10% Tumor Diameter Shrinkage on the First Follow‐Up Computed Tomography Predicts Clinical Outcome in Patients With Advanced Renal Cell Carcinoma Treated With Angiogenesis Inhibitors: A Follow‐Up Validation Study

Background.

Vascular endothelial growth factor (VEGF)-targeted agents are standard therapies for metastatic renal cell carcinoma (mRCC), associated with variable tumor shrinkage. Response Evaluation Criteria in Solid Tumors (RECIST) is of limited utility in this setting, and other imaging changes are sought to reliably predict outcome early. We aim to validate 10% tumor shrinkage as the best early indicator of outcome.

Methods.

In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study, 66 mRCC patients with 165 lesions on clinical trials of VEGF-targeted agents underwent thoracic and abdominal computed tomography at baseline and at first follow-up after therapy. Measurements were performed according to RECIST and tumor shrinkage of ≥10% decrease in sum of the longest diameter (−10%SLD). Correlation with time-to-treatment failure (TTF) and overall survival (OS) were compared and stratified by response to the radiologic criteria. Receiver-operating characteristics (ROC) analysis yielded the optimal threshold change in SLD, defining patients with prolonged survival.

Results.

More than −10%SLD significantly differentiated responders from nonresponders (median TTF 8.4 vs. 4.1 months, p = .001), whereas partial response by RECIST did not (median TTF 6.9 vs. 5.5 months in responders vs. nonresponders, p = .34). −10%SLD was also significantly predictive of OS (median OS 35.1 vs. 15.0 months in responders vs. nonresponders, p = .003). ROC curve analysis yielded −9.3% in SLD as the optimal threshold for response/no response.

Conclusion.

Ten percent tumor shrinkage is validated as a reliable early predictor of outcome in mRCC patients receiving VEGF-targeted therapies and may provide a practical measure to guide therapeutic decisions.     

Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism

Huntington's disease (HD) is a fatal neurodegenerative disorder. Despite a tremendous effort to develop therapeutic tools in several HD models, there is no effective cure at present. Acidosis has been observed previously in cellular and in in vivo models as well as in the brains of HD patients. Here we challenged HD models with amiloride (Ami) derivative benzamil (Ben), a chemical agent used to rescue acid-sensing ion channel (ASIC)-dependent acidotoxicity, to examine whether chronic acidosis is an important part of the HD pathomechanism and whether these drugs could be used as novel therapeutic agents. Ben markedly reduced the huntingtin-polyglutamine (htt-polyQ) aggregation in an inducible cellular system, and the therapeutic value of Ben was successfully recapitulated in the R6/2 animal model of HD. To reveal the mechanism of action, Ben was found to be able to alleviate the inhibition of the ubiquitin-proteasome system (UPS) activity, resulting in enhanced degradation of soluble htt-polyQ specifically in its pathological range. More importantly, we were able to demonstrate that blocking the expression of a specific isoform of ASIC (asic1a), one of the many molecular targets of Ben, led to an enhancement of UPS activity and this blockade also decreased htt-polyQ aggregation in the striatum of R6/2 mice. In conclusion, we believe that chemical compounds that target ASIC1a or pharmacological alleviation of UPS inhibition would be an effective and promising approach to combat HD and other polyQ-related disorders.     

Effect of dietary zinc deficiency on ischemic vulnerability of the brain

Deficiency of zinc, which modulates glutamate release, might increase ischemic vulnerability of the brain. We examined effects of dietary zinc deficiency for 2 weeks on ischemic vulnerability in several brain regions using dynamic positron autoradiography technique and [¹⁸F]2-fluoro-2-deoxy-d-glucose with rat brain slices. In the normal diet group, the cerebral glucose metabolic rate (CMRglc) was not significantly different from that of the ischemia-unloaded control even after the loading of ischemia for 45 min. However, in the zinc-deficient diet group, CMRglc was significantly lower than that of the ischemia-unloaded control after loading of ischemia for 45 min. With treatment of MK-801 (NMDA receptor antagonist) from the start of ischemia loading, CMRglc was not significantly different from that of the ischemia-unloaded control. These findings, obtained for all analyzed brain regions, suggest that dietary zinc deficiency increased ischemic vulnerability in the brain, and that glutamate might contribute to this effect through activation of the NMDA receptor.     

Effect of human leukocyte antigen class II genes on insulin deficiency in slow-onset type 1 diabetes in the Japanese population

The aim of this study is to determine the contribution of human leukocyte antigen (HLA) class II genes to insulin deficiency in slow-onset type 1 diabetes (T1D). Our results suggest that the susceptibility conferred by HLA subtypes to slow-onset T1D differs between insulin-deficient patients and non-insulin-deficient patients.     

