Neuropeptide VGF-Derived Peptide LQEQ-19 has Neuroprotective Effects in an In Vitro Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease caused by the loss of upper and lower motor neurons resulting in muscle weakness and paralysis. Recently, VGF, a neuropeptide that is a precursor of bioactive polypeptides, was found to be decreased in ALS patients, and its inducer exerted protective effects in models of ALS. These findings suggested that VGF was involved in the pathology of ALS. Here, we investigated the neuroprotective effects of various VGF-derived peptides in an in vitro ALS model. We applied seven VGF-derived peptides (TLQP-21, AQEE-30, AQEE-11, LQEQ-19, QEEL-16, LENY-13, and HVLL-7) to the motor neuron-derived cell line, NSC-34, expressing SOD1G93A, which is one of the mutated proteins responsible for familial ALS. Nuclear staining revealed that AQEE-30 and LQEQ-19, which are derived from the C-terminal polypeptide of the VGF precursor protein, attenuated neuronal cell death. Furthermore, immunoblot analysis demonstrated that LQEQ-19 promoted the phosphorylation of Akt and extracellular signal-regulated kinase (ERK) 1/2, and inhibiting these mitogen-activated MAP kinases (MAPKs) with phosphoinositide 3-kinase or MEK/ERK inhibitors, eliminated the neuroprotective effects of LQEQ-19. In conclusion, these results suggest that VGF C-terminal peptides exert their neuroprotective effects via activation of MAPKs such as Akt and ERK1/2. Furthermore, these findings indicate that VGF-derived peptides have potential application in ALS therapy.

Recurrent peritoneal inclusion cysts successfully treated with oral contraceptives: a report of two cases.

OBJECTIVE: To examine whether conservative treatment with oral contraceptives is effective in the shrinkage of a peritoneal inclusion cyst (PIC). This is a case report of two patients with a PIC that developed after gynecological surgery. CASES: Both cases were suspected of a PIC based on the medical history, laboratory data, and image findings. It was difficult in differentiate a PIC from an ovarian tumor. Surgery was chosen at first. However, PICs in both cases recurred after surgery and were treated with oral contraceptives as a conservative treatment. PICs shrank after the treatment of oral contraceptives in both cases. CONCLUSION: Due to the high rate of recurrence following surgery, conservative treatment is recommended to treat PICs. Hormone therapy using oral contraceptives seems to have some therapeutic benefit for the PICs.

Identification of insulin-like growth factor 2 mRNA-binding protein 3 as a radioresistance factor in squamous esophageal cancer cells.

Identification of reliable markers of radiosensitivity and the key molecules that donate susceptibility to anticancer treatments to esophageal cancer cells would be highly desirable. We found that the mRNA expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was higher in radioresistant TE-5 and TE-9 cells than in radiosensitive TE-12 cloneA1 cells. Conversely, knocking down expression of IGF2BP3 mRNA in TE-5 and TE-9 cells using small interfering RNA significantly enhanced their radiosensitivity. Furthermore, patients with squamous cell esophageal cancers strongly expressing IGF2BP3 tended to respond poorly to chemoradiation. These data suggest that IGF2BP3 may be a key marker of radiosensitivity that diminishes the susceptibility of squamous cell esophageal cancer cells to radiotherapy. IGF2BP3 may, thus, be a useful target for improving radiotherapy for patients with esophageal squamous cell carcinoma.

Heterotopic pregnancy diagnosed before the onset of severe symptoms: case report.

BACKGROUND: A heterotopic pregnancy (HP) is an extremely rare disease that represents the simultaneous occurrence of two or more implantation sites in the uterus and extrauterus. Early diagnosis of HP is difficult because of the presence of an intrauterine pregnancy (IUP). In most cases, a precise diagnosis was made after symptoms develop through the rupture or bleeding of the ectopic pregnancy (EP). The authors present a case that was successfully diagnosed as an undemonstrative HP. CASE: A 24-year-old multiparous woman became pregnant after taking clomiphene citrate. At ten weeks of pregnancy, an ultrasonography revealed gestational sacs containing fetuses in the uterus and the right adnexal region, respectively. The patient was diagnosed as having a HP and an emergency right tubal resectomy was performed. The IUP progressed normally and the fetus was delivered at 37 weeks of pregnancy. DISCUSSION: Even if a gestational sac can be confirmed in the uterus, a careful ultrasonographic examination should always be considered to determine the presence of a concurrent extrauterine pregnancy.

