Open-label phase II study of the efficacy of nivolumab for cancer of unknown primary.

BACKGROUND: Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. PATIENTS AND METHODS: Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. RESULTS: Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. CONCLUSIONS: Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.

Internal Delensing of Cosmic Microwave Background Polarization B-Modes with the POLARBEAR Experiment.

Using only cosmic microwave background polarization data from the polarbear experiment, we measure B-mode polarization delensing on subdegree scales at more than 5σ significance. We achieve a 14% B-mode power variance reduction, the highest to date for internal delensing, and improve this result to 22% by applying for the first time an iterative maximum a posteriori delensing method. Our analysis demonstrates the capability of internal delensing as a means of improving constraints on inflationary models, paving the way for the optimal analysis of next-generation primordial B-mode experiments.

A phase II dose-ranging study of palonosetron in Japanese patients receiving moderately emetogenic chemotherapy, including anthracycline and cyclophosphamide-based chemotherapy.

BACKGROUND: The 5-HT(3) receptor antagonists (RAs) help maintain the standard of care, in various combinations with other agents, for prevention of chemotherapy-induced nausea and vomiting (CINV). Palonosetron is a new generation 5-HT(3) RA with indication not only acute but also delayed nausea and vomiting induced by moderately emetogenic chemotherapy (MEC). This study was carried out to determine the optimal dosage of palonosetron in combination with dexamethasone in patients in Japan. PATIENTS AND METHODS: This study evaluated the efficacy and safety of palonosetron in patients receiving MEC combined with dexamethasone. Patients received single doses of 0.075, 0.25, or 0.75 mg of palonosetron before MEC. Dexamethasone was infused before palonosetron, at 20 mg for the patients receiving paclitaxel (Taxol) and 8 mg for the patients not receiving paclitaxel. The primary end point was complete response (CR: no emetic episodes and no rescue medication) in the acute phase (0-24 h). RESULTS: In total, 204 patients (88 men, 116 women; 96 with paclitaxel, 108 without paclitaxel) were assessable for efficacy. No dose-response relationship was observed regarding the CR rate in the acute phase. CR rates increased dose dependently for delayed (24-120 h) and overall (0-120 h) phases in patients receiving anthracyclines and cyclophosphamide combination (AC/EC, n = 80); however, the difference in CR rates among doses was not statistically significant. The most commonly reported adverse events related to palonosetron were constipation and headache, confirming the class safety profile. CONCLUSION: This study indicates a statistically nonsignificant trend for the dose-response relationship for antiemetic protection in the delayed and overall phases in AC/EC patients (the regimen currently considered to be more emetogenic than MEC).

A phase II study of palonosetron combined with dexamethasone to prevent nausea and vomiting induced by highly emetogenic chemotherapy.

BACKGROUND: This is a randomized, double-blind, dose-ranging study in patients receiving highly emetogenic chemotherapy (HEC) to evaluate the safety, efficacy, and pharmacokinetics of palonosetron, in combination with dexamethasone. MATERIALS AND METHODS: We randomized 233 patients to receive palonosetron as a single i.v. bolus dose of 0.075, 0.25, or 0.75 mg before administration of HEC. Dexamethasone (12-16 mg i.v. on day 1, 8 mg i.v. on day 2, and 4-8 mg i.v. on day 3) was administered for prophylactic antiemesis. Pharmacokinetics of palonosetron was analyzed in 24 patients. RESULTS: In this study, all patients were given > or =50 mg/m(2) cisplatin, which was considered to be HEC. No significant differences in complete response (CR: no emesis and no rescue medication) rates were found in the first 24 h between the 0.075-, 0.25-, and 0.75-mg groups (77.6%, 81.8%, and 79.5%, respectively). In the 120-h period of overall observation, CR rates increased in a dose-dependent manner. In the 0.75-mg group, we observed a significantly longer time to treatment failure than in the 0.075-mg group (median time >120 versus 82.0 h, P = 0.038). Palonosetron was tolerated well and did not show any dose-related increase in adverse effects. CONCLUSIONS: Palonosetron at doses of 0.25 and 0.75 mg was shown to be effective in preventing chemotherapy-induced nausea and vomiting with high CR rates of patients treated with HEC in Japan. All tested doses of palonosetron were tolerated well.

Impact of double-balloon endoscopy on the diagnosis of jejunoileal involvement in primary intestinal follicular lymphomas: a case series.

