prognostic factors suggested a consistent prognostic impact of sarcopenia. Sarcopenia was identified as a significant risk factor, particularly in patients who had higher CA125 levels (HR, 2.47; 95% CI, 1.07 to 5.69; p=0.034) and a higher neutrophil-to-lymphocyte ratio (HR, 2.92; 95% CI, 1.02 to 8.31; p=0.045). CONCLUSION: Sarcopenia significantly shortened the overall survival of patients with platinum-resistant recurrent ovarian cancer.

Re-administration of platinum-based chemotherapy for recurrent endometrial cancer: an ancillary analysis of the SGSG-012/GOTIC-004/Intergroup study.

BACKGROUND: We previously demonstrated the applicability of the concept of "platinum sensitivity" in recurrent endometrial cancer. Although immune checkpoint inhibitors have been widely incorporated into endometrial cancer treatment, the debate continues regarding treatment options in patients with recurrent endometrial cancer who have previously received platinum-based chemotherapy. In this study, we assessed the duration of response to secondary platinum-based treatment using pooled data from the SGSG-012/GOTIC-004/Intergroup study. METHODS: Among the 279 participants in the SGSG-012/GOTIC-004/Intergroup study wherein platinum-based chemotherapy was re-administered for managing recurrent endometrial cancer between January 2005 and December 2009, 130 (47%) responded to chemotherapy. We compared the relationship between platinum-free interval and duration of secondary platinum-based treatment using pooled data. RESULTS: In 40 patients (31%), the duration of response to secondary platinum-based treatment exceeded the platinum-free interval. The duration of response to secondary platinum-based treatment exceeded 12 months in 51 patients (39%) [platinum-free interval: < 12 months, 14/48 (29%); 12-23 months, 18/43 (42%); 24-35 months, 8/19 (42%); ≥ 36 months, 11/20 (55%)]. In particular, in eight patients (6%), the duration of response to secondary platinum-based treatment exceeded 36 months [platinum-free interval: < 12 months, 3/48 (6%); 12-23 months, 0/19 (0%); 24-35 months, 2/19 (11%); ≥ 36 months, 3/20 (15%)]. CONCLUSIONS: Re-administration of platinum-based chemotherapy for recurrent endometrial cancer may result in a long-term response exceeding the platinum-free interval in some patients. Even in the current situation, where immune checkpoint inhibitors have been introduced, re-administration of platinum-based chemotherapy is worth considering.

Nationwide trends in and regional factors associated with minimally invasive hysterectomy for benign indications in Japan.

OBJECTIVE: To examine the prevalence trends of minimally invasive hysterectomy for benign indications in Japan and investigate regional disparities. STUDY DESIGN: A retrospective cohort and ecological study using "The National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data". SETTING: Nationwide Japan. PATIENTS: Individuals who underwent hysterectomy for benign indications from 2014 to 2020. INTERVENTIONS: Trend analysis of minimally invasive surgery (MIS) rates through laparoscopic hysterectomies (LH) and robotic-assisted laparoscopic hysterectomies (RA-LH) at the national and prefecture levels. Examination of regional factors contributing to the disparity in MIS implementation rates by second medical service area (SMSA). RESULTS: The number of LH has increased from 16,016 in 2014 to 27,755 in 2020. The nationwide MIS hysterectomy rate increased from 29% in 2014 to 55% in 2020 (p less than 0.001). More than 50% of hysterectomies have been performed as MIS since 2019. There was an increasing trend in MIS rates in all age groups. All prefectures except one showed a significant upward trend (p less than 0.05) in the MIS rates, but MIS rates varied widely (23-84%). In a multivariable model, the MIS was more likely to be performed in the SMSAs in western Japan (p = 0.011), in the SMSAs where the number of laparoscopy-qualified gynecologists is 5-10 (p = 0.013), and 11 or higher (p less than 0.001). CONCLUSIONS: This study reveals a shift towards minimally invasive surgery (MIS) in total hysterectomy procedures in Japan. However, significant disparities in the prevalence of MIS hysterectomy exist, potentially influenced by the number of laparoscopy-qualified gynecologists.

