Association between the Absolute Baseline Lymphocyte Count and Response to Neoadjuvant Platinum-based Chemotherapy in Muscle-invasive Bladder Cancer.

AIMS: Platinum-based neoadjuvant chemotherapy (NAC) improves overall survival in muscle-invasive bladder cancer (MIBC). A pathological complete response (pCR) at radical cystectomy after NAC is associated with better overall survival, but there are no established predictive biomarkers of response to NAC in MIBC. The aim of this study was to find laboratory variables associated with pCR following NAC. MATERIALS AND METHODS: We carried out a retrospective review of MIBC patients treated with NAC followed by radical cystectomy at the Sheba Medical Center between 2005 and 2015. Overall survival was calculated using the Kaplan-Meier product-limit method and compared between patients who achieved or did not achieve pCR using the Log-rank test. Baseline and pre-surgery laboratory values were collected and compared between patients who subsequently achieved pCR and those who did not using logistic regression. RESULTS: Fifty-eight patients underwent radical cystectomy after NAC, with a median follow-up of 32 (range 4.8-111.4) months from diagnosis. Of 55 patients with documented pathological outcome on radical cystectomy, 17 (31%) achieved pCR (complete responders). Of the 15 complete responders with follow-up data, 13 (87%) were still alive at time of last follow-up for this study (July 2015). Patients who did not achieve pCR had a significantly worse overall survival than complete responders (P = 0.0007). The baseline lymphocyte count, neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were significantly associated with response (P = 0.037, P = 0.045, P = 0.042, respectively) on univariate analysis, whereas baseline albumin, haemoglobin, neutrophils, platelets and the total white blood count were not significantly associated with response. Lymphocyte counts were significantly higher in responders than non-responders throughout three time points (P = 0.003 using a generalised linear mixed model). CONCLUSIONS: A high baseline level of lymphocytes is associated with the achievement of pCR at radical cystectomy after NAC, which, in turn, is associated with a significantly longer overall survival. Our results suggest that chemosensitivity in MIBC is associated with lymphocyte count.

The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

BACKGROUND: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT-drug development programmes before patent expiration. METHODS: We identified novel drug-radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time. RESULTS: The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001). CONCLUSIONS: Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug-RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes.

Assessing the quality of conformal treatment planning: a new tool for quantitative comparison.

We develop a novel radiotherapy plan comparison index, critical organ scoring index (COSI), which is a measure of both target coverage and critical organ overdose. COSI is defined as COSI=1-(V(OAR)>tol/TC), where V(OAR)>tol is the fraction of volume of organ at risk receiving more than tolerance dose, and TC is the target coverage, VT,PI/VT, where VT,PI is the target volume receiving at a least prescription dose and VT is the total target volume. COSI approaches unity when the critical structure is completely spared and the target coverage is unity. We propose a two-dimensional, graphical representation of COSI versus conformity index (CI), where CI is a measure of a normal tissue overdose. We show that this 2D representation is a reliable, visual quantitative tool for evaluating competing plans. We generate COSI-CI plots for three sites: head and neck, cavernous sinus, and pancreas, and evaluate competing non-coplanar 3D and IMRT treatment plans. For all three sites this novel 2D representation assisted the physician in choosing the optimal plan, both in terms of target coverage and in terms of critical organ sparing. We verified each choice by analysing individual DVHs and isodose lines. Comparing our results to the widely used conformation number, we found that in all cases where there were discrepancies in the choice of the best treatment plan, the COSI-CI choice was considered the correct one, in several cases indicating that a non-coplanar 3D plan was superior to the IMRT plans. The choice of plan was quick, simple and accurate using the new graphical representation.

The potential of 5-fluorocytosine/cytosine deaminase enzyme prodrug gene therapy in an intrahepatic colon cancer model.

