Blockage of Akt activation suppresses cadmium-induced renal tubular cellular damages through aggrephagy in HK-2 cells.

We have reported that an environmental pollutant, cadmium, promotes cell death in the human renal tubular cells (RTCs) through hyperactivation of a serine/threonine kinase Akt. However, the molecular mechanisms downstream of Akt in this process have not been elucidated. Cadmium has a potential to accumulate misfolded proteins, and proteotoxicity is involved in cadmium toxicity. To clear the roles of Akt in cadmium exposure-induced RTCs death, we investigated the possibility that Akt could regulate proteotoxicity through autophagy in cadmium chloride (CdCl2)-exposed HK-2 human renal proximal tubular cells. CdCl2 exposure promoted the accumulation of misfolded or damaged proteins, the formation of aggresomes (pericentriolar cytoplasmic inclusions), and aggrephagy (selective autophagy to degrade aggresome). Pharmacological inhibition of Akt using MK2206 or Akti-1/2 enhanced aggrephagy by promoting dephosphorylation and nuclear translocation of transcription factor EB (TFEB)/transcription factor E3 (TFE3), lysosomal transcription factors. TFEB or TFE3 knockdown by siRNAs attenuated the protective effects of MK2206 against cadmium toxicity. These results suggested that aberrant activation of Akt attenuates aggrephagy via TFEB or TFE3 to facilitate CdCl2-induced cell death. Furthermore, these roles of Akt/TFEB/TFE3 were conserved in CdCl2-exposed primary human RTCs. The present study shows the molecular mechanisms underlying Akt activation that promotes cadmium-induced RTCs death.

Efficacy and safety of abiraterone acetate plus prednisolone in patients with early metastatic castration-resistant prostate cancer who failed first-line androgen-deprivation therapy: a single-arm, phase 4 study.

AIM: The aim was to evaluate the efficacy and safety of abiraterone acetate plus prednisolone in patients with chemotherapy-naïve early metastatic castration-resistant prostate cancer who failed first-line androgen deprivation therapy. METHODS: Patients with early metastatic castration-resistant prostate cancer with confirmed prostate-specific antigen progression within 1-year or prostate-specific antigen progression without having normal prostate-specific antigen level (<4.0 ng/mL) during first-line androgen deprivation therapy were enrolled and administered abiraterone acetate (1000 mg) plus prednisolone (10 mg). A minimum of 48 patients were required according to Simon's minimax design. The primary endpoint was prostate-specific antigen response rate (≥50% prostate-specific antigen decline by 12 weeks), secondary endpoints included prostate-specific antigen progression-free survival and overall survival. Safety parameters were also assessed. RESULTS: For efficacy, 49/50 patients were evaluable. Median age was 73 (range: 55-86) years. The median duration of initial androgen deprivation therapy was 32.4 (range: 13.4-84.1) weeks and 48 patients experienced prostate-specific antigen progression within 1-year after initiation of androgen deprivation therapy. prostate-specific antigen response rate was 55.1% (95% confidence interval: 40.2%-69.3%), median prostate-specific antigen-progression-free survival was 24.1 weeks, and median overall survival was 102.9 weeks (95% confidence interval: 64.86 not estimable [NE]). Most common adverse event was nasopharyngitis (15/50 patients, 30.0%). The most common ≥grade 3 adverse event was alanine aminotransferase increased (6/50 patients, 12.0%). CONCLUSIONS: Abiraterone acetate plus prednisolone demonstrated a high prostate-specific antigen response rate of 55.1%, suggesting tumor growth still depends on androgen synthesis in patients with early metastatic castration-resistant prostate cancer. However, prostate-specific antigen-progression-free survival was shorter than that reported in previous studies. Considering the benefit-risk profile, abiraterone acetate plus prednisolone would be a beneficial treatment option for patients with chemotherapy-naive metastatic prostate cancer who show early castration resistance.

Renal arteriolar hyalinosis, not intimal thickening in large arteries, is associated with cardiovascular events in people with biopsy-proven diabetic nephropathy.

