Case Report: Thrombotic-Thrombocytopenic Purpura Following Ipilimumab and Nivolumab Combination Immunotherapy for Metastatic Melanoma.

A man in his early 50s presented with small bowel obstruction, requiring emergency laparoscopic small bowel resection for the metastatic melanoma of the jejunum with no identifiable primary lesion. One week after his first treatment with ipilimumab and nivolumab, he presented with diffuse abdominal pain, constipation, and fatigue. A computerized tomography scan did not identify a cause for his symptoms. This was rapidly followed by thrombocytopenia on day 11 and then anemia. He commenced intravenous corticosteroids for a suspected diagnosis of immune-related thrombocytopenia. On day 15, a generalized onset motor seizure occurred, and despite plasmapheresis later that day, the patient died from fatal immune-related thrombotic thrombocytopenic purpura (TTP). This was confirmed with suppressed ADAMTS13 (<5%) testing on day 14. Immune-related TTP is a rare and, in this case, fatal immune- related adverse event. Further studies are required to identify additional immunosuppressive management for immune-related TTP.

Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer.

OBJECTIVE: The AGO-OVAR16 study was designed to test the efficacy, safety, and tolerability of pazopanib maintenance after first-line chemotherapy in patients with newly diagnosed advanced ovarian cancer (AOC). METHODS: Nine hundred and forty patients with histologically confirmed AOC, International Federation of Gynecology and Obstetrics (FIGO) stage II-IV, were randomized in a 1:1 ratio to receive either 800 mg pazopanib once daily or placebo for up to 24 months, unless there was disease progression, toxicity, withdrawal of consent, or death. The primary endpoint (investigator-assessed progression-free survival [PFS]) was met and previously reported. The results of final analyses of overall survival (OS) are reported here. RESULTS: A third OS interim analysis showed futility and led to study closure and a final OS analysis after last patient last visit. At the time of the final OS analysis, 494 (89.7% of the planned 551) events had occurred. No difference was observed in OS between pazopanib and placebo. The hazard ratio (HR) was 0.960 (95% confidence interval [CI]: 0.805-1.145), and the median OS from randomization was 59.1 months in pazopanib and 64.0 months in placebo arms. For the East Asian patients, similar to the first three interim OS analyses, a numerical negative trend was observed favoring placebo (HR, 1.332; 95% CI: 0.863-2.054). Exploratory analyses showed a trend for a longer time to first subsequent anti-cancer therapy or death with pazopanib over placebo (HR, 0.829; 95% CI: 0.713-0.965), with a median estimate of 19.0 and 14.5 months, respectively. No new safety signals were observed. CONCLUSION: Although pazopanib prolonged PFS, this was not associated with improvement in median OS. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov: NCT00866697.

Quality of life in patients with advanced epithelial ovarian cancer (EOC) randomized to maintenance pazopanib or placebo after first-line chemotherapy in the AGO-OVAR 16 trial. Measuring what matters-patient-centered end points in trials of maintenance therapy.

Background: Health-related quality of life (HRQoL) was a secondary end point in AGO-OVAR 16, which randomized 940 patients with EOC after first-line chemotherapy to maintenance pazopanib (PZ) or placebo (P). Additional post hoc analyses were carried out to investigate additional patient-centered end points. Patients and methods: HRQoL was measured with EORTC-QLQ-C30, QLQ-OV28 and EQ-5D-3L. Pre-specified end points included mean differences in HRQoL between treatment arms. Exploratory analyses included quality-adjusted progression-free survival (QAPFS), impact of specific symptoms and progressive disease (PD) on HRQoL and time to second-line chemotherapy. The objective was to provide clinical perspective to the significant median PFS gain of 5.6 months with PZ. Results: There were statistically significant differences between PZ and P in QLQ-C30 global health status [5.5 points; 95% confidence interval (CI), 0.7-10.4, P = 0.024] from baseline to 25 months, but not EQ-5D-3L (0.018 points; 95% CI - 0.033 to 0.069, P = 0.485). The impact of diarrhea was captured in QLQ-OV28 Abdominal/GI-Symptoms scale (8.1 points; 95% CI 3.6-12.5, P = 0.001). QAPFS was 386 days (95% CI 366-404 days) with PZ versus 359 days (95% CI 338-379 days) with placebo (P = 0.052). PD was associated with a decline in HRQoL (P < 0.0001). Median time to second-line chemotherapy was 19.7 months with PZ and 15.0 months with P [hazard ratio (HR) 0.72, 95% CI 0.69-0.86, P = 0.0001]. Conclusions: There were small to no significant mean score differences in global HRQoL and EQ5D-3L between PZ and placebo, respectively, despite the increased toxicity of PZ. Exploratory end points including QAPFS, impact of specific symptoms on HRQoL during treatment and at PD help place the PFS gain with PZ in context and interpret the results. Additional patient-centered end points should be considered in trials of maintenance therapy in EOC beyond mean differences in HRQoL scores alone, to support the benefit to patients of prolongation of PFS. Clinical Trials Registration Number: NCT00866697.

