Takeshi Yokoi

Partial gastrectomy using natural orifice translumenal endoscopic surgery (NOTES) for gastric submucosal tumors: early experience in humans

BackgroundTransvaginal endoscopic gastric surgery is one of the cutting edge procedures in the field of natural orifice translumenal endoscopic surgery (NOTES). Its feasibility has been shown sporadically in bariatric cases but not in oncologic conditions. The authors report their early experience with hybrid transvaginal NOTES gastrectomy for gastric submucosal tumors (SMTs).MethodsTwo female patients with SMTs in the distal stomach participated in this institutional review board (IRB)-approved study. Surgical indication was determined according to the National Comprehensive Cancer Network (NCCN) sarcoma guidelines, and the study adhered to the following oncologic principles: no direct handling of the lesion, full-thickness resection, and reasonable surgical margins. The study protocol required a minimum of two laparoscopic ports to ensure procedural safety and aforementioned oncologic appropriateness. Under laparoscopic guidance, a transvaginal route was created and secured with a 50-cm flexible overtube. A gastrointestinal endoscope was introduced, and the perigastric dissection was performed using an insulation-tipped diathermy knife (IT knife) and needle knife. This process was assisted with two laparoscopic graspers. After perigastric mobilization, the transvaginal endoscope was replaced with a digital stapling device, and partial gastrectomy was accomplished. The resected specimen was isolated and delivered through the vagina, and the vaginal wound was closed under direct vision. Outcomes measurements included surgical results, pain scoring, and clinical outcomes.ResultsBoth operations were completed successfully in compliance with the aforementioned oncologic principles. The operating time was 365 and 170xa0min, respectively. The estimated blood loss was negligible. A minilaparotomy for specimen delivery was successfully avoided in both cases. A minimal vaginal incision was added for one patient at retrieval. Postoperatively, both patients reported no pain and recovered rapidly. The final diagnosis was hemorrhagic lipoma and gastrointestinal stromal tumor (GIST), respectively.ConclusionOur initial experience with human transvaginal NOTES gastrectomy showed it to be feasible and safe for gastric SMTs. It is a complex but promising surgical alternative for female oncologic patients undergoing partial gastric resection.

SNAP-25 is essential for cortical granule exocytosis in mouse eggs

Synaptosome-associated protein of 25 kDa (SNAP-25) has been shown to play an important role in Ca2+-dependent exocytosis in neurons and endocrine cells. During fertilization, sperm-egg fusion induces cytosolic Ca2+ mobilization and subsequently Ca2+-dependent cortical granule (CG) exocytosis in eggs. However, it is not yet clear whether SNAP-25 is involved in this process. In this study, we determined the expression and function of SNAP-25 in mouse eggs. mRNA and SNAP-25 were detected in metaphase II (MII) mouse eggs by RT-PCR and immunoblot analysis, respectively. Next, to determine the function of SNAP-25, we evaluated the change in CG exocytosis with a membrane dye, tetramethylammonium-1,6-diphenyl-1,3,5-hexatriene, after microinjection of a botulinum neurotoxin A (BoNT/A), which selectively cleaves SNAP-25 in MII eggs. Sperm-induced CG exocytosis was significantly inhibited in the BoNT/A-treated eggs. The inhibition was attenuated by coinjection of SNAP-25. These results suggest that SNAP-25 may be involved in Ca2+-dependent CG exocytosis during fertilization in mouse eggs.