Colorectal cancer can metastasize to the liver, but remain liver confined for years. A critical step in developing treatments for intrahepatic cancer involves assessment in an orthotopic intrahepatic model. The purpose of this study was to develop a noninvasive intrahepatic tumor model to study the efficacy of 5-flucytosine/yeast cytosine deaminase (5FC/yCD)-based gene therapy for liver tumors. Luciferase expressing human colorectal carcinoma (HT-29luc) cells were generated by retroviral infection and implanted in the left liver lobe of nude mice. The bioluminescence was measured every week for a period of 1 month, then animals were killed and tumors were measured by calipers. After we found a correlation between photon counts and tumor size, animals were implanted with tumors composed of either 0%, 10%, or 100% yCD/HT-29luc cells, and treated with 5FC. Tumor bioluminescence was measured during treatment and tumor histology examined at the time of death. We found that 5FC caused significant regression of yCD expressing tumors. Furthermore, visible tumors at the time of death, which emitted little bioluminescence, contained little or no viable tumor. We then developed an adenoviral vector for yCD. Intraperitoneal administration of adenovirus containing yCD led to the production of yCD enzyme within intrahepatic tumors. These results suggest that (1) intrahepatic cancer responds to 5FC when cells express yCD; (2) the luciferin-luciferase system permits non-invasive real time imaging of viable intrahepatic cancer; and (3) this system can be used to carry out gene therapy experiments using yCD adenovirus.

Selective radioprotection of hepatocytes by systemic and portal vein infusions of amifostine in a rat liver tumor model.

PURPOSE: The tolerance of the liver to radiation is too low to permit an effective dose to be delivered to patients who have diffuse intrahepatic cancer. In this study we evaluated whether systemic or portal venous administration of the aminothiol compound, amifostine, could protect the normal liver from the effects of ionizing radiation without compromising tumor cell kill in a rat liver tumor model. METHODS AND MATERIALS: Rats implanted with liver tumors were infused with 200 mg/kg amifostine over 15 min via the femoral or portal vein. The livers were irradiated with a single 6-Gy fraction 15-20 min after the termination of amifostine infusion. Protection of the liver was assessed by an in vitro hepatocyte micronucleus assay and tumor protection by an in vivo-in vitro clonogenic survival assay. Tissue levels of the active metabolite, free WR-1065, were determined in the tumor and in the normal liver using a specific HPLC assay with electrochemical detection. RESULTS: After a 6-Gy fraction, the frequency of hepatocyte micronuclei after administration of saline, systemic amifostine, and portal venous amifostine was 18.7+/-1%, 6.8+/-1%, and 9.9+/-2%, respectively, corresponding to a radiation equivalent effect of 6 Gy +/- 0.5, 1.8 Gy +/- 0.3, and 2.5 Gy +/- 1.3, respectively. Both amifostine conditions showed considerably less radiation effect than saline-treated controls (p < 0.01); the two amifostine conditions did not differ (p = 0.3). The surviving fraction of tumor cells was not affected by amifostine treatment and was 0.03+/-0.02 and 0.05+/-0.03 for systemic and portal venous delivery and 0.06+/-0.02 for control animals (ANOVA analysis showed no significant difference of the means p = 0.34). Portal venous delivery produced significantly less WR-1065 in the tumor compared to systemic administration (54 microM +/- 36 vs. 343 microM +/- 88, respectively, p = 0.03). CONCLUSIONS: Both systemic and portal venous administration of amifostine effectively protect hepatocytes from ionizing radiation without compromising tumor cell kill in a clinically relevant animal model. These findings suggest that amifostine may be a selective normal tissue radioprotectant in liver cancer and that regional/portal infusions may be preferable to systemic dosing.

Selective delivery of doxorubicin to patients with breast carcinoma metastases by stealth liposomes.

BACKGROUND: Stealth liposomes hold promise as a mode of delivering cytotoxic agents selectively to tumors in cancer patients. The objective of this study was to determine whether stealth liposomal doxorubicin accumulates selectively in bone metastases based on clinical material obtained from two patients with breast carcinoma. METHODS: Tumor tissue was obtained from two women (ages 33 years and 41 years, respectively) with metastatic breast carcinoma who responded to treatment with stealth liposomal doxorubicin and later underwent a surgical fixation procedure to treat a pathologic fracture of the femur. Drug levels in the tumor and adjacent muscle were examined by high performance liquid chromatography analysis in both patients and by fluorescence microscopy in one of the patients. RESULTS: Bone tumor fragments obtained during surgery performed 6 days after the administration of the 12th course of stealth liposomal doxorubicin in 1 patient and 12 days after the administration of the 16th course of stealth liposomal doxorubicin in the second patient had a 10-fold greater concentration of liposomal doxorubicin than tumor free muscle. Doxorubicin fluorescence and specific nuclear staining showed good colocalization, thus confirming the presence of the liposome-delivered drug in the nuclei of tumor cells. CONCLUSIONS: Using skeletal muscle as a comparator, stealth liposomal doxorubicin accumulates selectively in metastatic breast carcinoma cells within bone.