In recent years, primary gastrointestinal follicular lymphoma has been increasingly detected in the duodenum on esophagogastroduodenoscopy (EGD). Primary gastrointestinal follicular lymphomas are frequently distributed to multiple sites in the gastrointestinal tract. Therefore, investigation into the spread of follicular lymphomas in the small bowel is important in order to determine the most appropriate treatment strategy. The performance of double-balloon endoscopy (DBE) in the diagnosis of jejunoileal follicular lymphoma lesions has not been fully evaluated. We aimed to investigate the value of DBE in addition to computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the diagnosis of jejunoileal follicular lymphoma. DBE with biopsy was performed in seven patients with primary duodenal follicular lymphoma diagnosed by EGD, in order to investigate jejunoileal involvement. Jejunoileal follicular lymphoma lesions were detected by DBE in six out of the seven patients (three in the jejunum and three in the jejunum and ileum), whereas CT and (18)F-FDG-PET failed to detect the existence of these lesions. Endoscopic findings of the jejunoileal lesions revealed multiple white nodules and white villi, which were similar to those of duodenal lesions. DBE was more useful for the diagnosis of jejunoileal involvement in primary intestinal follicular lymphoma than CT and (18)F-FDG-PET. The use of DBE will become important for determining the most appropriate treatment for gastrointestinal follicular lymphoma.

Novel quantum criticality in CeRu2Si2 near absolute zero observed by thermal expansion and magnetostriction.

We report linear thermal expansion and magnetostriction measurements for CeRu2Si2 in magnetic fields up to 52.6 mT and at temperatures down to 1 mK. At high temperatures, this compound showed Landau-Fermi-liquid behavior: The linear thermal expansion coefficient and the magnetostriction coefficient were proportional to the temperature and magnetic field, respectively. In contrast, a pronounced non-Fermi-liquid effect was found below 50 mK. The negative contribution of thermal expansion and magnetostriction suggests the existence of an additional quantum critical point.

Overexpression of inducible nitric oxide synthase and accumulation of 8-OHdG in nasopharyngeal carcinoma.

AIMS: Nitric oxide (NO), produced by inducible NO synthase (iNOS), has been suggested to cause oxidative stress, leading to 8-hydroxydeoxyguanosine (8-OHdG) accumulation and subsequent transversion mutation of DNA. The aim was to evaluate iNOS expression and the status of oxidative stress in nasopharyngeal carcinoma (NPC). METHODS AND RESULTS: Seventy-three cases of NPC were investigated to examine the immunohistochemical expression of iNOS, 8-OHdG and latent membrane protein-1 (LMP-1) and Epstein-Barr virus-encoded small RNA (EBER) expression using in situ hybridization. iNOS mRNA expression and p53 gene mutations were also assessed. Overexpression of iNOS, LMP-1 and EBER was observed in 62 (84.9%), 28 (38.4%) and 53 (72.6%) cases respectively. p53 gene mutation was found in 10 of 73 (13.7%) cases. Immunohistochemical iNOS expression was associated with the 8-OHdG labelling index, iNOS mRNA expression and p53 gene alteration (P < 0.0001, P = 0.016 and 0.0082 respectively). CONCLUSIONS: Our present findings suggest that the expression of iNOS induces oxidative stress in NPC. Although the presence of p53 mutation was associated with iNOS overexpression, the type of acid-base change of p53 was transition, but not transversion, which suggests that the p53 gene is not the direct target of DNA damage by 8-OHdG accumulation.

Comparison in prognosis after VATS lobectomy and open lobectomy for stage I lung cancer: retrospective analysis focused on a histological subgroup.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) has become an attractive surgical procedure, but several issues remain to be resolved. Prognosis after VATS lobectomy is important to evaluate the adequacy of VATS lobectomy as a cancer operation. Interestingly, several investigators, including us, have reported that prognosis after VATS lobectomy was superior to that after open lobectomy in early non-small-cell lung cancer (NSCLC). One of the possible reasons is the low invasiveness of VATS lobectomy. But we considered that patient bias might have some influence favoring VATS lobectomy. To evaluate our hypothesis, we reviewed medical records of stage I NSCLC patients undergoing operation between 1993 and 2002. We compared and evaluated the relationship between patient characteristics and prognosis after VATS and open lobectomy. We focused particularly on histological type, classifying it into four subgroups; (1) bronchioloalveolar carcinoma (BAC), (2) mixed BAC + papillary adenocarcinoma (BAC + Pap), (3) other adenocarcinoma (Other adeno), (4) squamous cell carcinoma + others (Sq + others). RESULTS: A total of 165 patients underwent VATS lobectomy, and 123 patients underwent open lobectomy. The 5-year survival rate of the VATS lobectomy group was 94.5% and that of the open lobectomy group was 81.5%. Univariate Cox regression of survival revealed that male, CEA > 5, Other adeno, Sq + others, open lobectomy, and tumor size > 3 cm were significant negative prognostic variables. Multivariate Cox regression of survival revealed that histological subtype and tumor size were independent prognostic factors, but surgical procedure was not an independent prognostic factor. COMMENTS: Prognosis after VATS lobectomy was superior to that after open lobectomy, but patient bias influenced the prognosis in favor of VATS lobectomy, and the surgical procedure itself was not a prognostic factor.