AIMS: Diabetic nephropathy, a pathologically diagnosed microvascular complication of diabetes, is a strong risk factor for cardiovascular events, which mainly involve arteries larger than those affected in diabetic nephropathy. However, the association between diabetic nephropathy pathological findings and cardiovascular events has not been well studied. We aimed to investigate whether the pathological findings in diabetic nephropathy are closely associated with cardiovascular event development. METHODS: This retrospective cohort study analysed 377 people with type 2 diabetes and biopsy-proven diabetic nephropathy, with a median follow-up of 5.9 years (interquartile range 2.0 to 13.5). We investigated how cardiovascular events were impacted by two vascular diabetic nephropathy lesions, namely arteriolar hyalinosis and arterial intimal thickening, and by glomerular and interstitial lesions. RESULTS: Of the 377 people with diabetic nephropathy, 331 (88%) and 295 (78%) had arteriolar hyalinosis and arterial intimal thickening, respectively. During the entire follow-up period, those with arteriolar hyalinosis had higher cardiovascular event rates in the crude Kaplan-Meier analysis than those without these lesions (P = 0.005, log-rank test). When fully adjusted for clinically relevant confounders, arteriolar hyalinosis independently predicted cardiovascular events [hazard ratio (HR) 1.99; 95% confidence interval (CI) 1.12, 3.86], but we did not find any relationship between arterial intimal thickening and cardiovascular events (HR 0.89; 95% CI 0.60, 1.37). Additionally, neither glomerular nor interstitial lesions were independently associated with cardiovascular events in the fully adjusted model. CONCLUSIONS: Arteriolar hyalinosis, but not intimal thickening of large arteries, was strongly associated with cardiovascular events in people with diabetic nephropathy.

Follow-up Survey of Donor Candidates for Living Related Kidney Transplantation With Prostate Cancer.

INTRODUCTION: With the increasing number of elderly kidney donor candidates due to the lack of available donors, prostate cancer has sometimes been detected in these candidates during pretransplant screening examinations. There are currently no guidelines or consensus on prostate cancer screening and treatment in donors. We retrospectively evaluated the clinical course of donor candidates with prostate cancer. METHODS: Between January 2006 and December 2016, 9 donor candidates for living related kidney transplantation were incidentally diagnosed with prostate cancer at our institution. All male kidney transplant donor candidates routinely received prostate-specific antigen (PSA) testing. The patients with PSA levels > 4.0 ng/mL underwent prostate biopsies. For future kidney transplantation, treatment for localized prostate cancer was prostatectomy. RESULTS: Seven low- or intermediate-risk patients according to the D'Amico risk classification underwent endoscopic prostatectomy, while 2 high-risk patients underwent high dose-rate brachytherapy to prioritize prostate cancer treatment. Of the 7 who underwent surgery, 3 patients ultimately became living related kidney transplantation donors for their wives. There was no recurrence of PSA elevation after treatment. CONCLUSION: This study showed that donor candidates with prostate cancer could safely donate a kidney after a thorough evaluation to exclude those with high-risk prostate cancer. Transmission of prostate cancer through kidney transplantation seems unlikely and robot-assisted laparoscopic prostatectomy may be feasible for donor candidates with localized prostate cancer.

Radical Prostatectomy for Localized Prostate Cancer in Renal Transplant Recipients: 13 Cases Studied at a Single Center.

