Higher preoperative serum levels of PD-L1 and B7-H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF-targeted therapy and unfavorable prognosis of renal cell carcinoma.

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer. Although antivascular endothelial growth factor (VEGF) therapies achieve impressive responses in some patients, many tumors eventually develop resistance to such therapy. The B7 family molecules such as CTLA-4, PD-1, and PD-L1 are pivotal players in immune checkpoints that positively or negatively regulate various immune responses. Recently, immunotherapy based on blocking immune checkpoints with anti-CTLA4, anti-PD-1, or anti-PD-L1 antibodies has been proposed as a potential new approach to the treatment of metastatic RCC. Higher expression of PD-L1 and B7-H4 in the tumors is associated with a poor prognosis in RCCs, however, the clinical impact of serum levels of B7 family molecules has not been elucidated in patients with metastatic RCCs receiving VEGF-targeted agents. We assessed the preoperative serum levels of B7 family molecules, including CD80, CD86, PD-1, PD-L1, B7-H3, B7-H4, and CTLA-4, and CD28 in RCC patients, and determined their relations with various clinicopathological characteristics. Elevated preoperative serum levels of PD-L1 and B7-H4 were correlated with less differentiated tumors, higher invasive and metastatic potential, a worse response to anti-VEGF therapy, and shorter overall survival. These findings suggested that investigating preoperative serum levels of PD-L1 and B7-H4 might not only be useful to assess the biological aggressiveness of RCCs, but also to predict the efficacy of anti-VEGF therapy and the eventual prognosis, indicating the future design of clinical trials of therapies targeting immune checkpoint in advanced RCCs.

The prevalence and characteristics of metabolic syndrome in patients with vertigo.

OBJECTIVES/HYPOTHESIS: Metabolic syndrome (MetS) is a condition that increases the risk of coronary artery disease and cerebral infarction. We determined the prevalence of MetS in vertigo patients and clinically investigated the association between MetS and vertigo. STUDY DESIGN: Case-control study. METHODS: The subjects were 333 patients, including 107 males and 226 females, who presented with vertigo as a primary symptom. MetS was diagnosed according to the International Diabetes Federation definition, which is based on waist circumference, blood serum levels, and blood pressure. RESULTS: MetS was detected in 53 (15.9%) of 333 vertigo patients, including 24 males (22.4%) and 29 females (12.8%); i.e., the frequency of MetS was significantly higher among the male patients than the female patients. The overall prevalence of MetS (15.9%) among vertigo patients did not differ from that observed among general adults in previous Japanese surveillance studies; however, MetS was significantly more common among the vertigo patients in males than general adult males. The prevalence of MetS was also examined in five types of vertigo, Concomitant MetS was noted in many males with vertebrobasilar insufficiency (VBI) and isolated vertigo of unknown etiology. CONCLUSION: It was suggested that MetS is involved in the development of vertigo in males. MetS might be a risk factor for vascular vertigo such as VBI in males. The high frequency of MetS among males with vertigo of unknown etiology suggested that the pathogenesis of metabolic syndrome is involved in this type of isolated vertigo.

Increased expression of system large amino acid transporter (LAT)-1 mRNA is associated with invasive potential and unfavorable prognosis of human clear cell renal cell carcinoma.

BACKGROUND: The system L amino acid transporter (LAT) has an important role in the transport of various amino acids, and there have been reports about the relation of this system to cancer. Although LATs are highly expressed in the kidneys, little is known about their influence on human renal cancer. METHODS: To clarify the role of LATs in human clear cell renal cell carcinoma (RCC), we investigated the expression of mRNAs for LAT1, LAT2, LAT3, LAT4, and 4F2hc in clear cell RCC tissues. The mRNAs of these five genes were analyzed by the real-time reverse transcription polymerase chain reaction in matched sets of tumor and non-tumor tissues obtained at operation from 82 Japanese patients with clear cell RCC. We also measured phosphorylated S6 ribosomal protein (Ser-235/236) proteins levels in 18 paired tumor and non-tumor tissues of the patients by Western blotting. RESULTS: Expression of LAT1 mRNA was significantly increased in tumor tissue compared with non-tumor tissue, while expression of LAT2 and LAT3 mRNAs was reduced. There was no difference in the expression of LAT4 and 4F2hc mRNAs between tumor and non-tumor tissues. Increased expression of LAT1 mRNA was associated with less differentiated tumors, local invasion, microscopic vascular invasion, and metastasis. Kaplan-Meier survival analysis showed that a higher serum LAT1 mRNA level was associated with a shorter overall survival time. Phosphorylated S6 ribosomal protein levels were associated with metastatic potential. LAT1 mRNA levels positively correlated with phosphorylated S6 ribosomal protein proteins levels in primary tumors. CONCLUSIONS: These findings suggest that LAT1 mRNA is related to the invasive and progressive potential of clear cell RCC.