Real-time PCR method for quantification of Staphylococcus aureus in milk.

A reproducible real-time PCR method that targets the putative transcriptional regulator gene of Staphylococcus aureus was developed to quantify this microorganism in milk samples. On the basis of partial sequences of this gene determined from S. aureus strains, we designed the specific primers and probe for use in a quantitative PCR assay. These specificities were confirmed with 25 strains of S. aureus and 35 strains of other bacteria. A real-time PCR assay with serial 10-fold dilutions of purified DNA and pure culture was conducted. It was possible to construct standard curves with a high correlation coefficient (r2 = 0.99) in the range of 50 ng to 50 fg for purified DNA and 10(7) to 10(1) CFU/ml for a pure culture. The constructed standard curve for milk samples was similar to that for the pure culture, and the quantification of S. aureus in the range of 10(7) to 10(1) CFU/ml was possible. Moreover, to determine how our real-time PCR method would perform under actual analytical conditions, we quantified the DNA from S. aureus after two types of heat treatments were used for the pasteurization of milk. The amount of DNA found was affected after heat treatment at 63 degrees C for 30 min (low-temperature long-time method) but not at 72 degrees C for 15 s (high-temperature short-time method). The results indicate that the real-time PCR method developed in this study is effective for monitoring S. aureus contamination in milk because of its high specificity and sensitivity.

Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer.

Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0-4.9).

Salmonella prevalence and total microbial and spore populations in spices imported to Japan.

A total of 259 samples of 40 types of spices were tested for Salmonella prevalence and total microbial and spore populations. Salmonella enterica serotypes Weltevreden and Senftenberg were isolated from a black- and red-pepper sample, respectively. Because Salmonella was not detected by the most-probable-number method, it indicated that at least one cell of the microorganism was present in 25 g of sample. The mean aerobic bacterial count was greater than 5.39 log CFU/g in turmeric, garam masala, curry powder, and paprika. The mean bacterial spore counts were greater than 4.33 log CFU/g in turmeric and curry powder. The mean aerobic bacterial count in the two Salmonella-isolated samples was 6.93 log CFU/g. These results indicate that spices can be a source of contamination in the products where they are used as ingredients, and methods to reduce the microbial load in spices should be used.

Exotic radiation from a photonic crystal excited by an ultrarelativistic electron beam.

We report the observation of an exotic radiation (unconventional Smith-Purcell radiation) from a one-dimensional photonic crystal. The physical origin of the exotic radiation is direct excitation of the photonic bands by an ultrarelativistic electron beam. The spectrum of the exotic radiation follows photonic bands of a certain parity, in striking contrast to the conventional Smith-Purcell radiation, which shows solely a linear dispersion. Key ingredients for the observation are the facts that the electron beam is in an ultrarelativistic region and that the photonic crystal is finite. The origin of the radiation was identified by comparison of experimental and theoretical results.

High-transmission waveguide with a small radius of curvature at a bend fabricated by use of a circular photonic crystal.

A bent photonic crystal waveguide was fabricated by use of a lattice pattern of a circular photonic crystal that allowed high transmission for a broad band of wavelengths with a small radius of curvature at a bend. The waveguide was fabricated by use of alumina rods with a diameter of 3 mm. Windows of high transmission as a result of waveguiding were observed near 9 and 15 GHz. By measurement of the relative wave intensity [E]2 along the line defects, the propagation losses in the straight and the bent sections were estimated at 9.3 GHz to be 0.04 and 0.03 dB/mm, respectively.

Study of peroxisome proliferator-activated receptor (PPAR)-gamma in renal ischemia-reperfusion injury.