Prophylactic cranial irradiation in small cell lung cancer: a single institution experience.

BACKGROUND: Prophylactic cranial irradiation (PCI) is used to prevent the development of brain metastases in small cell lung carcinoma. PCI confers an overall survival (OS) benefit in both limited and extensive stage disease. AIMS: We analyze the incidence of symptomatic brain metastases, progression-free survival (PFS) and OS in a cohort of patients who received PCI, in a 5-year period. METHODS: A retrospective review of all patients who had received PCI between 2006 and 2011 at the Whitfield Clinic was completed. Patient- and disease-related characteristics, the number of patients who developed brain metastases, PFS and OS data were collected. RESULTS: 24 patients were identified. 14 (58.3 %) patients were male, 10 (41.7 %) were female, with a mean age of 62.5 years (range 31-78). All patients were smokers. 12 (50 %) patients had limited stage small cell lung cancer (SCLC), 12 (50 %) had extensive stage disease. 2 (8.2 %) patients developed brain metastases post PCI (p = 0.478.) The median PFS for limited stage SCLC was 13 months (range 3-20) and 10 months (range 5-18) for extensive stage SCLC. Median OS was 15 months (range 4-29) in limited stage SCLC, and 11 months (range 5-29) in extensive stage SCLC. CONCLUSIONS: Our study demonstrated a low incidence of symptomatic brain metastases and favourable median PFS and OS in the patients that received PCI, when compared to published phase III data.

An Irish breast cancer survivorship study: are we meeting our patients' needs?

UNLABELLED: Irish breast cancer survivor's needs have not been studied. Physical, psychological, social and spiritual concerns were investigated. Patient satisfaction with hospital discharge, GP follow-up, and the benefit of a discharge pack was investigated. A cohort of patients from the South East Cancer Centre was identified. INCLUSION CRITERIA: localized breast cancer, completion of adjuvant therapy, GP-led follow-up in the last 5 years. An anonymous questionnaire was developed, and ethical approval obtained. Subgroup analyses for age and time since diagnosis and discharge were completed. 80 patients were identified. 44 patients (55%) completed the questionnaire, 5 (6%) were excluded. Commonest concerns included: fatigue (51%), fear of recurrence (69%) and second cancers concerns (69%) 23 (59%) and 25 patients (64%) were satisfied with discharge and GP follow-up respectively. 27 patients (67%) reported benefit from a discharge pack. Irish breast cancer survivors had concerns, and were satisfied with GP follow-up.

Trabecular scaffolds created using micro CT guided fused deposition modeling.

