M. Del Vecchio

Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma

BACKGROUND Patients with advanced uveal melanoma have a poor prognosis and limited treatment options. Ipilimumab is approved for pre-treated adult patients with advanced melanoma. However, because previous clinical trials with ipilimumab have excluded patients with uveal melanoma, data in this patient population are limited. PATIENTS AND METHODS Pre-treated patients with advanced uveal melanoma received ipilimumab 3 mg/kg through an expanded access programme, every 3 weeks for four doses. Tumour assessments were conducted at baseline and after completion of treatment and patients were monitored throughout for adverse events. RESULTS Among 82 assessable patients, 4 (5%) had an immune-related objective response and 24 (29%) had immune-related stable disease lasting ≥3 months for an immune-related disease control rate of 34%. With a median follow-up of 5.6 months, median overall survival (OS) was 6.0 months and median progression-free survival (PFS) was 3.6 months. The 1-year rates of OS and PFS were 31% and 11%, respectively. The safety profile of ipilimumab was similar to that in patients with cutaneous melanoma. CONCLUSIONS These data suggest ipilimumab 3 mg/kg is a feasible option in pre-treated patients with metastatic uveal melanoma. Evidence of disease control and a 1-year survival rate of 31% indicate the need for further investigation in randomised, controlled trials to determine the optimal timing and use of ipilimumab in this patient population.

Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab

BACKGROUND Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. PATIENTS AND METHODS Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. RESULTS The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. CONCLUSIONS Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.

A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma

BACKGROUND The efficacy and safety of nab-paclitaxel versus dacarbazine in patients with metastatic melanoma was evaluated in a phase III randomized, controlled trial. PATIENTS AND METHODS Chemotherapy-naïve patients with stage IV melanoma received nab-paclitaxel 150 mg/m(2) on days 1, 8, and 15 every 4 weeks or dacarbazine 1000 mg/m(2) every 3 weeks. The primary end point was progression-free survival (PFS) by independent radiologic review; the secondary end point was overall survival (OS). RESULTS A total of 529 patients were randomized to nab-paclitaxel (n = 264) or dacarbazine (n = 265). Baseline characteristics were well balanced. The majority of patients were men (66%), had an Eastern Cooperative Oncology Group status of 0 (71%), and had M1c stage disease (65%). The median PFS (primary end point) was 4.8 months with nab-paclitaxel and 2.5 months with dacarbazine [hazard ratio (HR), 0.792; 95.1% confidence interval (CI) 0.631-0.992; P = 0.044]. The median OS was 12.6 months with nab-paclitaxel and 10.5 months with dacarbazine (HR, 0.897; 95.1% CI 0.738-1.089; P = 0.271). Independently assessed overall response rate was 15% versus 11% (P = 0.239), and disease control rate (DCR) was 39% versus 27% (P = 0.004) for nab-paclitaxel versus dacarbazine, respectively. The most common grade ≥3 treatment-related adverse events were neuropathy (nab-paclitaxel, 25% versus dacarbazine, 0%; P < 0.001), and neutropenia (nab-paclitaxel, 20% versus dacarbazine, 10%; P = 0.004). There was no correlation between secreted protein acidic and rich in cysteine (SPARC) status and PFS in either treatment arm. CONCLUSIONS nab-Paclitaxel significantly improved PFS and DCR compared with dacarbazine, with a manageable safety profile.

Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy.

Background:Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg−1 among patients participating in an expanded access programme in Italy.Methods:Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg−1 every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events.Results:Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported.Conclusions:For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials.

Effect of a Bacterial Lipopolysaccharide Treatment on Rabbit Testis and Ejaculated Sperm

In a previous study, we reported the short- and long-term effects of bacterial lipopolysaccharide (LPS)-induced inflammation on rabbit sperm quality. This study was aimed at exploring the spermatogenesis of the rabbit model focussing on the possible damages occurring to the testis and ejaculated sperm. Twenty New Zealand White rabbit bucks were divided into two groups. One group was inoculated intra-peritoneally with LPS, the other group, considered as control, was treated under the same conditions with saline only. Semen samples were collected before LPS injection, the 7th, 14th, 21st, 30th, 45th, 60th and 90th day after LPS treatment. Semen parameters were evaluated following international guidelines. The kinetic characteristics of ejaculated sperm were analysed using a computer-assisted sperm analyzer and the ultrastructural characteristics were explored by transmission electron microscopy (TEM). On the 7th, 14th and 30th day, testis from treated rabbits and controls were obtained. Testis samples were analysed by light microscopy and TEM. The induced LPS lesions in the testis became evident the 7th day after treatment, with a decrease in germinal cells and with an increase in structurally altered Sertoli cells; normal spermatogenesis was restored on the 30th day. The testicular damages observed on day 7 were probably responsible for the reduction in sperm concentration and motility and the ultrastructural alterations that were detected in the ejaculated sperm on the 14th through the 30th days after treatment. In conclusion, rabbit buck treated with LPS could be a useful model for studying the effect of an induced systemic inflammation on spermatogenesis.