Eyelid and Vaginal Adhesions as Severe Sequelae of Toxic Epidermal Necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are mucocutaneous diseases featured by severe sequelae and high mortality rates. In addition to ocular involvement, gynecological involvement is often observed in patients with TEN with possible occurrence of partial or complete adhesions of the labia majora, labia minora, and vaginal walls as severe sequelae. Although the gynecological sequelae of TEN severely affect patients' quality of life, there is a lack of awareness among medical professionals. Moreover, preventive measures and the effectiveness of treatment have not yet been fully verified. Herein, we describe a case of TEN with severe sequelae of eyelid and vaginal adhesions.

Comprehensive hemocompatibility analysis on the application of diamond-like carbon to ePTFE artificial vascular prosthesis.

The aim of this study was to obtain comprehensive data regarding the hemocompatibility of diamond-like carbon (DLC)-coated expanded polytetrafluoroethylene (ePTFE). DLC increased the hydrophilicity and smoothened the surface and fibrillar structure, respectively, of the ePTFE. DLC-coated ePTFE had more albumin and fibrinogen adsorption and less platelet adhesion than uncoated ePTFE. There were scarce red cell attachments in in vitro human and in vivo animal (rat and swine) whole blood contact tests in both DLC-coated and uncoated ePTFE. DLC-coated ePTFE had a similar but marginally thicker band movement than uncoated-ePTFE with SDS-PAGE after human whole blood contact test. In addition, survival studies of aortic graft replacement in rats (1.5 mm graft) and arteriovenous shunt in goats (4 mm graft) were performed to compare the patency and clot formation between DLC-coated and uncoated ePTFE grafts. Comparable patency was observed in both animal models. However, clots were observed in the luminal surface of the patent 1.5 mm DLC-coated ePTFE grafts, but not in that of uncoated ePTFE grafts. In conclusions, hemocompatibility of DLC-coated ePTFE was high and comparable to that of uncoated ePTFE. However, it failed to improve the hemocompatibility of 1.5 mm ePTFE graft probably because increased fibrinogen adsorption canceled the other beneficial effects of DLC.

Diamond-like carbon coating to inner surface of polyurethane tube reduces Staphylococcus aureus bacterial adhesion and biofilm formation.

Staphylococcus aureus is one of the main causative bacteria for polyurethane catheter and artificial graft infection. Recently, we developed a unique technique for coating diamond-like carbon (DLC) inside the luminal resin structure of polyurethane tubes. This study aimed to elucidate the infection-preventing effects of diamond-like carbon (DLC) coating on a polyurethane surface against S. aureus. We applied DLC to polyurethane tubes and rolled polyurethane sheets with our newly developed DLC coating technique for resin tubes. The DLC-coated and uncoated polyurethane surfaces were tested in smoothness, hydrophilicity, zeta-potential, and anti-bacterial properties against S. aureus (biofilm formation and bacterial attachment) by contact with bacterial fluids under static and flow conditions. The DLC-coated polyurethane surface was significantly smoother, more hydrophilic, and had a more negative zeta-potential than did the uncoated polyurethane surface. Upon exposure to bacterial fluid under both static and flow conditions, DLC-coated polyurethane exhibited significantly less biofilm formation than uncoated polyurethane, based on absorbance measurements. In addition, the adherence of S. aureus was significantly lower for DLC-coated polyurethane than for uncoated polyurethane under both conditions, based on scanning electron microscopy. These results show that applying DLC coating to the luminal resin of polyurethane tubes may impart antimicrobial effects against S. aureus to implantable medical polyurethane devices, such as vascular grafts and central venous catheters.

Case of suspected lobular endocervical glandular hyperplasia in a cervical cystic lesion during pregnancy.

Lobular endocervical glandular hyperplasia (LEGH) is characterized by clinically profuse and watery vaginal discharge. In pregnancy with LEGH, with watery fluid leakage persisting throughout pregnancy, it is often difficult to visually diagnose PROM. Adding to this difficulty, auxiliary diagnostic tests might also show positive results, complicating treatment and management.