Absence of effect of SLC22A2 genotype on cisplatin-induced nephrotoxicity in oesophageal cancer patients receiving cisplatin and 5-fluorouracil: report of results discordant with those of earlier studies.

WHAT IS KNOWN AND OBJECTIVE: Cancer patients treated with cisplatin chemotherapy frequently experience drug-induced nephrotoxicity. Clinical studies using a single chemotherapeutic regimen or large sample sizes for patients with the SLC22A2 808T allele have not been reported. Here, we examined 95 patients with oesophageal cancer who received 5-fluorouracil and cisplatin (FP) to determine whether nephrotoxicity was affected by SLC22A2 808G>T polymorphism. METHODS: The change rate of the estimated glomerular filtration rate (eGFR) was used for the evaluation of cisplatin-induced nephrotoxicity and calculated for each patient according to the following formula: change rate = (prechemotherapy value - post-chemotherapy value)/prechemotherapy value. Genotyping of SLC22A2 808G>T was carried out using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The eGFR after FP chemotherapy was significantly lower than that before chemotherapy, and the mean difference in eGFR was 25·7 mL/min (P < 0·01). There was no significant difference in the mean change rate of the eGFR following FP chemotherapy between the SLC22A2 808GG genotype (n = 70) and the 808GT+TT genotypes (n = 25) (27·9% and 27·8%, respectively). In multiple regression analyses, the change rate of eGFR following FP chemotherapy was associated with the eGFR value prior to chemotherapy (P = 0·04). WHAT IS NEW AND CONCLUSION: In FP chemotherapy for oesophageal cancers, cisplatin-induced nephrotoxicity seems to be unaffected by the SLC22A2 808G>T polymorphism. The eGFR prior to chemotherapy might be an important risk factor for cisplatin-induced nephrotoxicity. Our present study was estimated with a single chemotherapeutic regimen, eGFR, and was calculated using serum creatinine, age and the sex of the patient and sample sizes of 25 patients with SLC22A2 808T allele. However, further examinations with a larger sample size to corroborate the study results might be necessary.

Ethnic disparities in perioperative management among foreigners residing in Japan.

The objectives of this research were to examine the current status of perioperative treatment among foreigners, to elucidate the health status/outcome disparities that contribute to ethnic differences, and to recommend counter-measures to rectify these ethnic disparities. The authors identified 36 non-Japanese and 111 Japanese females who underwent gynecological surgery from 2004 to 2009 at a single institution. Electronic medical records were reviewed and telephone survey was conducted in order to obtain patient background, preoperative, operative, and postoperative data. The non-Japanese group showed significantly larger number of uninsured, shorter length of stay (LOS), higher rate of emergency surgery, and higher cases of spinal anesthesia. There were significant differences in length of residency in Japan and LOS among four foreign countries. Seventy-nine percent of patients contacted by phone understood informed consent from doctors, 73.7% understood explanation in operating room (OR), and 84.2% understood explanation from anesthesiologists. This research was the first survey of the ethnic disparities in perioperative management among foreign patients treated in Osaka. The authors have demonstrated differences in operative method, emergency surgery, anesthesia, and American Society of Anesthesiologists physical status (ASA-PS) due to the difference in disease structure, language, and culture. It is recommended that the barriers between non-Japanese patients and medical staff are rectified during the perioperative period when mutual understanding is needed the most.

Outcomes of endoscopic and surgical resection for a second primary cancer in the residual cervical esophagus after thoracic esophagectomy.