Free form fabrication and high resolution imaging techniques enable the creation of biomimetic tissue engineering scaffolds. A 3D CAD model of canine trabecular bone was produced via micro CT and exported to a fused deposition modeler, to produce polybutylene terephthalate (PBT) trabeculated scaffolds and four other scaffold groups of varying pore structures. The five scaffold groups were divided into subgroups (n=6) and compression tested at two load rates (49 N/s and 294 N/s). Two groups were soaked in a 25 °C saline solution for 7 days before compression testing. Micro CT was used to compare porosity, connectivity density, and trabecular separation of each scaffold type to a canine trabecular bone sample. At 49 N/s the dry trabecular scaffolds had a compressive stiffness of 4.94±1.19 MPa, similar to the simple linear small pore scaffolds and significantly more stiff (p<0.05) than either of the complex interconnected pore scaffolds. At 294 N/s, the compressive stiffness values for all five groups roughly doubled. Soaking in saline had an insignificant effect on stiffness. The trabecular scaffolds matched bone samples in porosity; however, achieving physiologic connectivity density and trabecular separation will require further refining of scaffold processing.

Fluorescence relaxation in 3D from diffraction-limited sources of PAGFP or sinks of EGFP created by multiphoton photoconversion.

The relaxation of fluorescence from diffraction-limited sources of photoactivatable green fluorescent protein (PAGFP) or sinks of photobleached enhanced GFP (EGFP) created by multiphoton photo-conversion was measured in solutions of varied viscosity (eta), and in live, spherical Chinese hamster ovary (CHO) cells. Fluorescence relaxation was monitored with the probing laser fixed, or rapidly scanning along a line bisected by the photoconversion site. Novel solutions to several problems that hamper the study of PAGFP diffusion after multiphoton photoconversion are presented. A theoretical model of 3D diffusion in a sphere from a source in the shape of the measured multiphoton point-spread function was applied to the fluorescence data to estimate the apparent diffusion coefficient, D(ap). The model incorporates two novel features that make it of broad utility. First, the model includes the no-flux boundary condition imposed by cell plasma membranes, allowing assessment of potential impact of this boundary on estimates of D(ap). Second, the model uses an inhomogeneous source term that, for the first time, allows analysis of diffusion from sources produced by multiphoton photoconversion pulses of varying duration. For diffusion in aqueous solution, indistinguishable linear relationships between D(ap) and eta(-1) were obtained for the two proteins: for PAGFP, D(aq)= 89 +/- 2.4 microm2 s(-1) (mean +/- 95% confidence interval), and for EGFP D(aq)= 91 +/- 1.8 microm2 s(-1). In CHO cells, the application of the model yielded D(ap)= 20 +/- 3 microm2 s(-1) (PAGFP) and 19 +/- 2 microm2 s(-1) (EGFP). Furthermore, the model quantitatively predicted the decline in baseline fluorescence that accompanied repeated photobleaching cycles in CHO cells expressing EGFP, supporting the hypothesis of fluorophore depletion as an alternative to the oft invoked 'bound fraction' explanation of the deviation of the terminal fluorescence recovery from its pre-bleach baseline level. Nonetheless for their identical diffusive properties, advantages of PAGFP over EGFP were found, including an intrinsically higher signal/noise ratio with 488-nm excitation, and the requirement for approximately 1/200th the cumulative light energy to produce data of comparable signal/noise.

Phase I study of temozolomide plus paclitaxel in patients with advanced malignant melanoma and associated in vitro investigations.

The purpose of this study was to determine activity of temozolomide combined with paclitaxel or epothilone B in vitro, and to investigate the combination of temozolomide with paclitaxel in a Phase I clinical trial. Melanoma cell lines A375P and DX3 were treated with temozolomide and either paclitaxel or epothilone B. Combination indices were determined to assess the degree of synergism. In a clinical study, 21 patients with malignant melanoma were treated with increasing doses of temozolomide (orally, days 1-5), in combination with a fixed dose of paclitaxel (i.v. infusion day 1), followed by dose escalation of the latter drug. Cycles of treatment were repeated every 3 weeks. Pharmacokinetics of both agents were determined on day 1, with temozolomide pharmacokinetics also assessed on day 5. All three compounds were active against the melanoma cell lines, with epothilone B being the most potent. There was a strong degree of synergism between temozolomide and either paclitaxel or epothilone B. In the clinical study, no pharmacokinetic interaction was observed between temozolomide and paclitaxel. Dose escalation of both drugs to clinically active doses was possible, with no dose-limiting toxicities observed at 200 mg m(-2) day(-1) temozolomide and 225 mg m(-2) day(-1) paclitaxel. There were two partial responses out of 15 evaluable patients. One patient remains alive and symptom-free at 4 years after treatment. Temozolomide and paclitaxel may be administered safely at clinically effective doses. Further evaluation of these combinations in melanoma is warranted.