Recent studies of ischemia-reperfusion (I/R) injury have focused on the function of neutrophils, the action mechanism of inflammatory cytokines. However, few reports have addressed peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma is a ligand-activated transcriptional factor belonging to the steroid receptor superfamily. It plays a role in both adipocyte differentiation and tumorigenesis. We researched the expression of PPAR-gamma in renal I/R injury of the rat. Male Lewis rats were used. The right kidney was harvested and the left renal artery and vein were clamped at 90 minutes of ischemic time. Rats were killed at 0, 1.5, 3, 5, and 12 hours after reperfusion. PPAR-gamma expression was studied by immunohistostaining. PPAR-gamma expression was observed only on mesangial and endothelial cells of normal kidney. From 1.5 to 3 hours after reperfusion, PPAR-gamma expression gradually became stronger on mesangial and endothelial cells. PPAR-gamma expression was most intense on mesangial cells and endothelial cells at 3 hours after reperfusion. Twelve hours after reperfusion, necrosis extended throughout the ischemic kidney and nearly all the tubular epithelial cells were destroyed, but 12 hours after reperfusion PPAR-gamma expression gradually became weaker on mesangial and endothelial cells. PPAR-gamma was expressed in the rat model having renal I/R injury. Several hours after maximal of PPAR-gamma expression, maximal renal I/R injury was observed. These results may indicate a relationship between PPAR-gamma expression and renal I/R injury.

Interchange of the quantum states of confined excitons caused by radiative corrections in CuCl films.

The energy states of a particle confined in a narrow space are discrete and lined up in the order of n=1,2,3,.... However, if the particle interacts with a radiation field, modification of the energy, referred to radiative correction, will occur and quantum states are expected to interchange. We investigated the center-of-mass confinement of excitons in CuCl films by a new method based on "nondegenerate two-photon excitation scattering." The energies of confined excitons in a 19.3 nm thick film are found to be lined up in the order of n=1,3,5, because the radiative correction is very weak. On the other hand, in a 35.3 nm thick film, in which the radiative correction becomes large, the energies of quantum states are ordered n=2,3,4,1,5,7. This interchange is confirmed by comparing the calculated scattering spectra, in which radiative correction is taken into account, with the measured ones.

Isotropic photonic gaps in a circular photonic crystal.

We investigated the optical properties of a circular photonic crystal (CPC) for which the distance between lattices was systematically distributed. The transmission spectra of CPC composed of alumina cylinders were examined in the frequency region from 0 to 20 GHz. We show that photonic gaps are obtained not only in CPCs but also in phase-shifted CPCs. The isotropic photonic gaps are evidenced by changes in the incident angle of a millimeter wave.

Observation of millimeter-wave radiation generated by the interaction between an electron beam and a photonic crystal.

We observed directional light emission in the millimeter-wave region when a high-energy (150 MeV) electron beam passes just above a photonic crystal made of polytetrafluoroethylene beads ( approximately 3.2 mm in diameter). The relation between the momentum and the energy of the emitted photons strongly suggests that the observed light is generated by the umklapp scattering process that changes the evanescent waves emitted by the electron beam into observable ones. By comparing the observed spectra with calculated ones based on the photonic band structure, we found that generated photons excite the photonic band modes making them observable as enhanced fine structures in the emission spectra.

Phase I/II study of docetaxel and cisplatin with concurrent thoracic radiation therapy for locally advanced non-small-cell lung cancer.

Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.

Temporary amniotic membrane patching for acute chemical burns.

PURPOSE: To describe the surgical technique, and its usefulness, of temporary amniotic membrane patching (AMP) in the acute phase of ocular chemical injury. METHODS: Temporary AMP with modification in suture placement was performed on five eyes of five consecutive patients inflicted with acute chemical injury having a greater than grade II injury by the Roper-Hall classification. RESULTS: All patients reported herein presented with a large epithelial defect on the cornea and conjunctiva. Case 3 was classified as grade III while the other four cases were classified as grade II. The causative chemical agents were anhydrous acetic acid in Case 1, calcium oxide in Case 2, sodium hydroxide in Case 3, sodium silicate in Case 4, and sulphuric acid in Case 5. All cases experienced rapid relief of pain after AMP. Epithelialization of the cornea with improvement of visual acuity was observed in all cases when the amniotic membrane was removed within 2 weeks after surgery. During the mean follow-up of 19.6 months, the ocular surface remained stable and no cicatricial complications were noted. CONCLUSIONS: These results suggest that immediate AMP is quite useful for managing moderately severe acute ocular chemical injury by facilitating rapid epithelialization and pain relief, and securing ocular surface integrity.