Flexible Magnifying Endoscopy with Narrow Band Imaging for Diagnosing Uterine Cervical Neoplasms: A Multicenter Prospective Study.

We aimed to investigate the diagnostic ability of magnifying endoscopy with narrow band imaging (ME-NBI) for cervical intraepithelial neoplasia grade 2 or worse (CIN2+). This was a multicenter prospective study. Eligible patients had positive Pap smear results or follow-up high-grade cytology or CIN3 diagnosed in referring hospitals. Patients underwent ME-NBI by a gastrointestinal endoscopist, followed by colposcopy by a gynecologist. One lesion with the worst finding was considered the main lesion. Punch biopsies were collected from all indicated areas and one normal area. The reference standard was the highest histological grade among all biopsy specimens. The primary endpoint was the detection rate of patients with CIN2+ in the main lesion. The secondary endpoints were diagnostic ability for CIN2+ lesions and patients' acceptability. We enrolled 88 patients. The detection rate of ME-NBI for patients with CIN2+ was 79% (95% CI: 66-88%; p = 1.000), which was comparable to that of colposcopy (79%; p = 1.000). For diagnosing CIN2+ lesions, ME-NBI showed a better sensitivity than colposcopy (87% vs. 74%, respectively; p = 0.302) but a lower specificity (50% vs. 68%, respectively; p = 0.210). Patients graded ME-NBI as having significantly less discomfort and involving less embarrassment than colposcopy. ME-NBI did not show a higher detection ability than colposcopy for patients with CIN2+, whereas it did show a better patient acceptability.

Drug screening and grouping by sensitivity with a panel of primary cultured cancer spheroids derived from endometrial cancer.

Several molecular targeting drugs are being evaluated for endometrial cancer; selecting patients whose cancers are sensitive to these agents is of paramount importance. Previously, we developed the cancer tissue-originated spheroid method for primary cancer cells taken from patients' tumors as well as patient-derived xenografts. In this study, we successfully prepared and cultured cancer tissue-originated spheroids from endometrial cancers. Characteristics of the original tumors were well retained in cancer tissue-originated spheroids including morphology and expression of p53 or neuroendocrine markers. We screened 79 molecular targeting drugs using two cancer tissue-originated spheroid lines derived from endometrioid adenocarcinoma grade 3 and serous adenocarcinoma. Among several hits, we focused on everolimus, a mammalian target of rapamycin complex 1 inhibitor, and YM155, a survivin inhibitor. When sensitivity to everolimus or YM155 was assessed in 12 or 11 cancer tissue-originated spheroids, respectively, from different endometrial cancer patients, the sensitivity varied substantially. The cancer tissue-originated spheroids sensitive to everolimus showed remarkable suppression of proliferation. The phosphorylation status of the mammalian target of rapamycin complex 1 downstream molecules before and after everolimus treatment did not predict the effect of the drug. In contrast, the cancer tissue-originated spheroids sensitive to YM155 showed remarkable cell death. The effect of YM155 was also confirmed in vivo. The histological type correlated with YM155 sensitivity; non-endometrioid adenocarcinomas were sensitive and endometrioid adenocarcinomas were resistant. Non-canonical autophagic cell death was the most likely cause of cell death in a sensitive cancer tissue-originated spheroid. Thus, sensitivity assays using cancer tissue-originated spheroids from endometrial cancers may be useful for screening drugs and finding biomarkers.

Radiation sensitivity assay with a panel of patient-derived spheroids of small cell carcinoma of the cervix.