OBJECTIVES: We aimed to evaluate the feasibility and efficacy of surgical prostatectomy in renal transplant recipients (RTRs). METHODS: Between January 2008 and February 2017, we identified 13 RTRs who were diagnosed with localized prostate cancer and underwent radical prostatectomy. We reviewed all available clinicopathologic data for these 13 patients. RESULTS: The median patient age was 61 years and median serum prostate-specific antigen (PSA) was 8.79 ng/mL. The mean period between transplantation and diagnosis of prostate cancer was 136 months. The sources for the kidney transplants included 10 living and 3 deceased donors. Biopsies indicated that the Gleason scores were 7 in 10 patients and 8 to 10 in 3 patients. Meanwhile, the D'Amico risk classification indicated an intermediate risk in 9 patients and a high risk in 4 patients. Eight patients were at stage cT1 and 5 were at stage cT2. The surgical procedure was retropubic radical prostatectomy in one recipient, laparoscopic radical prostatectomy in 3 recipients, and robot-assisted radical prostatectomy in 9 RTRs. Intraoperative complications were not noted in any patient, although one patient demonstrated postoperative complications (Clavien grade ≥ 3). An indwelling urinary catheter was required in 3 patients for over 3 weeks due to delayed wound healing. Biochemical recurrence evaluated by PSA monitoring occurred in four patients. Postoperative graft function was stable in all but one patient who required resumption of dialysis before prostatectomy; however, all patients are alive at the time of publication with 12 patients showing well-functioning renal allografts. CONCLUSION: Prostatectomy may be a feasible and effective technique as an initial treatment for RTRs with localized prostate cancer.

Living Related Renal Transplantation Using a Saphenous Vein Graft: A Case Report.

We report a case of living related renal transplantation that used the recipient's saphenous vein as a graft to extend the length of the right donor renal vein. A 41-year-old woman underwent ABO-incompatible living related renal transplantation from her 74-year-old mother in November 2014. A retroperitoneal laparoscopic right donor nephrectomy was performed, because the right kidney showed a cyst on preoperative computed tomography. As the right kidney after donor nephrectomy had a short renal vein and the kidney was large at 280 g, anastomosis with the external iliac vein was difficult. Therefore, we obtained the recipient's 15-cm-long right saphenous vein and created a 1 cm saphenous vein graft. We anastomosed 1 side of the saphenous vein graft to the allograft renal vein in bench surgery and performed end-to-side anastomosis of the other end to the recipient's external iliac vein. The allograft renal artery was used to perform end-to-end anastomosis to the recipient's internal iliac artery. Allograft kidney function was good after transplantation. When the longer axis of the renal graft vein is short, as in the right kidney, a saphenous vein graft may be useful.

Clinical and Pathological Analyses of Cases of Acute Vascular Rejection After Kidney Transplantation.

BACKGROUND: We performed a clinical and pathological analysis of cases of acute vascular rejection (AVR), characterized by intimal arteritis and transmural arteritis (Banff v score) after kidney transplantation, in an attempt to clarify the mechanisms underlying the development and prognostic significance of AVR. METHODS: AVR (Banff score: v >0) was diagnosed in 31 renal allograft biopsy specimens (BS) obtained from 31 renal transplant patients receiving follow-up care at the Department of Urology, Tokyo Women's Medical University, between January 2010 and April 2016. RESULTS: AVR was diagnosed at a median of 124.6 days after transplantation. Among the 31 BS showing evidence of AVR, AVR was mild (v1 in Banff's classification) in 25 cases, moderate (v2) in 6, and severe (v3) in none. We classified the 31 BS with evidence of AVR by their overall histopathological features as follows: isolated v lesions were observed in 6 BS, acute antibody-mediated rejection (AAMR) in 7, acute T-cell-mediated rejection (ATCMR) in 12, and both ATCR and AAMR in 6. Loss of the renal allograft occurred during the observation period in 3 patients, and, of the remaining cases with functioning grafts, deterioration of renal allograft function after biopsy occurred in only 2 patients. CONCLUSIONS: The results of our study suggest that ATCMR contributes to AVR in 40% to 60% of cases, AAMR in 20% to 40% of cases, and isolated v lesions in 20% of cases. The prognosis of the patient with the graft that had AVR was relatively good under the present immunosuppression protocol and current anti-rejection therapies.

Living Kidney Donation From a Donor With Pulmonary Sarcoidosis: A Case Report and Review of the Literature.