Intraluminal diamond-like carbon coating with anti-adhesion and anti-biofilm effects for uropathogens: A novel technology applicable to urinary catheters.

OBJECTIVES: To examine anti-adhesion and anti-biofilm effects of a diamond-like carbon coating deposited via a novel technique on the inner surface of a thin silicon tube. METHODS: Diamond-like carbon coatings were deposited into the lumen of a silicon tube with inner diameters of 2 mm. The surface of the diamond-like carbon was evaluated using physicochemical methods. We used three clinical isolates including green fluorescent protein-expressing Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. We employed a continuous flow system for evaluation of both bacterial adhesion and biofilm formation. Bacterial adhesion assays consisted of counting the number of colony-forming units and visualization of adhered bacterial cells by scanning electron microscope to evaluate the diamond-like carbon-coated/uncoated samples. The biofilm structure was analyzed by confocal laser scanning microscopy on days 3, 5, 7 and 14 for green fluorescent protein-expressing Pseudomonas aeruginosa. RESULTS: The smooth and carbon-rich structure of the intraluminal diamond-like carbon film remained unchanged after the experiments. The numbers of colony-forming units suggested lower adherence of green fluorescent protein-expressing Pseudomonas aeruginosa and Escherichia coli in the diamond-like carbon-coated samples compared with the uncoated samples. The scanning electron microscope images showed adhered green fluorescent protein-expressing Pseudomonas aeruginosa cells without formation of microcolonies on the diamond-like carbon-coated samples. Finally, biofilm formation on the diamond-like carbon-coated samples was lower until at least day 14 compared with the uncoated samples. CONCLUSIONS: Intraluminal diamond-like carbon coating on a silicone tube has anti-adhesion and anti-biofilm effects. This technology can be applied to urinary catheters made from various materials.

Inspection for micrometastasis is essential for predicting the prognosis of serous endometrial intraepithelial carcinoma: Case report and literature review.

Serous endometrial intraepithelial carcinoma is the precursor of invasive uterine serous carcinoma. Here, we present two cases of serous endometrial intraepithelial carcinoma with omental micrometastasis and discuss their clinical significance. Two menopausal patients with abnormal endometrial biopsy findings underwent hysterectomy and comprehensive surgical staging (bilateral salpingo-oophorectomy, omentectomy, and pelvic and para-aortic lymphadenectomy). Although gross examination failed to detect tumors, the pathological diagnosis was serous endometrial intraepithelial carcinoma. Both patients had omental micrometastasis; they were diagnosed with International Federation of Gynecology and Obstetrics stage IVB disease and received postoperative chemotherapy. One patient died of the carcinoma 9 months after the hysterectomy, and the other had a recurrence of carcinoma 17 months after the end of the initial therapy. The present cases and literature review highlight the importance of meticulous inspection for micrometastasis in the abdominal cavity, including the omentum and peritoneum, for predicting prognosis.

Outcome of Radiation Therapy for Stage IVB Uterine Cervical Cancer With Distant Lymph Nodes Metastases; Sequential Irradiation for Distant Lymph Nodes Metastases.

BACKGROUND/AIM: This study aimed to evaluate the outcome of radiation therapy for patients with distant lymph node (LN) metastases, without organ metastases from uterine cervical cancer (UCC). PATIENTS AND METHODS: Twenty-six patients with UCC with distant LN metastases received radiotherapy and were retrospectively analyzed. The sites of distant LN metastasis were as follows; Supraclavicular in 19, inguinal in nine, axillary in four, and others in three. The mean dose prescribed for these was 50 (range=40-60) Gy. RESULTS: The 2-year overall, cause-specific, and progression-free survival, and local control of primary tumor rates were 51.3%, 51.3%, 46.9%, and 67.9%. In multivariate analysis, performance status ≥1 (p=0.007), para-aortic LN metastases (p=0.001), and lack of high-dose-rate intracavitary brachytherapy (p=0.033) were significantly associated with poor overall survival. Performance status ≥1 (p=0.004), and para-aortic LN metastases (p=0.014) were significantly associated with poor cause-specific survival. CONCLUSION: This study demonstrated favorable local control in patients with UCC with distant LN metastases.