Treatment of endometriosis with a decreasing dosage of a gonadotropin-releasing hormone agonist (nafarelin): a pilot study with low-dose agonist therapy (“draw-back” therapy)

OBJECTIVEnTo evaluate the efficacy of half-dose GnRH agonist therapy for endometriosis.nnnDESIGNnProspective, longitudinal pilot study.nnnSETTINGnOsaka University Hospital.nnnPATIENT(S)nPatients with symptomatic endometriosis.nnnINTERVENTION(S)nFifteen patients were randomized to receive either full-dose nafarelin treatment (200 microgram b.i.d.) for 24 weeks (n = 7) or full-dose nafarelin treatment for 4 weeks followed by half-dose nafarelin treatment (200 microgram daily) for 20 weeks (n = 8).nnnMAIN OUTCOME MEASURE(S)nClinical symptoms and the results of physical examinations. Serum E(2) and carcinoma antigen 125 (CA125) levels, lipid profiles, and urinary levels of the N-telopeptide of type I collagen. Bone mineral density of the lumbar spine.nnnRESULT(S)nSubjective and objective manifestations of endometriosis were decreased to a similar extent in both study groups. Adverse effects were markedly reduced with half-dose administration. In the half-dose group, the mean serum E(2) level was significantly suppressed by 4 weeks of treatment with full-dose nafarelin and remained at approximately 30 pg/mL with half-dose nafarelin. Loss of bone mineral density was significantly less with half-dose treatment.nnnCONCLUSION(S)nHalf-dose administration of nafarelin after pituitary down-regulation with full-dose nafarelin (draw-back therapy) is a new protocol for the treatment of endometriosis that is effective and associated with fewer adverse effects.

Reirradiation using high-dose-rate interstitial brachytherapy for locally recurrent cervical cancer: a single institutional experience.

Objectives This study aimed to evaluate the effectiveness and feasibility of reirradiation using high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with recurrent cervical cancer. Methods The records of 52 consecutive women with central pelvic recurrence who were salvaged with HDR-ISBT–based reirradiation were retrospectively reviewed. Data regarding the primary disease, follow-up findings, recurrence, the treatment outcome, and toxicities were collected. Multivariate analysis was performed using the Cox proportional hazards regression model to identify predictors of the response to HDR-ISBT. Survival rate was calculated using the Kaplan-Meier method and compared using the log-rank test. Results A total of 52 patients who had been treated with HDR-ISBT–based reirradiation were included in our database. The local control rate was 76.9% (40/52), and the median postrecurrence survival period was 32 months. Grade 3 or 4 late toxicities were observed in 13 patients (25%). Multivariate analysis revealed that tumor size and the treatment-free interval were significant poor prognostic factors of postrecurrence survival. In a comparison between the patients who were salvaged with HDR-ISBT–based reirradiation (ISBT group) and those who were treated with palliative therapy alone (palliative group), we found that among the patients who displayed 0 or 1 poor prognostic factors, the patients in the ISBT group survived significantly longer than those in the palliative group. In contrast, similar survival rates were seen in both groups among the patients with 2 or more poor prognostic factors. Conclusions Reirradiation using HDR-ISBT is effective and feasible in patients with recurrent cervical cancer. Our 2-clinical variable prognostic model might enable physicians to identify patients who would not derive clinical benefit from HDR-ISBT and offer them the opportunity to receive other types of treatment.

Utility of serum squamous cell carcinoma antigen levels at the time of recurrent cervical cancer diagnosis in determining the optimal treatment choice

Objective To investigate the utility of serum squamous cell carcinoma antigen (SCC-Ag) levels upon the diagnosis of recurrent cervical cancer for decision making in patient management. Methods Clinical records from 167 cervical cancer patients who developed recurrence between April 1996 and September 2010 were reviewed. A Cox proportional hazards regression model was used to investigate the prognostic significance of serum SCC-Ag levels at the time of recurrence. The effects of various salvage treatments on survival outcomes of recurrent cervical cancer were examined with respect to serum SCC-Ag levels. Results Serum SCC-Ag levels were elevated (>2.0 ng/mL) in 125 patients (75%) when recurrence was diagnosed. These patients exhibited significantly shorter postrecurrence survival than those with normal SCC-Ag levels (log-rank; p=0.033). Multivariate analyses revealed that an elevated serum SCC-Ag level was an independent prognostic factor for poor postrecurrence survival. In patients with SCC-Ag levels <14.0 ng/mL, radiotherapy or surgery resulted in improved survival compared with chemotherapy or supportive care. In contrast, in patients with SCC-Ag levels of ≥14.0 ng/mL, salvage treatment with radiotherapy had only a minimal impact on postrecurrence survival. Conclusion The serum SCC-Ag level measured when cervical cancer recurrence is diagnosed can be useful for deciding upon the appropriate salvage treatment.