BACKGROUND: Sarcoidosis is a chronic systemic disease that is characterized by the formation of noncaseating granuloma and whose etiology is unclear. It is unclear whether patients with sarcoidosis are suitable organ donors. CASE: We treated a 56-year-old woman with pulmonary sarcoidosis who donated her kidney. She was previously in good health and was diagnosed with pulmonary sarcoidosis during her preoperative examination. Because she presented with no symptoms and was otherwise in good condition, donor nephrectomy was performed. RESULTS: Baseline biopsy examination showed no evidence of sarcoidosis. One year after transplantation, both the donor and the recipient had not developed kidney dysfunction or recurrence of sarcoidosis. CONCLUSION: This is a rare case in which a patient with pulmonary sarcoidosis donated a kidney for transplantation, and both the recipient and the donor were clinically healthy. A patient with sarcoidosis and no kidney lesion can donate a living kidney, because transplantation appears to be safe for both the recipient and the donor.

Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results. METHODS: Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival. RESULTS: Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed. CONCLUSIONS: Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.

Clinicopathologic Impact of Early Medullary Ray Injury in Patients Following Kidney Transplantation.

BACKGROUND: Previously, we explored the histopathologic characteristics of medullary ray injury (MRI) inducing interstitial fibrosis and tubular atrophy (IF/TA) to determine its etiologies, which include calcineurin inhibitor (CNI) toxicity and urologic complications. However, we did not examine the effects of these etiologies on long-term kidney allograft prognosis, because biopsy timing differed among cases. AIM: We examined the influence of early MRI on kidney allograft prognosis using protocol biopsies taken within a 3-month time frame. METHODS: We defined early MRI as tubular degeneration with interstitial edema or mild fibrosis localized to the medullary ray. We divided 53 protocol biopsies into 2 groups, with and without early MRI. Early MRI+ cases with isometric vacuolization were classified as CNI toxicity; those with Tamm-Horsfall protein in the interstitium and a thyroidlike appearance were classified as urinary tract system abnormalities; remaining cases were classified as "others." We compared changes in serum levels of creatinine (sCr) over 3 years and fibrosis extent at 1 year. RESULTS: The sCr levels were significantly higher in the MRI+ group than the MRI- group at 3 years (P = .024). Examining the 3 MRI+ subgroups, only the MRI+ urinary tract system abnormalities group had significantly high sCr levels compared to the MRI- group (P = .019). The MRI+ group showed significant signs of IF/TA at 1 year. CONCLUSIONS: Early MRI after kidney transplantation was significantly more likely to develop IF/TA at 1 year and had higher sCr levels at 3 years. In such cases, intervention might preserve graft function over the long term.

Utility of the Japanese Glomerular Filtration Rate Equation in Estimating Glomerular Filtration Rate of Donor Kidney.

BACKGROUND: An equation for the estimated glomerular filtration rate (eGFR) is generally used for evaluating renal function in Japan. OBJECTIVE: To assess the accuracy of the preoperative eGFR for estimating kidney donors' measured glomerular filtration rate (mGFR). METHODS: Between April 2009 and August 2014, 91 Japanese living kidney donors were included in this study. The eGFR was calculated as follows: eGFR = 194 × serum creatinine(-1.094) × Age(-0.287) (and × 0.739 for women), and the mGFR was evaluated using inulin clearance. The preoperative eGFR was then compared with the mGFR. RESULTS: Patients included 27 men and 64 women with a mean age of 56.8 ± 9.5 years (range, 36-79 years), mean body surface area of 1.56 ± 0.14 m(2) (range 1.27-1.92 m(2)), mean body mass index of 22.3 ± 2.3 kg/m(2) (range 14.0-27.0 kg/m(2)), and mean serum creatinine level of 0.66 ± 0.14 mg/dL (range 0.39-0.97 mg/dL). The mean eGFR was 81.3 ± 14.2 mL/min/1.73 m(2) (range 45.5-125.9 mL/min/1.73 m(2)), and the mean mGFR was 89.0 ± 15.5 mL/min/1.73 m(2) (range 45.4-130.7 mL/min/1.73 m(2)). The eGFR was significantly lower than the mGFR (P < .001). The correlation coefficient for the relationship between the eGFR and mGFR values was 0.503, and the mean difference between the 2 values was -7.8 (8.7%). CONCLUSIONS: Although the eGFR correlated with the mGFR, the eGFR values did not accurately estimate the mGFR in living kidney donors. Therefore, it is necessary to evaluate the mGFR, especially in marginal kidney donors.