A phase 2 study of intraperitoneal carboplatin plus intravenous dose-dense paclitaxel in front-line treatment of suboptimal residual ovarian cancer.

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/m2) 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.

Rapid detection of synthetic cannabinoids in herbal highs using surface-enhanced Raman scattering produced by gold nanoparticle co-aggregation in a wet system.

Synthetic cannabinoids (SCs) are a major category of new psychoactive substances that are frequently distributed after addition to plants. To date, various SCs with small differences in their chemical structures have prevailed in the illegal drug market. Thus, the development of a method for rapid detection with high discrimination capability is critically important for the forensic field. Vibrational spectroscopy is a possible analytical technique for this purpose because it can sensitively reflect differences among chemical structures. In this study, we applied surface-enhanced Raman scattering (SERS) with gold nanoparticle co-aggregation in a wet system to plant samples containing SCs. The experimental protocol used was simple and involved only mixing of the sample with several other solutions. It was possible to detect SERS spectra from various stock solutions of SCs by this method. The method was then applied to street samples containing SCs. Some of the plant samples containing SCs did not produce significant SERS signals even though stock solutions of the same SCs did produce SERS spectra. We investigated the reason for this discrepancy and speculated that the solubility in aqueous solutions was a factor determining whether a significant SERS signal could be detected or not. According to this hypothesis, minimal sample pre-treatment methods were applied. This allowed for the detection of SERS spectra from the examined plant samples. The developed approach is a powerful method for screening analysis of SCs in plant fragments.

Rapid detection of hypnotics using surface-enhanced Raman scattering based on gold nanoparticle co-aggregation in a wet system.

Sensitive detection of drugs using a method with high qualification capability is important for forensic drug analysis. Vibrational spectroscopy is a powerful screening technique because it can provide detailed structural information of the compounds included in samples with simple experimental protocols. Among various spectroscopic techniques, surface enhanced Raman scattering (SERS) spectroscopy has attracted enormous attention owing to its ultra-high sensitivity. In this study, we developed a method for rapid detection of hypnotics using SERS with gold nanoparticle co-aggregation in a wet system. The developed method required a simple analytical protocol. This enabled rapid analysis with high stability and repeatability. We analyzed various hypnotics (19 types including benzodiazepines and nonbenzodiazepines) to investigate the structure-spectrum relationship. As a proof of concept for application to real crime samples, simulated spiked beverages containing one hypnotic (etizolam, flunitrazepam, zolpidem, or zopiclone) were analyzed. Diluting the beverage samples decreased the matrix effect and allowed for detection of these hypnotics. Except for flunitrazepam, strong signals were observed for all hypnotics, and the estimated lower limit of detection was 50 ppm in apple drink. The developed approach is a rapid method for screening analysis of hypnotics with low sample requirements.

Laparoscopic repair of the vaginal cuff dehiscence: Dehiscence occurring after the first sexual intercourse after the laparoscopic modified radical hysterectomy.

Total vaginal cuff dehiscence (VCD) is an important adverse event after hysterectomy. Here, we showed two cases in whom laparoscopic repair of VCD was successful. This procedure is effective, safe, and thus minimally invasive for patients after hysterectomy.

Expression of multiple immune checkpoint molecules on T cells in malignant ascites from epithelial ovarian carcinoma.