Patients who have received subtotal esophagectomy for thoracic esophageal cancer must be closely monitored for second primary malignancies. The purpose of this study is to review and assess patients who developed a second primary esophageal cancer in the residual cervical esophagus. Between 1996 and 2010, 10 patients were diagnosed in our hospital with esophageal squamous cell cancer in the residual cervical esophagus after undergoing thoracic esophagectomy and were treated with endoscopic or surgical resection. Data from these patients were reviewed retrospectively. Seven of the 10 patients (70%) had multiple primary carcinoma lesions at the time of their esophagectomy. A second primary cancer in the residual cervical esophagus was detected in eight patients during follow-up endoscopic examinations while the patients were still asymptomatic. Seven of the patients underwent endoscopic resection for a superficial cancer. None of those patients experienced any complications, and all are currently alive and cancer-free. The remaining three patients underwent resection of the cervical esophagus with regional lymph node dissection. Two of those patients experienced severe complications; one subsequently died (hospital death) from pneumonia, 12 months after surgery, while the other died from recurrence of his cancer. The third patient is alive and cancer-free. Early detection of a second primary malignancy in the residual cervical esophagus followed by endoscopic resection is the best treatment strategy for patients who previously received subtotal esophagectomy for thoracic esophageal cancer. Surgical resection puts patients at high risk of mortality or morbidity.

Therapeutic strategy for the treatment of postoperative recurrence of esophageal squamous cell carcinoma: clinical efficacy of radiotherapy.

We investigated the effectiveness of chemoradiotherapy for the treatment of lymph node recurrence and hematogenous metastasis after esophagectomy for esophageal squamous cell carcinoma. Between 2001 and 2006, 216 patients with thoracic esophageal squamous cell carcinoma had curative esophagectomy. Of those, 23 with lymph node recurrence received chemoradiotherapy (50.0-68.8 Gy). In addition, five patients had isolated recurrences in a distant organ and received chemoradiotherapy (50.0-60.0 Gy). We analyzed outcomes from the radiotherapy for recurrent esophageal cancer. The 1-, 2-, and 5-year survival rates after recurrence for the 23 patients whose lymph node recurrence was treated with chemoradiotherapy were 52, 31, and 24%, respectively, and the median survival time was 13 months. Among the five patients with recurrent tumors in a distant organ, chemoradiotherapy produced a complete response in two patients, a partial response in one patient, and stable disease in two patients, giving an effectiveness rate of 60% (complete response + partial response). Chemoradiotherapy has a beneficial prognostic effect in patients with lymph node recurrence of esophageal squamous cell carcinoma. Chemoradiotherapy for a metastatic tumor in a distant organ may be the treatment of choice in cases where systemic chemotherapy has proven ineffective.

Small cell carcinoma of the esophagus treated with esophagectomy and following chemotherapy: case report with review of the literature.

We report 2 cases of small cell carcinoma of the esophagus treated with esophagectomy as a primary treatment and following chemotherapy. One patient (pT1N1M0) achieved long-term survival, while the other patient (pT1N1M1-lym) died 18 months after surgery. We used reports on 47 Japanese patients receiving esophagectomy as a primary treatment to determine when esophagectomy for small cell carcinoma of the esophagus is indicated. We conclude that esophagectomy as a local treatment provides relatively good long-term survival only in patients without lymph node involvement.

Preventive wrapping of the fragile tracheobronchial wall using a flap of latissimus dorsi muscle during esophagectomy after chemoradiotherapy.

BACKGROUND: Thanks to significant recent progress in the application of chemoradiotherapy (CRT) in the treatment of esophageal cancer, the numbers of operations on patients who have undergone preoperative CRT are increasing. In these patients, preoperative CRT often leads to formation of an unstable, scleroid layer comprised of what appears to be scar tissue around the tracheobronchial wall. This scleroid layer must be removed with the tumor, thereby weakening the wall. METHOD: We performed preventive intrathoracic transposition of a pedicled latissimus dorsi muscle flap on 6 patients with clinically T4 esophageal cancer (6 males; age: 63-75 years). All 6 patients had undergone preoperative CRT (median, 43.0 Gy; range, 32.0-60.0 Gy; with cisplatin + 5-fluorouracil infusion) to relieve direct invasion of the airway. RESULTS: In 6 patients, preventive use of a pedicled latissimus dorsi muscle flap resulted in uneventful recovery from the tracheobronchial wall weakness. Anastomotic leakage, recurrent nerve paralysis and pneumonia occurred in 2 patients each (33.3%); there were no life-threatening complications or operation-related deaths, however. CONCLUSIONS: When performing an esophagectomy for thoracic esophageal squamous-cell cancer in patients who have received preoperative CRT, the weakened tracheobronchial wall can potentially be reinforced using a pedicled latissimus dorsi muscle flap.