EXPRESSION OF RAB3A IN THE CORTICAL REGION IN MOUSE METAPHASE II EGGS

Rab3A, a member of the small GTP-binding protein superfamily, has been implicated in regulated exocytosis at presynapses. At fertilization, sperm-egg fusion induces cytosolic calcium mobilization and cortical granule (CG) exocytosis in the egg. However, it is not yet clear whether Rab3A is involved in this process. We previously reported that Rabphilin-3A functions in calcium-dependent CG exocytosis. Rabphilin-3A is known to bind with Rab3A, Rab3B, and Rab3C. In this study, we clarified which member of the Rab3 was expressed in mouse metaphase II eggs. Messenger RNA encoding Rab3A but not Rab3B or Rab3C, was detected in unfertilized metaphase II eggs by RT-PCR. Rab3A protein was also detected in unfertilized metaphase II eggs by immunoblot analysis. Next the expression and the localization of Rab3A in eggs at various stages of development were determined by immunofluorescence analysis using confocal laser scanning microscopy. Rab3A protein was specifically distributed in the cortical region in eggs from before fertilization to the two-cell stage. However, it was not detected at the three- or four-cell stage 40 hr after fertilization. These results suggest that Rab3A may function with Rabphilin-3A in CG exocytosis.

A phase II study of postoperative concurrent carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy followed by consolidation chemotherapy in surgically treated cervical cancer patients with positive pelvic lymph nodes

OBJECTIVESnA phase II study was conducted to evaluate the efficacy and toxicity of carboplatin plus paclitaxel (TC)-based postoperative concurrent chemoradiotherapy (CCRT) followed by TC-based consolidation chemotherapy in surgically-treated early-stage cervical cancer patients.nnnMETHODSnWomen with surgically-treated early-stage cervical cancer with positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic intensity modulated radiotherapy (50.4Gy) and concurrent weekly carboplatin (AUC: 2) and paclitaxel (35mg/m(2)) (TC-based CCRT). Three cycles of consolidation chemotherapy involving carboplatin (AUC: 5) and paclitaxel (175mg/m(2)) were administered after TC-based CCRT.nnnRESULTSnThirty-one patients were enrolled and treated. Overall, the treatment was well tolerated, and 26 patients (83.9%) completed the planned TC-based CCRT. The most frequently observed acute grade 3/4 hematological toxicities were leukopenia and neutropenia, and diarrhea was the most common acute grade 3/4 non-hematological toxicity. After a median follow-up period of 36.5months, 2 patients (6.5%) had developed recurrent disease. The patients estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 88.5% and 93.8%, respectively. In comparisons with historical control groups, TC-based CCRT followed by TC-based consolidation chemotherapy was found to be significantly superior to CCRT involving a single platinum agent in terms of PFS (p=0.026) and significantly superior to extended-field radiotherapy in terms of both PFS (p=0.0004) and OS (p=0.034).nnnCONCLUSIONSnIn women with surgically treated early-stage cervical cancer, pelvic TC-based CCRT followed by TC-based consolidation chemotherapy is feasible and highly effective. Future randomized trials are needed to verify the efficacy of this regimen.

A phase I study of concurrent weekly carboplatin and paclitaxel combined with intensity-modulated pelvic radiotherapy as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes.