Expression of immune checkpoint molecules, including programmed cell death protein-1 (PD-1), has been reported on T cells in various types of cancer. However, the expression status of these molecules in the tumor microenvironment of epithelial ovarian cancer (EOC) has not yet been studied. A total of 54 cases of malignant ascites from patients with EOC were analyzed in the present study. The expression of PD-1, lymphocyte-activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and B and T lymphocyte attenuator (BTLA) on cluster of differentiation (CD)4+ and CD8+ T cells in malignant EOC ascites were investigated using multicolor flow cytometric analysis. The expression of PD-L1 in tumor cells, PD-L2 in HLA-DR-positive cells and galectin-9 in ascitic fluid was also analyzed. In addition, cytokine profiling of ascitic fluid was performed to understand the immune microenvironment of EOC. PD-1, LAG-3 TIM-3, and BTLA were expressed on 65.8, 10.6, 4.3 and 37.6% of CD4+ T cells, and on 57.7, 5.0, 4.9 and 15.7% of CD8+ T cells, respectively. Programmed cell death protein-1 (PD-1), LAG-3 and BTLA were more frequently expressed on CD4+ compared with CD8+ T cells. The co-expression of immune checkpoints was further investigated and results indicated that 39 (72.2%) and 37 patients (68.5%) expressed multiple immune checkpoints on CD4+ T cells and CD8+ T cells, respectively. In addition, lower levels of TNF-α and interleukin-6 in ascitic fluid were significantly associated with multiple immune checkpoint expression on CD8+ T cells. The present findings indicated that multiple immune checkpoint molecules were expressed on T cells in the EOC tumor microenvironment and the results may suggest the significance of simultaneous blockade of immune checkpoints to control EOC.

Phase I Study of Multiple Epitope Peptide Vaccination in Patients With Recurrent or Persistent Cervical Cancer.

Cancer immunotherapy has now been established as a leading standard therapeutic option in a subset of patients with cancer. In this study, we conducted a phase I dose-escalation trial using a mixture of 5 peptides to vaccinate cervical cancer patients with HLA-A*2402. The primary endpoints were safety and determination of a recommended vaccine dose, and the secondary endpoints were evaluations of immunologic responses and clinical efficacy. All patients had recurrent or persistent disease and had failed to respond to or were intolerant to prior standard chemotherapy. Peptides derived from forkhead box protein M1 (FOXM1), maternal embryonic leucine zipper kinase (MELK), Holliday junction-recognition protein, and vascular endothelial growth factor receptors 1 and 2 were administered to 9 patients in a 3 patient-cohort design, with doses of 0.5, 1, or 2 mg of each of the individual peptides in a mixture with incomplete Freund's adjuvant. The major adverse events were anemia and injection site reactions, which were seen in 77.8% (7/9) and 66.7% (6/9) of patients, respectively. Grade 3 anemia was observed in 1 patient. No dose-limiting toxicity of the vaccine was observed. Seven (78%) patients achieved stable disease, and the median progression-free survival was 3.3 months (102 d). Interferon-γ enzyme-linked immunospot assays for each of the 5 antigens showed that 8 (89%) and 7 (78%) patients had high T-cell responses to FOXM1 and MELK, respectively. In conclusion, we demonstrated that this 5-peptide vaccine was tolerable, and that FOXM1 and MELK could be promising targets for immunotherapy in patients with cervical cancer.

The frequency of neoantigens per somatic mutation rather than overall mutational load or number of predicted neoantigens per se is a prognostic factor in ovarian clear cell carcinoma.

Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes. However, the number of neoantigens per missense mutation ("neoAg frequency") did correlate with clinical outcomes. Cox multivariate regression analysis demonstrated that low neoAg frequencies correlated with increased progression-free survival (PFS) and was an independent predictive factor for PFS in OCCC (p = 0.032), especially at stage I-II (p = 0.0045). Immunity-associated genes including those related to effector memory CD8 T cells were dominantly expressed in tumors with low neoAg frequencies in stage I-II patients, suggesting CD8 T cell-mediated elimination of immunogenic sub-clones expressing neoantigens (immunoediting) had occurred. In contrast, we observed decreased HLA-A, -B, and -C expression (p = 0.036, p = 0.026, and p = 0.030, respectively) as well as increased ratios of CTLA-4, PD-1, Tim-3, and LAG3 to CD8A expression (p = 0.0064, p = 0.017, p = 0.033 and p = 0.0136, respectively) in stage I-II tumors with high neoAg frequencies. Constrained anti-tumor immunity may thus result in limited immunoediting, and poor prognosis. Our results show that neoAg frequency in OCCC is an independent prognostic factor for clinical outcome and may become a potential candidate biomarker for immunomodulatory agent-based treatments.