The endogenous insulin-like growth factor system in radiocontrast nephropathy.

The response of insulin-like growth factor (IGF) I in acute renal failure was evaluated in a model of radiocontrast nephropathy associated with selective necrosis of medullary thick ascending limbs. In brief, rats were administered radiocontrast medium or vehicle injections for controls after combined inhibition of prostanoids and nitric oxide. Twenty-four hours after the insult, tissue mRNAs for IGF-I, the IGF-I receptor, and IGF-binding proteins (IGFBP) 1 and 3 were assayed in cortex, medulla, and liver by solution hybridization-RNase protection assay, and IGFBPs were measured in serum and tissue by Western ligand blotting. Cortical IGF-1 increased, whereas medullary IGF-I mRNA decreased. Renal IGFBPs decreased, whereas IGFBP-1 mRNA increased. The IGF system in the liver was unchanged. We conclude that general changes in renal IGFBPs in this experimental model of acute renal failure might increase the level of cortical IGF-I in a way that could modulate medullary recovery.

[Cyclosporin for severe ulcerative colitis].

In recent years there have been numerous reports of successful treatment of resistant ulcerative colitis with cyclosporin. A series of 9 patients with moderate to severe active ulcerative colitis was treated with cyclosporin between September 1993 and October 1994. All 9 had failed to respond to conventional therapy, including salazopyrine and intravenous corticosteroids. They underwent colonoscopy and after contraindications to therapy were ruled out, received intravenous cyclosporin, 4 mg/kg/day for 7-10 days. They were discharged on oral cyclosporin with average serum levels maintained at 200 ng/ml. Response was assessed using the clinical score system of Schroeder et al. 2 out of 9 patients (22%) responded with full clinical remissions lasting more than 6 months. 6 patients had partial responses to the intravenous therapy, but symptoms resumed shortly after its cessation. Factors predicting favorable response to cyclosporin therapy were a shorter duration of disease with a fulminant clinical course. The success rate was less than that reported in the literature, possibly because of comparatively low serum cyclosporin levels. Potential complications of therapy and high cost preclude the routine use of cyclosporin in ulcerative colitis. Larger controlled studies are required to assess its efficacy and safety. Until such studies are available, cyclosporin may be tried in poor surgical risks or those not yet ready psychologically for total colectomy.

Sacral herpes-zoster infection presenting as sciatic pain.

Acute herpes-zoster infection is a painful dermatomal lesion that can be manifested by a wide array of neurologic symptoms. We present a 55-year-old female with non-Hodgkin's lymphoma, who developed a left sciatic pain involving the S roots. Two weeks later, the patient developed fever and vesicular rash over the left gluteal area. Herpes-zoster infection was diagnosed and confirmed by the presence of immunoglobulin M (IgM) antibodies against varicella-zoster. The pain and rash resolved, after treatment with acyclovir. In the appropriate clinical setting, sacral herpes-zoster infection ought to be considered in the differential diagnosis of new-onset sciatic pain.

Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys.

Extensive DNA fragmentation, a marker for programmed cell death, was selectively and rapidly induced by hypoxia in the thick ascending limbs of rat kidneys. In isolated perfused kidneys, DNA breaks were present in medullary tubules as early as after 10 minutes of local hypoxia and were prevented by reduction of metabolic work. In a model of radiocontrast-induced acute renal failure, DNA breaks were detected selectively along thick ascending limbs as early as 15 minutes following insult, preceding overt morphological damage. Hypoxia induces rapid DNA fragmentation along thick ascending limbs, where programmed cell death could play an important role in nephron injury and kidney failure.