Randomized, Single-Blind, Parallel Study of the Effectiveness and Safety of Solifenacin versus Propiverine in the Treatment of Overactive Bladder.

OBJECTIVES: To compare the effectiveness and safety of solifenacin versus propiverine in the treatment of overactive bladder (OAB), in a single-blind, randomized parallel study. METHODS: Sixty-six patients with OAB (14 men and 52 women) were randomly assigned to groups: solifenacin (5 mg/day) or propiverine (20 mg/day) and treated for 8 weeks. The primary outcome variable was mean change from baseline to end of treatment in urgency of the OAB symptom score (OABSS). Secondary outcomes were bladder diary variables: change over 24 h in the mean number of voids (daytime and nighttime), episodes of micturition urgency and incontinence, and mean volume voided. Patients also completed total OABSS and the King's Health questionnaires. RESULTS: Group backgrounds were comparable except for the male to female proportion; 11:22 for solifenacin (n = 33) versus 3:30 for propiverine (n = 33). Adverse events were 6 of 29 (21%) for solifenacin versus 14 of 26 (54%) for propiverine (P = 0.017). Three patients were withdrawn for voiding difficulty (one in solifenacin and two in propiverine) and one patient for dry mouth (propiverine group). Change in OABSS urgency score was -2.3 ± 1.4 for solifenacin (n = 28) versus -1.3 ± 1.7 for propiverine (n = 23), (P = 0.0169). Total OABSS and other individual scores, and voiding diary parameters for both drugs showed improvements; however, between-group difference was not established. CONCLUSION: Although both solifenacin 5 mg and propiverine 20 mg were effective in the treatment of OAB, solifenacin appeared to be more effective and tolerable.

[Clinical analysis of metabolic syndrome in vertiginous diseases].

To explore the relationship between metabolic syndrome and vertigo, we measured waist circumference, plasma glucose, triglycerides and blood pressure in 333 subjects aged 20-79 years with vertigo. We found overall metabolic syndrome prevalence defined by Japanese diagnostic criteria to be 13.2%, similar to that in other national surveys by the Japanese Ministry of Health, Labour and Welfare. The 6-fold higher prevalence in men over women exceeded that of other reports, however. The highest frequency was in vertebrobasilar insufficiency (VBI) disorders, suggesting that conditions such as VBI in men with vertigo could involve metabolic syndrome as a risk factor for vertigo incidence.

Serum interferon alpha receptor 2 mRNA may predict efficacy of interferon alpha with/without low-dose sorafenib for metastatic clear cell renal cell carcinoma.

BACKGROUND: Interferon (IFN) alpha is one of the central agents in immunotherapy for renal cell carcinoma (RCC). It acts by binding to the IFN-alpha receptor (IFNAR). We previously reported that increased tumor expression of IFNAR2 mRNA was associated with the metastatic potential and progression of RCC, as well as with a poor response of metastatic RCC to IFN-alpha therapy. This study investigated the influence of serum IFNAR2 in RCC patients. METHODS: We measured serum IFNAR2 mRNA levels and quantified IFNAR mRNA expression in paired tumor and non-tumor tissues from the surgical specimens of 66 consecutive RCC patients by the real-time reverse transcription polymerase chain reaction (RT-PCR). We also measured phosphorylated Akt (Ser-473) and phosphorylated-S6 ribosomal protein (Ser-235/236) proteins levels in paired tumor and non-tumor tissues of patients with metastatic RCC by Western blotting. RESULTS: The serum level of IFNAR2 mRNA was not associated with its tumor tissue level. Serum IFNAR2 mRNA was positively correlated with tumor size (P < 0.05), but not with tumor grade, pT stage, metastasis, microscopic vascular invasion, or serum C-reactive protein. Serum levels of IFNAR2 mRNA were significantly higher in patients with a good response to IFN-alpha ± sorafenib than in those with a poor response (P < 0.0001). Tumor tissue IFNAR2 mRNA levels and phosphorylated-S6 ribosomal protein (Ser-235/236) levels were associated with metastatic potential (P < 0.001 and P < 0.01, respectively), and patients with a low IFNAR2 mRNA level and low phosphorylated Akt (Ser-473) protein level in the primary tumor showed a good response to IFN-α ± sorafenib (IFN-α ± Sor: CR-PR) (P < 0.01 and P < 0.05, respectively). Kaplan-Meier survival analysis showed that a higher serum IFNAR2 mRNA level was associated with longer overall survival of treated patients (P < 0.05), while a higher tumor tissue IFNAR2 mRNA level was related to shorter overall survival (P < 0.01). CONCLUSIONS: Our findings suggest that a high serum level of IFNAR2 mRNA may be a useful marker for predicting the response of metastatic RCC to IFN-alpha ± sorafenib therapy.