Phase 1 dose-escalation study of single-agent veliparib in Japanese patients with advanced solid tumors.

Veliparib (ABT-888) is a potent, orally bioavailable poly(ADP-ribose) polymerase-1 and -2 inhibitor. This phase 1 study evaluated the tolerability, pharmacokinetic profile, safety, and preliminary antitumor activity of single-agent veliparib in Japanese patients with advanced solid tumors. Eligible patients were assigned to treatment with veliparib at 200 or 400 mg dose; veliparib was self-administered orally twice daily on days 1-28 of 28-day cycles. Dose escalation, following a 3 + 3 design, defined dose-limiting toxicities, the maximum tolerated dose, and the recommended phase 2 dose. Sixteen patients were enrolled (median age, 59 years). Fourteen patients had high-grade serous ovarian cancer, one had primary peritoneal cancer, and one had BRCA-mutated breast cancer. The most frequent treatment-emergent adverse events were nausea and vomiting (93.8% each), decreased appetite (62.5%), abdominal pain, diarrhea, and malaise (31.3% each). A grade ≥3 toxicity was observed in 50% of patients; one patient each in the 200 mg (n = 4) and 400 mg (n = 12) cohorts experienced serious adverse events. Dose-limiting toxicities were observed for one patient at the 400 mg dose. No toxicities leading to death were reported. The recommended phase 2 dose was defined as 400 mg twice daily. The veliparib pharmacokinetic profile was consistent with that reported for the Western population. Two patients, both with ovarian cancer, had a RECIST partial response. Veliparib monotherapy showed manageable tolerability and safety profiles and a predictable pharmacokinetic profile at a 400 mg twice-daily dose, and supports the inclusion of Japanese patients in the multinational phase 3 study (NCT02470585).

Clinical significance of T cell clonality and expression levels of immune-related genes in endometrial cancer.

Immune microenvironment characterized by T cell clonality as well as expression signatures of immune-related genes in endometrial cancer tissues may play significant roles in clinical outcome of patients. We aimed to investigate the clinical significance of immune-related gene expression and TCR repertoire in endometrial cancer. Using total RNAs extracted from 32 endometrioid endometrial cancer cases, we performed quantitative real-time PCR to measure mRNA expression levels of immune-related genes including TRB, CD8, GZMA, HLA-A, CD11c and PD-L1. Higher mRNA expression levels of CD8 (P=0.039) and CD11c (P=0.046) in the 32 tissue samples were significantly associated with longer progression-free survival (PFS). Expression levels of CD8 (P<0.001) and CD11c (P=0.048) were also significantly associated with longer PFS in 540 cases in TCGA database. We also performed T cell receptor ß (TCRß) sequencing of tumor-infiltrating lymphocytes (TILs) on an Illumina MiSeq platform. To evaluate clonal expansion of TCRß clonotypes, we adjusted the number of abundant TCRß clonotypes by TRB mRNA expression levels and examined TCR clonality with the expression levels of immune-related genes and clinicopathological factors. The cases with high clonal T cell expansion along with high PD-L1 expression in cancer tissues was related to higher mRNA expression levels of CD8 (P<0.001), GZMA (P<0.001) and HLA-A (P=0.027), showed a significantly longer PFS (P=0.015), indicating a possibility that these parameters may serve as faborable prognostic factors. Considering clinical stage, mRNA expression of CD8 (P=0.037), GZMA (P=0.027) and HLA-A (P=0.022) was significantly higher in tumors at an early stage. Thus, we identified clinical and prognostic significance of immune microenvironment including the T cell clonality of TILs as well as PD-L1 and CD11c mRNA expression levels in endometrial cancer tissues.