Estimation of pulmonary oxygen consumption in the early postoperative period after thoracic surgery.

Lung injury, including pneumonia, can occur in the early postoperative period following thoracic surgery. Pulmonary oxygen consumption is thought to increase in patients with pulmonary infection. This study measured oxygen consumption in relationship to lung injury in the early postoperative period after thoracic surgery. Thirty-five patients who underwent thoraco-abdominal oesophagectomy for oesophageal cancer were studied. Measured oxygen-consumption was obtained by indirect calorimetry and calculated oxygen-consumption was simultaneously determined by the reverse Fick method. The difference in oxygen consumption was attributed to pulmonary oxygen consumption. The difference in oxygen consumption increased to 23.1 ml.min(-1).m(-2) on postoperative day 2. In patients with pneumonia the difference in oxygen consumption increased significantly to 39.0 ml.min(-1).m(-2) the day before clinical onset of pneumonia, and it increased further to 65.7 ml.min(-1).m(-2) on the day that pneumonia became clinically apparent. These findings suggest that the difference in oxygen consumption may be useful for estimating the extent of lung injury and for predicting pulmonary complications in the postoperative period.

Sound spectrogram analysis in patients receiving Kawahara's surgical voice restoration for advanced carcinoma of the hypopharynx and cervical esophagus.

Loss of voice after total laryngectomy is a major concern that has prompted much effort to develop methods of surgical voice restoration. In 1992, Kawahara described a tracheocolic shunt for voice restoration using a revascularized ileocolic graft. With this method, aspiration through the phonatory shunt is prevented by the ileocolic valve (Bauhin's valve), while vocalization is allowed. The purpose of this study was to use sound spectrogram analysis to evaluate voices surgically restored in that way. Between 2002 and 2005, 10 consecutive patients underwent laryngopharyngoesophagectomy with Kawahara's surgical voice restoration for advanced carcinoma of the hypopharynx and/or cervical esophagus at Akita University Hospital, Japan. We then used sound spectrography to analyze and compare the voices of patients receiving Kawahara's voice restoration, against healthy volunteers and patients who underwent the same surgery without voice restoration and spoke using an electronic larynx. We also evaluated the intelligibility of conversation and performed a listening test. The sound spectrograms showed that when produced by the electronic larynx, consonant sounds and voice frequencies below 300 Hz were not clearly recognized. By contrast, in patients who received Kawahara's surgical voice restoration, consonant and vowel sounds at frequencies above and below 300 Hz were clearly recognized. Although conversation was intelligible with both Kawahara's surgical voice restoration and the electronic device, listeners judged the voice produced by the former to be superior. Thus, the voice produced by Kawahara's surgical voice restoration is superior to that produced by the electronic larynx.

Extravascular lung water measured using single transpulmonary thermodilution reflects perioperative pulmonary edema induced by esophagectomy.

Pulmonary edema is the most frequent postoperative complication following esophagectomy for thoracic esophageal cancer. We enrolled 23 patients who underwent esophagectomy with extended lymph node dissection for thoracic esophageal cancer in a prospective observational clinical trial. We used the PiCCO device to measure extravascular lung water with the aim of determining whether it correlates with the respiratory index and whether it is predictive of pulmonary complications. Based on constant criteria, the tracheal tubes of 11 patients were removed on the morning of postoperative day 1 (extubation group), while 12 patients remained intubated (intubation group). These two groups significantly differed in that all patients in the extubation group recovered without any pulmonary complications, whereas 4 patients (33%) in the intubation group developed pulmonary complications. The extravascular lung water measured using PiCCO correlated significantly with the respiratory index. In the intubation group, both extravascular lung water and respiratory index were elevated 12 h after surgery and were even higher 24 h after surgery. The extravascular lung water measured using PiCCO reflects the level of postoperative pulmonary edema and predicts the pulmonary complications induced by esophagectomy with extended lymph node dissection.