Remineralization of demineralized albumin-calcium phosphate coatings.

Calcium phosphate and bovine serum albumin were coprecipitated (under physiological conditions of temperature and pH) upon the surfaces of titanium-alloy samples, which thereby became coated with a dense, proteinaceous mineral layer 30-50 microm in thickness. Dissolution of the inorganic phase by treatment with acidic saline yielded a self-supporting protein scaffold, 7-10 microm in thickness. Energy-dispersive X-ray analysis and Fourier-transform infrared spectroscopy confirmed the absence of inorganic components from the demineralized albumin scaffolds. When titanium-alloy samples bearing these demineralized protein scaffolds were immersed in a supersaturated solution of calcium phosphate (again at physiological temperature and pH), they remineralized. These redux albumin-calcium phosphate layers corresponded in thickness to the original coatings. When titanium-alloy discs bearing the demineralized protein scaffolds were implanted ectopically (subcutaneously) in mice, they, too, remineralized. No uniform mineral layer was deposited upon the surfaces of naked titanium-alloy implants. To the best of our knowledge, this is the first demonstration of remineralization within the interstices of a noncollagenous protein scaffold, either in vitro or in vivo.

Restrained rehabilitation: an approach to children and adolescents with unexplained signs and symptoms.

The validation of treatment approaches for children and adolescents diagnosed with unexplained signs and symptoms is made difficult by the variety of clinical presentations and the different developmental levels of different patients. There is little evidence about what combination of approaches is most successful. This article uses what evidence is available to develop a coordinated multidisciplinary rehabilitation package that ensures consistency and can be evaluated. The package is organised around a psychologically informed physical rehabilitation programme. The need for coordination and a common approach between medical, allied health and psychological staff, and family is formally addressed. The approach is illustrated with a case study.

Topotecan in combination with carboplatin: phase I trial evaluation of two treatment schedules.

BACKGROUND: Topotecan and cisplatin combinations have shown schedule-dependent toxicity, which may in part be due to cisplatin nephrotoxicity. As carboplatin is less nephrotoxic and increasingly replacing cisplatin in clinical practice, the aim of this study was to define the optimal sequence and dose for topotecan in combination with carboplatin. PATIENTS AND METHODS: Two parallel phase I trials, with pharmacokinetic studies, were conducted administering carboplatin on day 1 with topotecan on days 1-5 (schedule A) or days 8-12 (schedule B). repeated every 3 weeks. RESULTS: Twenty-one patients were treated over two dose levels, carboplatin AUC 4 [glomerular filtration rate (GFR) calculated from 51Cr-EDTA clearance] with topotecan 0.5 or 0.75 mg/m2. At the first dose level, six patients were evaluable for each schedule. With schedule A, from 34 cycles, there were two dose reductions and 10 treatment delays due to myelosuppression. With schedule B from 25 cycles, there was one reduction and 10 delays. At dose level 2, both patients in schedule A had dose-limiting neutropenia. In contrast, there was no dose-limiting toxicity with schedule B in six patients, although the majority of cycles were delayed. CONCLUSION: The combination of topotecan and carboplatin using these 3-weekly schedules lead to significant myelotoxicity with attendant dose reductions and delays; the optimal scheduling of these agents remains to be defined.

Constitutive "light" adaptation in rods from G90D rhodopsin: a mechanism for human congenital nightblindness without rod cell loss.