Late laryngeal radionecrosis in severe arteriosclerosis.

Laryngeal necrosis is a serious complication that usually occurs within the first year following completion of radiotherapy, although it is reported that cases can develop after a long period of latency. Factors such as dosage and irradiation technique employed, tumour invasion into the laryngeal cartilage, infection, continued smoking, trauma and general vascular condition of the patient have been considered to increase the rate and degree of development of radionecrosis. We report an unusual case of laryngeal radionecrosis in a patient with hypertension, hyperlipidaemia, diabetes and a history of cigarette smoking, which developed 25 years after radiotherapy for laryngeal carcinoma. His systemic illnesses and continued smoking were speculated to have contributed to the progress of the radionecrosis, suggesting that cessation of smoking and control of arteriosclerotic diseases should be considered to decrease its incidence.

[Weekly docetaxel treatment for head and neck cancer].

A pilot study was conducted to evaluate the safety and efficacy of weekly docetaxel(DOC) treatment for head and neck cancer as compared with those of 3-weekly DOC treatment at 60 mg/m(2). Weekly DOC was administered at doses ranging from 25-30 mg/m(2)/wk (mean dosage, 40 mg/body/wk) for 3 weeks followed by a 1-week rest or for 6 weeks followed by a 2-week rest. Weekly DOC was administered to 18 patients (1 of whom received prior chemotherapy), and 3-weekly DOC was administered to 29 patients (10 of whom received prior chemotherapy). The overall response rate was 22.2% in the weekly DOC group and 47.8% in the 3-weekly DOC group. In advanced or recurrent cancer, the overall response rate plus long NC (stable disease for at least 6 months) rate was 40.0% in the weekly DOC group, and 42.9% in the 3-weekly DOC group. Only 1 (5.6%) case of grade 3 mucositis developed in the group receiving weekly DOC, while 12 cases of grade 3 or 4 neutropenia (41.4%) and 2 of grade 3 or 4 thrombopenia (6.9%) developed in the 3-weekly DOC group. Based on these results, weekly DOC treatment appears to be useful and feasible for outpatients with head and neck cancer, even in high-risk and elderly patients.

Successful free osteocutaneous scapular flap transfer for mandibular reconstruction in a 93-year-old patient.

With the extension of the average life span and the development of surgical technique, anesthesia, and pre- and postoperative management, operations for elderly patients have become more widely accepted. In the field of plastic surgery, free-flap transfers using microvascular techniques have become a common surgical procedure in reconstruction of the head and neck region after surgical removal of a cancer. There have been several reports of free-flap transfer in patients older than 90 years, but the authors know of no reports of free osteocutaneous flap transfer for mandibular reconstruction, which is a very invasive free-flap surgery, for such patients. The mandible plays a significant role in various kinds of dynamic functions, such as mastication, deglutition, and articulation. Disorder of these functions causes a deterioration in the patient's quality of life. The authors have performed a mandibular reconstruction using an osteocutaneous scapular free flap after resection of a gingival cancer invading the mandibular bone in a 93-year-old Japanese woman. In our case, an osteocutaneous scapular free flap, which permits the patient rapid rehabilitation of the lower leg, is thought to be a good choice because it allows the patient to get out of bed as quickly as possible in the postoperative period to minimize additional complications.

[The usefulness of TS-1 for the treatment of head and neck cancer].

We investigated the usefulness of TS-1 for the treatment of head and neck carcinoma in 29 patients who received treatment on an outpatient basis at our institution. Among the 29 patients, 22 patients in whom the response was evaluable were included in the efficacy analysis. To assess the safety of TS-1, the severity of adverse events was examined in the 29 patients. Each course of treatment consisted of oral administration of TS-1 at a dose of 80 to 120 mg/day, depending on the body surface area (BSA), for 28 consecutive days, followed by a 14-day rest period. None of the patients showed complete response (CR), 7 showed partial response (PR), 10 showed no change (NC), and 5 showed progressive disease (PD). The response rate was thus 31.8%. Severe adverse events (grades 3 and 4) occurred in 2 patients. One developed grade 3 leukopenia and grade 4 thrombocytopenia. The other developed Stevens-Johnson syndrome that was assessed as grade 4. The findings indicate that TS-1 might be useful for the treatment of patients with head and neck carcinoma on an outpatient basis without affecting their quality of life (QOL), although careful monitoring is essential to watch for the development of severe adverse events.