Robot-Assisted Radical Prostatectomy for Localized Prostate Cancer in Asian Renal Transplant Recipients.

BACKGROUND: The purpose of this study was to present our experience with robot-assisted radical prostatectomy (RARP) for localized prostate cancer in renal transplant recipients (RTRs) and to determine the feasibility and efficacy of RARP in these patients. METHODS: We retrospectively reviewed the medical records of 236 patients who underwent RARP for localized prostate cancer at our institution between August 2011 and July 2015 and identified 3 patients who were RTRs. We reviewed the available clinical data of the 3 patients. RESULTS: All patients underwent RARP successfully without any major complications. The mean operation time was 162 minutes (range, 127-195 minutes). The mean estimated blood loss was 52 mL (range, 30-75 mL); therefore, the patients did not need any perioperative blood transfusion. In all cases, graft function, as determined according to the serum creatinine level, was stable during and after the operation. Pathological examination showed negative surgical margins with organ-confined disease in all patients. CONCLUSIONS: We reported 3 RTRs with localized prostate cancer who were treated with RARP. RARP might be a feasible and effective minimally invasive technique for the treatment of localized prostate cancer in carefully selected RTRs.

Efficacy and Feasibility of Low-Dose Rate Brachytherapy for Prostate Cancer in Renal Transplant Recipients.

BACKGROUND: In young patients with localized prostate cancer, radical prostatectomy is the treatment of choice in the general population. Radiotherapy, such as low-dose rate (LDR) brachytherapy or intensity-modulated radiotherapy, is a viable alternative as well. However, in transplant patients, irradiation is not proposed as often as it is in healthy adults because of the risk of post-radiation ureteral stenosis and gastrointestinal toxicity as the result of fragile tissue. The objective of the study was to assess the efficacy and feasibility of LDR brachytherapy for prostate cancer in renal transplant recipients (RTRs). METHODS: Between May 2007 and December 2014, all patients who had undergone LDR brachytherapy for clinically localized prostate cancer at our institution were retrospectively identified (n = 203). Of these patients, 2 had a history of renal transplantation. We reviewed all available clinical data retrospectively. One patient had a functioning graft and the other had re-started hemodialysis 7 years after the transplantation. RESULTS: The mean time from renal transplantation to prostate cancer diagnosis was 16 years. The mean follow-up after seed implantation was 45 months. There were no peri-operative complications after seed implantation. The 2 patients remained free of prostate-specific antigen progression during the follow-up period. The renal function of the patient with a functioning graft, as measured by serum creatinine, was stable during and after the operation. CONCLUSIONS: LDR brachytherapy is technically feasible and acceptable as a minimally invasive treatment in carefully selected RTRs with localized prostate cancer. This treatment should be considered a suitable option for RTRs with localized prostate cancer.

Efficacy and Feasibility of Intensity-Modulated Radiation Therapy for Prostate Cancer in Renal Transplant Recipients.

BACKGROUND: In transplant patients with localized prostate cancer, irradiation is not proposed as often as it is in healthy adults because of the post-radiation risks, such as ureteral stenosis and gastrointestinal toxicity as the result of fragile tissue. The objective of the study was to analyze the efficacy and feasibility of intensity-modulated radiation therapy (IMRT) for prostate cancer in renal transplant recipients (RTRs). METHODS: Between May 2005 and December 2014, all patients who had undergone IMRT for clinically localized prostate cancer at our institution were retrospectively identified (n = 365). Of these patients, 2 had a history of renal transplantation. We reviewed all available clinical data. One patient had a functioning graft and the other had restarted hemodialysis 7 years after the transplantation. RESULTS: The mean time from renal transplantation to prostate cancer diagnosis was 11 years. The mean follow-up after irradiation was 43 months. The 2 patients remain free of prostate-specific antigen progression. There was no severe acute and chronic genitourinary and gastrointestinal toxicity. Renal function of the patient with a functioning graft as measured by serum creatinine was stable during and after the irradiation. CONCLUSIONS: IMRT is feasible and acceptable as a minimally invasive treatment in the carefully selected RTRs with localized prostate cancer. This treatment should be considered a good option for RTRs with localized prostate cancer.