Small cell carcinoma of the uterine cervix (SCCC) is a rare cancer with a poor prognosis for which no standard treatment exists. Here, we successfully established panels of patient-derived spheroid cultures from six SCCC patient samples by cancer tissue-originated spheroids (CTOS) method. To assess the intrinsic radiosensitivity and mechanism of radioresistance in individual SCCC patients, we further developed an in vitro sensitivity assay for radiation. Radiation sensitivity in the CTOS assay varied among individual cases and was consistent with in vivo radiation sensitivity using CTOS-derived xenograft tumors in the examined cases. Furthermore, by comparing gene expression in CTOSs with different radiosensitivity, we found that expression of hypoxia-inducible factor-1α (HIF-1α) target genes was upregulated in resistant CTOSs. HIF-1α protein levels increased several hours after irradiation. In a radioresistant CTOS, an inhibitor of heat shock protein 90 (HSP90) suppressed radiation-induced HIF-1α expression. Suppression of HIF-1α by small hairpin RNA significantly enhanced the effect of radiation, at least in part by promoting radiation-induced apoptosis. HSP90 inhibitor also increased radiation sensitivity. Our results indicate that radiation-induced HIF-1α upregulation was one mechanism of radioresistance in a radioresistant SCCC CTOS. Accumulating CTOS lines may provide a good platform to study characters of rare cancers like SCCC.

Salvage chemotherapy using gemcitabine for taxane/platinum-resistant recurrent ovarian cancer: a single institutional experience.

BACKGROUND: The purpose of this study was to report on the safety and efficacy of gemcitabine used as salvage chemotherapy for ovarian cancer. PATIENTS AND METHODS: From January 2002 to October 2011, 27 patients were treated with gemcitabine for platinum-resistant recurrent ovarian cancer. Gemcitabine (800 mg/m(2)) was given on days 1, 8, and 15 of every 28 days. The patients' medical records were retrospectively reviewed. RESULTS: All 27 patients had previously received paclitaxel/carboplatin doublet and their disease had become platinum-resistant. The median number of previous chemotherapy regimens was 2 (range 1-7). A total of 114 cycles of single-agent gemcitabine were administered, with a median of 3 (range 1-10). No complete responses were observed. Partial response (PR) was observed in five patients (18.5%). Eight patients demonstrated stable disease (SD). The median duration of response for 5 responders was 4 months (range 2-6 months). The median survival time was 15 months. Patients with PR or SD (n=13) had significantly better survival compared with the group with progressive disease (n=14) (p=0.03, by univariate analysis). In addition, multivariate Cox proportional hazards analysis revealed that responses to gemcitabine were a significant factor for survival (hazard ratio=0.08, 95% confidence interval=0.0138 to 0.5614, p=0.01). Cases with hematological toxicity included 10 patients (37.0%) with grade 3/4 neutropenia, 3 patients (11.1%) with grade 3 thrombocytopenia, and 3 patients (11.1%) with grade 3 anemia. Non-hematological toxicity was well-tolerated. CONCLUSION: Gemcitabine (800 mg/m(2)) used for recurrent ovarian cancer possesses a modest activity and a well-tolerated toxicity.

[Unexpected vomiting during anesthetic induction in a patient with a history of anterosternal esophageal reconstruction].

A 73-year-old woman with spinal canal stenosis was scheduled for a lumbar fenestration surgery. The patient had received esophagectomy for cancer and anterosternal esophageal reconstruction 5 years before. After the supper the day before the operation, the fast situation to the operation was maintained. On entering operating room, oxygenation was performed for the patient with adequate pressing of the gastric tube on the sternum, and rapid anesthetic induction was performed with propofol, remifentanil and rocuronium. During the induction, a significant amount of solid food residues appeared suddenly in the throat pharynx before positive pressure ventilation. Oral suction was done immediately, and tracheal intubation was performed. After the intubation, while the suction tube could not be inserted to the stomach tube, we positioned it at near the anastomosis between esophagus and gastric tube. Metoclopramide was administered intravenously during the surgery. At the postoperative period, no severe complications including aspiration were observed. When anesthetizing the patient with a history of anterosternal esophageal reconstruction, we should mind the possibility of nonavoidable vomiting during the induction. We strongly recommend the strict restriction of eating and drinking and suction tube insertion to remove the food residues from the patient preoperatively.