A glypican-1-targeted antibody-drug conjugate exhibits potent tumor growth inhibition in glypican-1-positive pancreatic cancer and esophageal squamous cell carcinoma

An antibody-drug conjugate (ADC) is a promising therapeutic modality because selective and effective delivery of an anti-cancer drug is achieved by drug-conjugated antibody-targeting cancer antigen. Glypican 1 (GPC1) is highly expressed in malignant tumors, including pancreatic ductal adenocarcinoma (PDAC) and esophageal squamous cell carcinoma (ESCC). Herein, we describe the usefulness of GPC1-targeting ADC. Humanized anti-GPC1 antibody (clone T2) was developed and conjugated with monomethyl auristatin E (MMAE) via maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (mc-vc-PABC) linkers (humanized GPC1-ADC[MMAE]). Humanized GPC1-ADC(MMAE) inhibited the growth of GPC1-positive PDAC and ESCC cell lines via inducing cycle arrest in the G2/M phase and apoptosis in vitro. The binding activity of humanized GPC1-ADC(MMAE) with GPC1 was comparable with that of the unconjugated anti-GPC1 antibody. The humanized GPC1-ADC(MMAE) was effective in GPC1-positive BxPC-3 subcutaneously xenografted mice but not in GPC1-negative BxPC-3-GPC1-KO xenografted mice. To assess the bystander killing activity of the humanized GPC1-ADC(MMAE), a mixture of GPC1-positive BxPC-3 and GPC1-negative BxPC-3-GPC1-KO-Luc cells were subcutaneously inoculated, and a heterogenous GPC1-expressing tumor model was developed. The humanized GPC1-ADC(MMAE) inhibited the tumor growth and decreased the luciferase signal, measured with an in vivo imaging system (IVIS), which suggests that the suppression of the BxPC-3-GPC1-KO-Luc population. The humanized GPC1-ADC(MMAE) also inhibited the established liver metastases of BxPC-3 cells and significantly improved the overall survival of the mice. It exhibited a potent antitumor effect on the GPC1-positive PDAC and ESCC patient-derived xenograft (PDX) models. Our preclinical data demonstrate that GPC1 is a promising therapeutic target for ADC.     

Increased ratio of calcineurin immunoreactive neurons in the caudate nucleus of patients with schizophrenia

Calcineurin (CaN) has been investigated extensively in numerous biochemical, behavioral, and genetic studies in schizophrenia because its function is closely related to dopamine-glutamate signal transduction, which is thought to be associated with pathophysiological changes in schizophrenia. Although evidence has suggested that dysfunction of CaN may be a risk factor for schizophrenia, there have been few reports focusing on the expression of CaN mRNA and CaN protein levels in the brains of schizophrenic patients. In addition, findings on CaN expression in postmortem brains from patients with schizophrenia have been inconsistent. Here, we conducted immunohistochemical examinations of several regions in postmortem brains, including the dorsolateral prefrontal cortex (DLPFC), hippocampus, caudate nucleus, and putamen, using specific antibodies, and compared the results from the brains of nine schizophrenic subjects to nine age- and sex-matched control subjects. There was no significant difference in the ratio of CaN immunoreactive (IR) neurons between schizophrenia and control groups in the DLPFC or hippocampus, and a significantly increased ratio of CaN-IR neurons was seen in the caudate nucleus in the brains from schizophrenia patients. As the striatum contains most of the brain dopamine, the results of the present study have critical implications and suggest that alterations in CaN signaling in the caudate contribute to the pathogenesis of schizophrenia. This is the first report of caudate CaN abnormalities in schizophrenia.     

Imaging of lung cancer in the era of molecular medicine

Recent discoveries characterizing the molecular basis of lung cancer brought fundamental changes in lung cancer treatment. The authors review the molecular pathogenesis of lung cancer, including genomic abnormalities, targeted therapies, and resistance mechanisms, and discuss lung cancer imaging with novel techniques. Knowledge of the molecular basis of lung cancer is essential for radiologists to properly interpret imaging and assess response to therapy. Quantitative and functional imaging helps assessing the biologic behavior of lung cancer.     

A case of primary malignant lymphoma of the prostate

A 79-year-old man presented with a chief complaint of difficulty in urination. Digital rectal examination and transrectal ultrasonography showed an enlarged prostate. Holmium laser enucleation of the prostate (HoLEP) was performed. Histological findings revealed diffuse large B-cell lymphoma by immunohistochemical studies. Pelvic Lymph nodes were swollen on fluoro deoxygiucose-positron emission tomography examination. Therefore, the disease was classified into clinical stage II according to Ann Arbor's criteria. The patient achieved complete response after 6 cycles of combination chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone (R-THP-COP). Now, 1 year 8 months after the chemotherapy, he remains free of the disease.     

Time course of vitamin C distribution and absorption after oral administration in SMP30/GNL knockout mice

Objective

Because vitamin C (VC) has multiple metabolic and antioxidant functions, we investigated the movement of VC throughout the tissues of senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice.

Methods

SMP30/GNL KO mice, which cannot synthesize VC in vivo, were divided into two groups: VC sufficient and VC deficient. Starting at 2 mo of age, both groups had free access to water containing 1.5 and 0.0375 g/L of VC for 1 mo.

Results

The average rate of VC retention in 20 tissues of VC-deficient SMP30/GNL KO mice was only 13.7% of that in VC-sufficient mice. Tissues that retained over 20% of VC were the cerebellum, white fat, testes, eyeballs, and pancreas, and those with less than 5% VC were the kidneys and heart. These results clearly indicate the different VC retention capacities among tissues. Next, we examined the time course of VC distribution and absorption in VC-deficient SMP30/GNL KO mice. After oral VC administration, VC content in the liver and kidney peaked at 3 h and then decreased. VC content in the lungs, adrenal glands, skin, white fat, and pancreas peaked at 6 h and in the cerebellum, cerebrum, skeletal muscles, eyeballs, thyroid gland, and testes at 12 h.

Conclusion

In this study, we found that exogenous VC administered orally in VC-deficient SMP30/GNL KO mice was distributed at distinctly different rates within individual tissues. The SMP30/GNL KO mice used in this study are a useful animal model that provides unique opportunities for investigating VC movement and metabolism in the entire body.