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells.

Recently, the immune-regulating potential of invariant natural killer T (iNKT) cells has attracted considerable attention. We previously reported that a combination treatment with a liposomal ligand for iNKT cells and an anti-CD154 antibody in a sublethally irradiated murine bone marrow transplant (BMT) model resulted in the establishment of mixed hematopoietic chimerism through in vivo expansion of regulatory T cells (Tregs). Herein, we show the lack of alloreactivity of CD8(+) T cells in chimeras and an early expansion of donor-derived dendritic cells (DCs) in the recipient thymi accompanied by a sequential reduction in the donor-reactive Vß-T cell receptor repertoire, suggesting a contribution of clonal deletion in this model. Since thymic expansion of donor DCs and the reduction in the donor-reactive T cell repertoire were precluded with Treg depletion, we presumed that Tregs should preform before the establishment of clonal deletion. In contrast, the mice thymectomized before BMT failed to increase the number of Tregs and to establish CD8(+) T cell tolerance, suggesting the presence of mutual dependence between the thymic donor-DCs and Tregs. These results provide new insights into the regulatory mechanisms that actively promote clonal deletion.

Plasma Cell-Rich Rejection After Kidney Transplantation and the Role of Donor-Specific Antibodies: A Case Report and Review of the Literature.

OBJECTIVE: We report a case of the clinical course and pathologic findings for a kidney transplant recipient with plasma cell-rich rejection (PCRR) accompanied by antibody-mediated rejection (ABMR). METHODS: A 29-year-old man with end-stage renal disease caused by lupus nephritis received an ABO-compatible living kidney transplant. RESULTS: Eighteen months after transplantation, the patient presented with proteinuria and increased serum creatinine. An episode biopsy revealed severe tubulointerstitial infiltration with plasma cells accompanied by peritubular capillaritis and positive findings on immunofluorescent C4d staining. Donor-specific antibodies were positive for DR52, and the patient was subsequently diagnosed with PCRR accompanied by ABMR. Treatment was initiated with high-dose steroids, intravenous immunoglobulin, gusperimus hydrochloride, muronmonab antibody CD3, and rituximab. However, ABMR persisted and allograft failure developed 20 months after onset. CONCLUSIONS: We argue that PCRR accompanied by ABMR is a subtype of PCRR that can progress to allograft failure owing to persistent ABMR.

HSV-1 as a novel therapy for breast cancer meningeal metastases.

Meningeal metastasis is a fatal complication of breast cancer that affects 5-8% of patients. When cancer cells seed in the meninges, their subsequent growth results in severe neurological complications involving the cranial nerves, cerebrum and spinal cord, limiting life expectancy to less than 4 months. The incidences of meningeal metastases increase with prolonged lifespan resulting from treatment advances for primary breast cancer and their metastases. Currently, there is no cure. Aggressive multimodal therapies such as radiation and chemotherapy (intra-cerebrospinal fluid (CSF) and systemic) are ineffective. Therapeutic agents are often quickly cleared from the CSF, while higher doses that can achieve a therapeutic response are highly toxic. The secure guarding of the subarachnoid space by the blood-brain barrier on one side and the blood-CSF barrier on the other prevents chemotherapy from reaching cancer cells in the meninges. These challenges with treating meningeal metastases highlight the urgent need for a new therapeutic modality. An ideal treatment would be an agent that avoids rapid clearance, remains within the CSF, reaches the meninges and selectively destroys tumor cells. Replication conditional oncolytic herpes simplex virus type 1 (HSV-1) may be effective in this regard. Viral oncolysis, the destruction of cancer cells by replicating virus, is under clinical investigation for cancers that are unresponsive to current therapies. It is based on the model of multiple cycles of lytic virus replication in cancer cells that amplify the injected dose. The therapeutic potential of oncolytic HSV-1 for breast cancer meningeal metastases is discussed here. HSV-1 could be a potential novel treatment for meningeal metastases that can be translated to the clinic.