Clinical outcomes of uterine sarcomas: results from 14 years worth of experience in the Kinki district in Japan (1990-2003).

To review clinical outcomes and therapeutic varieties, we were invited to submit data from the patients who were treated for uterine sarcomas in Japan from 1990 to 2003. Uterine sarcomas were defined as leiomyosarcoma (LMS), endometrial stromal sarcoma (ESS), and carcinosarcoma (CS). Of a total of 97 patients, 36 (37.1%) were diagnosed with LMS of the uterine corpus, 15 (15.5%) with ESS, 46 (47.4%) with CS. Median age at diagnosis was 59 (21-85) years. Clinical stages based on FIGO were 41 (42.3%) with stage I disease, 6 (6.2%) with staged II, 34 (35.1%) with stage III, and 16 (16.5%) with stage IV. The median follow-up period for all patients was 13 (1-108) months and median disease-free period was 9 (0-96) months. The 1-year survival rate and disease-free survival (DFS) rate were calculated in patients with all sarcomas (overall survival [OAS], 61.3%; DFS, 46.6%). Statistical analysis showed that younger age (less than 50 years), early stage (stages I and II), and surgical procedure (extended hysterectomy [EH] and radical hysterectomy [RH]) were associated with significantly better OAS. Histologic types did not affect the survival period. In conclusion, aggressive surgery including EH or RH at the time of initial operation offers the possibility of prolonged survival.

A case of postirradiation vaginal angiosarcoma treated with recombinant interleukin-2 therapy.

Angiosarcoma of the vagina is an extremely rare neoplasm and is characterized by frequent recurrence and early metastatic spread. Although previous reports emphasized the poor prognosis of this disease, effective treatment strategies have not been adequately stated. We report a case of angiosarcoma of the vagina, in which the diagnosis was made 9 years after intrapelvic irradiation, and recombinant interleukin-2 (rIL-2) therapy could be effective to suppress the development of distant metastasis. We recommend rIL-2 therapy in combination with irradiation as a palliative therapeutic option for vaginal angiosarcoma when the tumor is inoperable or the patient refuses to undergo surgery. Although vaginal angiosarcoma is an extremely rare condition, its possibility should be borne in mind when finding a vaginal mass in a previously irradiated patient.

Effect of cis-diammine dichloroplatinum on vascular endothelial growth factor expression in uterine cervical carcinoma.

PURPOSE OF INVESTIGATION: In this study, we investigated the effects of cis-diammine dichloroplatinum (CDDP) on VEGF mRNA expression and VEGF production in uterine cervical carcinoma tissues obtained from patients with locally advanced disease and in CaSki cells cultured in vitro. METHODS: VEGF in cultured CaSki cells and in the culture media was measured using a sensitive enzyme-linked immunosorbent assay (ELISA) before and 24 h, 48 h and 72 h after 3 h exposure to CDDP. VEGF mRNA expression in CaSki cells was assessed by the semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) before and 24 h and 48 h after 3 h exposure to CDDP. We also examined the effect of CDDP on microvessel counts in uterine cervical carcinoma tissues obtained before and after high-dose CDDP intraarterial chemotherapy. Immunohistochemical staining using a monoclonal antibody against CD34 was carried out with cervical carcinoma tissue specimens, and microvessel counts were quantified by counting vessels. RESULTS: CDDP treatment resulted in significant increases in not only VEGF concentrations in cultured CaSki cells and culture media but also in VEGF mRNA expression levels in cultured CaSki cells in a time-dependent and dose-dependent manner compared to untreated controls (p < 0.05, n = 5). On the other hand, VEGF concentrations and microvessel counts in cervical carcinoma tissues were significantly lower in cases with complete response (CR) and partial response (PR), compared to those before treatment (p < 0.05, n = 5 ). By contrast, in cases with no change (NC) to CDDP, both VEGF concentrations and microvessel counts did not decrease and rather showed a somewhat increase compared with levels prior to the treatment. CONCLUSIONS: These results suggest that CDDP-induced increases in VEGF production by cervical carcinoma cells may stimulate angiogenesis in the tumor lesion after CDDP treatment.