A dominant form of human congenital nightblindness is caused by a gly90-->asp (G90D) mutation in rhodopsin. G90D has been shown to activate the phototransduction cascade in the absence of light in vitro. Such constitutive activity of G90D rhodopsin in vivo would desensitize rod photoreceptors and lead to nightblindness. In contrast, other rhodopsin mutations typically give rise to nightblindness by causing rod cell death. Thus, the proposed desensitization without rod degeneration would be a novel mechanism for this disorder. To explore this possibility, we induced mice to express G90D opsin in their rods and then examined rod function and morphology, after first crossing the transgenic animals with rhodopsin knock-out mice to obtain appropriate levels of opsin expression. The G90D mouse opsin bound the chromophore and formed a bleachable visual pigment with lambda(max) of 492 nm that supported rod photoresponses. (G+/-, R+/-) retinas, heterozygous for both G90D and wild-type (WT) rhodopsin, possessed normal numbers of photoreceptors and had a normal rhodopsin complement but exhibited considerable loss of rod sensitivity as measured electroretinographically. The rod photoresponses were desensitized, and the response time to peak was faster than in (R+/-) animals. An equivalent desensitization resulted by exposing WT retinas to a background light producing 82 photoisomerizations rod(-1) sec(-1), suggesting that G90D rods in darkness act as if they are partially "light-adapted." Adding a second G90D allele gave (G+/+, R+/-) animals that exhibited a further increase of equivalent background light level but had no rod cell loss by 24 weeks of age. (G+/+, R-/-) retinas that express only the mutant rhodopsin develop normal rod outer segments and show minimal rod cell loss even at 1 year of age. We conclude that G90D is constitutively active in mouse rods in vivo but that it does not cause significant rod degeneration. Instead, G90D desensitizes rods by a process equivalent to light adaptation.

Membrane protein diffusion sets the speed of rod phototransduction.

Retinal rods signal the activation of a single receptor molecule by a photon. To ensure efficient photon capture, rods maintain about 109 copies of rhodopsin densely packed into membranous disks. But a high packing density of rhodopsin may impede other steps in phototransduction that take place on the disk membrane, by restricting the lateral movement of, and hence the rate of encounters between, the molecules involved. Although it has been suggested that lateral diffusion of proteins on the membrane sets the rate of onset of the photoresponse, it was later argued that the subsequent processing of the complexes was the main determinant of this rate. The effects of protein density on response shut-off have not been reported. Here we show that a roughly 50% reduction in protein crowding achieved by the hemizygous knockout of rhodopsin in transgenic mice accelerates the rising phases and recoveries of flash responses by about 1.7-fold in vivo. Thus, in rods the rates of both response onset and recovery are set by the diffusional encounter frequency between proteins on the disk membrane.

SCA-12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion.

OBJECTIVE: To characterize the clinical and neuroradiologic features of a new spinocerebellar ataxia, SCA-12, in the index family. BACKGROUND: The authors recently linked SCA-12 to a novel CAG repeat expansion on chromosome 5q31-33 that is located within the 5' region of PPP2R2B, a gene encoding a brain-specific regulatory subunit of protein phosphatase 2A. METHODS: Neurologic features of the proband and nine symptomatic relatives in the first SCA-12 family were compiled and, in some individuals, related to changes found on brain MRI or CT. RESULTS: SCA-12 typically presented in the 4th decade of life with action tremor of the head or arms (present in 10/10 of the affected individuals). Hyperreflexia (8/10) was a common feature, and cerebellar signs (8/10), including ataxia, dysmetria, and dysarthria, developed gradually but were less prominent and disabling than cerebellar dysfunction in other SCA. Subtle parkinsonian features (9/10) and dementia (2/10) were observed in later stages of SCA-12, and psychiatric symptoms, including depression, anxiety, or delusions, were present in some affected family members (4/10). Two individuals studied had nondisabling neurologic signs neonatally, including nystagmus and lower extremity dystonia. Brain images of affected individuals revealed cerebral and cerebellar atrophy. CONCLUSIONS: SCA-12 is a slowly progressive, autosomal dominant, neurodegenerative disorder that differs from other SCA in that it typically presents with action tremor in patients in their mid 30s and usually includes hyperreflexia and subtle parkinsonian signs. Cerebellar dysfunction, including gait ataxia, is relatively nondisabling, and cognitive or psychiatric disorders may occur. Neuroradiologic studies reveal atrophy of the cerebellum and cerebral cortex.