Phase II/III study of second-line chemotherapy comparing irinotecan-alone with S-1 plus irinotecan in advanced gastric cancer refractory to first-line treatment with S-1 (JACCRO GC-05).

BACKGROUND: In Japan, S-1 plus cisplatin has been used as first-line therapy for advanced gastric cancer (AGC). Patients with no response to first-line treatment with S-1 often receive a taxane-alone or irinotecan-alone as second-line treatment. However, second-line treatment with S-1 plus irinotecan is widely used in patients with AGC resistant to first-line S-1-based chemotherapy. The goal of this trial was to determine whether the consecutive use of S-1 plus irinotecan improves survival when compared with irinotecan-alone as second-line treatment for AGC. PATIENTS AND METHODS: Patients who had disease progression during first-line S-1-based chemotherapy were randomly assigned to receive S-1 plus irinotecan or irinotecan-alone. The S-1 plus irinotecan group received oral S-1 (40-60 mg/m(2)) on days 1-14 and intravenous irinotecan (150 mg/m(2)) on day 1 of a 21-day cycle. The irinotecan-alone group received the same dose of irinotecan intravenously on day 1 of a 14-day cycle. The primary end point was overall survival (OS). RESULTS: From February 2008 to May 2011, a total of 304 patients were enrolled. The median OS was 8.8 months in the S-1 plus irinotecan group and 9.5 months in the irinotecan-alone group. This difference was not significant (hazard ratio for death, 0.99; 95% confidence interval 0.78-1.25; P = 0.92). Grade 3 or higher toxicities were more common in the S-1 plus irinotecan group than in the irinotecan-alone group. CONCLUSION: The consecutive use of S-1 plus irinotecan is not recommended as second-line treatment in patients who are refractory to S-1-based first-line chemotherapy. ClinicalTrials.gov ID: NCT00639327.

A novel approach inducing transplant tolerance by activated invariant natural killer T cells with costimulatory blockade.

Invariant natural killer T (iNKT) cells are one of the innate lymphocytes that regulate immunity, although it is still elusive how iNKT cells should be manipulated for transplant tolerance. Here, we describe the potential of a novel approach using a ligand for iNKT cells and suboptimal dosage of antibody for CD40-CD40 ligand (L) blockade as a powerful method for mixed chimerism establishment after allogenic bone marrow transplantation in sublethally irradiated fully allo recipients. Mixed-chimera mice accepted subsequent cardiac allografts in a donor-specific manner. High amounts of type 2 helper T cytokines were detected right after iNKT cell activation, while subsequent interferon-gamma production by NK cells was effectively inhibited by CD40/CD40L blockade. Tolerogenic components, such as CD11c(low) mPDCA1(+) plasmacytoid dendritic cells and activated regulatory T cells (Tregs) expressing CD103, KLRG-1 and PD-1, were subsequently augmented. Those activating Tregs seem to be required for the establishment of chimerism because depletion of the Tregs 1 day before allogenic cell transfer resulted in a chimerism brake. These results collectively suggest that our new protocol makes it possible to induce donor-specific tolerance by enhancement of the innate ability for immune tolerance in place of the conventional immunosuppression.

Comparison of melanoma guidelines in the U.S.A., Canada, Europe, Australia and New Zealand: a critical appraisal and comprehensive review.

There are several well-established guidelines for the staging of melanoma and the size of excisional margins, along with recommendations for sentinel lymph node biopsy. Guidelines have been proposed in the U.S.A. (National Comprehensive Cancer Network), Canada (Cancer Care Ontario and Canadian Medical Association), Europe (European Society for Medical Oncology) and Australia and New Zealand (Australian Cancer Network). The guidelines set by these groups are largely based on current evidence, or expert panel consensus where evidence is lacking. The recommendations are more controversial and varying where there is a lack of level-one evidence in the literature (e.g. screening, adjuvant therapy, follow-up intensity). We review the evidence and available literature for the management of melanoma worldwide.