Objectives The objective of this study was to determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLTs) of intravenous carboplatin plus paclitaxel combined with intensity-modulated pelvic radiotherapy (pelvic IMRT) as an adjuvant treatment for early-stage cervical cancer patients with positive pelvic lymph nodes. Methods Women with uterine cervical cancer who were treated with radical hysterectomy and pelvic lymphadenectomy and displayed positive pelvic lymph nodes were eligible for this study. The patients were postoperatively treated with pelvic IMRT (50.4 Gy). The concurrent weekly chemotherapy consisted of carboplatin (area under the curve [AUC], 2) and paclitaxel (starting at 35 mg/m2 and escalating by 5 mg/m2 in 3 patient cohorts). The primary end point of the escalation study was acute DLT that occurred within 30 days of the completion of radiation therapy. Results Nine patients were enrolled and treated at 2 dose levels until DLT occurred. The median age of the patients was 47 years (range, 28–66 years). The median radiotherapy treatment time was 39.5 days (range, 38–64 days). At dose level I (35 mg/m2 paclitaxel), 2 grade 3 leukopenia and a neutropenia were observed, but no DLT occurred. At dose level II (40 mg/m2 paclitaxel), the first patient experienced a grade 2 hypersensitive reaction, which resulted in discontinuation of planned treatment. Thus, 2 more patients were evaluated at this dose level. Of these, 1 patient experienced febrile neutropenia, which was considered to be a DLT, and the other patient experienced long-lasting grade 3 leukopenia and grade 3 neutropenia, which resulted in the discontinuation of chemotherapy for 2 weeks (a DLT). We then evaluated 3 more patients at dose level 1, but no DLT occurred. The MTD of paclitaxel and carboplatin was thus defined as 35 mg/m2 and an AUC of 2.0, respectively. Conclusions Weekly paclitaxel/carboplatin and pelvic IMRT is a reasonable adjuvant treatment regimen for cervical cancer patients after radical hysterectomy. The MTD of paclitaxel and carboplatin for future phase II trials of this regimen is 35 mg/m2 and an AUC of 2.0, respectively.

Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6)

PurposeTo develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy.MethodsPatients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800xa0mg/m2, respectively; level 2: 100 and 1000xa0mg/m2) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity.ResultsA total of 35 patients were enrolled. The recommended dose was defined as 100xa0mg/m2 irinotecan and 1000xa0mg/m2 gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8xa0months (95% CI 2.1–6.0xa0months) and 17.4xa0months (95% CI 9.9–21.9xa0months), respectively, while the 1-year survival rate was 58.6%.ConclusionsCombination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.

Clinical Significance of Atypical Squamous Cells of Undetermined Significance among Patients Undergoing Cervical Conization.

BACKGROUNDnAtypical squamous cells of undetermined significance (ASCUS) feature a wide variety of cervical cells, including benign and malignant examples. The management of ASCUS is complicated. Guidelines for office gynecology in Japan recommend performing a high-risk human papillomavirus (HPV) test as a rule. The guidelines also recommend repeat cervical cytology after 6 and 12 months, or immediate colposcopy. The purpose of this study was to determine the clinical significance of ASCUS.nnnMATERIALS AND METHODSnBetween January 2012 and December 2014, a total of 162 patients underwent cervical conization for cervical intraepithelial neoplasia grade 3 (CIN3), carcinoma in situ, squamous cell carcinoma, microinvasive squamous cell carcinoma, and adenocarcinoma in situ at our hospital. The results of cervical cytology prior to conization, the pathology after conization, and high-risk HPV testing were obtained from clinical records and analyzed retrospectively.nnnRESULTSnBased on cervical cytology, 31 (19.1%) of 162 patients were primarily diagnosed with ASCUS. Among these, 25 (80.6%) were positive for high-risk HPV, and the test results of the remaining 6 patients (19.4%) were uncertain. In the final pathological diagnosis after conization, 27 (87.1%) and 4 patients (12.9%) were diagnosed with CIN3 and carcinoma in situ, respectively.nnnCONCLUSIONSnAlthough ASCUS is known as a low-risk abnormal cervical cytology, approximately 20% of patients who underwent cervical conization had ASCUS. The relationship between the cervical cytology of ASCUS and the final pathological results for CIN3 or invasive carcinoma should be investigated statistically. In cases of ASCUS, we recommend HPV tests or colposcopic examination rather than cytological follow-up, because of the risk of missing CIN3 or more advanced disease.