Transient increase in squamous cell carcinoma antigen expression in cultured cervical carcinoma CaSki cells in response to exposure to cis-diamminedichloroplatinum.

The present study was conducted to elucidate the molecular mechanism underlying the transient increase in circulating squamous cell carcinoma antigen (SCC Ag) levels in response to CIS-diamminedichloroplatinum (CDDP) infusion using an in vitro model. The uterine cervical squamous carcinoma CaSki cells were cultured for 72 h after 3 h exposure to 5.0 microg/ml CDDP. The effects of CDDP exposure on the proliferative activity and apoptosis in cultured CaSki cells were determined by bromodeoxyuridine (BrdU) uptake and cell counting and by the TUNEL assay, respectively. SCC Ag levels in cultured CaSki cells and culture media were determined with the use of SCC-RIA kit. The expression of SCC Ag-1 mRNA and SCC Ag-2 mRNA in cultured CaSki cells was assessed using semiquantitative RT-PCR with Southern blot analysis. The number of BrdU-positive CaSki cells significantly decreased 6 h after exposure to CDDP, whereas the apoptosis-positive rate of cultured CaSki cells significantly increased 12 h after the CDDP exposure. The number of cultured CaSki cells significantly decreased 72 h after the CDDP exposure. The total SCC Ag protein levels in both cultured CaSki cells and the culture media after the 3-hour CDDP exposure increased in a time-dependent manner during the subsequent incubation for 48 h. Semiquantitative RT-PCR revealed that the expression levels of both SCC Ag-1 and SCC Ag-2 mRNA increased (1.7- and 2.7-fold, respectively) 12 h after the exposure to CDDP relative to those before the subsequent cultures. Exposure of uterine cervical squamous carcinoma CaSki cells to CDDP resulted in a transient increase in SCC Ag protein and mRNA expression in those cells during the initial 12 h after the exposure, being associated with decreased proliferative activity and increased apoptosis of those cells.

Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population.

We analyzed genetic alterations in BRCA1 and BRCA2 genes among 82 ovarian cancer families in Japan. The clinical characteristics of BRCA-associated ovarian cancer patients were compared with cases carrying no mutations as well as with population controls. Using a direct sequencing method, 45 of the 82 ovarian cancer families were found to carry BRCA1 or BRCA2 germ-line mutations (40 with BRCA1 and 5 with BRCA2). In 24 independent mutations of BRCA1, 5 recurrent mutations were found and 2 of them, the L63X and Q934X mutations, were detected in seven and eight independent families, respectively. In addition, 16 mutations of BRCA1 and 3 mutations of BRCA2 have never been described previously. In consideration of clinicopathological features, there was a significantly higher proportion of tumors with serous adenocarcinoma and of cases of advanced stages in the BRCA1 or BRCA2 cases than in those of the controls. On the other hand, there were no differences of mean age at diagnosis between patients with BRCA1 or BRCA2 mutation and those of the controls. Our results indicate that the features of BRCA-associated ovarian cancer in Japan appear to be similar to those in Western countries, and the L63X and Q934X mutations of BRCA1 appear to be common founder mutations unique to the Japanese population.

Cancer of the gastric tube reconstructed through the posterior mediastinal route after radical surgery for esophageal cancer.

Among 750 patients diagnosed with esophageal carcinoma in our department between 1972 and 1997, we reviewed our 10 cases in which cancer occurred within gastric tubes reconstructed through the posterior mediastinal route after radical surgery for esophageal cancer. The interval between esophagectomy and cancer onset in the reconstructed gastric tube was relatively long (mean interval: 72 months). Five of our 10 subjects had gastric tube cancer detected at follow-up endoscopy. Four underwent total or partial gastric tube resection with open thoracotomy using colonic or jejunal reconstruction; 3 underwent endoscopic resection. To the best of our knowledge, this is the first report on patients undergoing total resection of gastric tubes reconstructed through the posterior mediastinal route after esophagectomy and rereconstruction using the pedicled colon for the gastric tube cancer.