Secretion patterns and effect of prostate-derived granules on the sperm acrosome reaction of rabbit buck

There is increasing evidence that the particulate fraction of seminal plasma plays an important role in reproduction of several mammalian species. However, the origin and role of these granules in the physiology of rabbit spermatozoa is partially unknown. The aim of this study was to investigate the implication of prostate gland in the production and secretion of granules into the rabbit semen and the role of prostate-derived granules in the sperm acrosome reaction. Light and electron microscopy of the prostate gland showed that the anterior and middle tracts of the prostate (namely the proprostate and prostate, respectively) are chiefly implicated in the secretion of granules of different size: smaller granules (SG; 0.5 μm) and large granules (LG; 4 μm). Two major patterns of secretion were identified, based on electron microscope views: storage granules (large granules) seem to empty inner smaller granules directly into the duct by exocytosis, or the storage vesicle itself is released in toto into the ducts (diacytosis). In vitro experiments using granules from vasectomized rabbits, to exclude testicular origin of granules, showed that granules reduce the acrosome reaction of Percoll-selected spermatozoa, independently of the size. Interestingly, spermatozoa incubated with heat-treated granules showed a higher sperm acrosome reaction rate, suggesting a potential role of granule-derived proteins in this process. Inhibition of the acrosome reaction is a crucial event in rabbit reproduction; ejaculated spermatozoa have to wait for a long time (8-16 h) for egg availability in the female tract after mating. Taking together, our results demonstrate that prostate granules secreted either by exocytosis or diacytosis can preserve spermatozoa fertilizing ability, by preventing sperm acrosome reaction. The type of granule-derived proteins or other macromolecules implicated in this process should be further investigated.

State of the art on autologous mesothelial transplant in animals and humans.

Sixteen years ago rabbit and human mesothelial cells were successsfully cultured and autoimplanted. The aim of the study was merely to demostrate that mesothelial implant was possible and interesting not only in peritoneal dialysis, but also in the vaster field of medicine and surgery concerning all the mesothelial districts of the body. The aim of this paper is to recollect the steps which have led to autolougous mesothelial transplantation and verify if the tecnique has been validated and adopted by others. Review of the literature published in the last 15 years shows that intraperitoneal transplantation of mesothelial cells has been effective in reducing the formation of peritoneal adhesions, and in remodeling the area of mesothelial denudation. New studies on the mesothelial cell opened the way to costruction of transplantable tissue-engineered artificial peritoneum, to the utilization of mesothelial progenitor cells and to find simple metods to collect autologous mesothelial cells. Finally mesothelial trasnsplantation may represent a new neovascular therapy in the prevention and treatment of ischemic coronaric heart disease.

Histological and genetic heterogeneity in synchronous hepatocellular carcinoma

Editor,—The recent paper by Sirivatanauksorn et al ( (1999) Gut 45:761–5; [OpenUrl][1][Abstract/FREE Full Text][2] ) focused once again on the unresolved question as to whether (i) hepatocellular carcinoma (HCC) in human liver develops from a single clone or from multiple parallel clones and (ii) among multiple tumour nodules present in many patients, the smaller lesions represent intrahepatic metastases or “de novo” cancers. The authors correctly acknowledge that “information on the clonal origin of tumours will influence management strategies for prevention of recurrence after operation”. They used arbitrarily primed polymerase chain reaction (AP-PCR)1 to compare the DNA fingerprint of HCCs and regenerative nodules (RNs) removed from 13 cirrhotic explant livers. They found considerable genomic heterogeneity in 54 HCCs and 31 RNs that were microdissected. No two nodules (either RNs or HCCs) had identical electrophoretic patterns. Contrary to … [1]: {openurl}?query=rft.jtitle%253DNucleic%2BAcids%2BResearch%26rft.stitle%253DNucleic%2BAcids%2BRes%26rft.issn%253D0305-1048%26rft.aulast%253DWelsh%26rft.auinit1%253DJ.%26rft.volume%253D18%26rft.issue%253D24%26rft.spage%253D7213%26rft.epage%253D7218%26rft.atitle%253DFingerprinting%2Bgenomes%2Busing%2BPCR%2Bwith%2Barbitrary%2Bprimers%26rft_id%253Dinfo%253Adoi%252F10.1093%252Fnar%252F18.24.7213%26rft_id%253Dinfo%253Apmid%252F2259619%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/ijlink?linkType=ABST&journalCode=nar&resid=18/24/7213&atom=%2Fgutjnl%2F49%2F1%2F155.2.atom

Transitional cell carcinoma of the ureteral stump 13 years after nephrectomy for benign disease.

A case of primary carcinoma of the ureteral stump occurring 13 years after nephrectomy for benign disease is reported. The literature is reviewed.

Effects of 7,12-dimethylbenz (A) anthracene on thymus cortex in the rat. A morphological and histometrical analysis.

SummaryIn the rat, administration of 7,12-dimethylbenz(a)anthracene (DMBA) causes necrosis of the inner layers of the adrenal cortex and provokes rising levels of plasma cortisol. Histological and ultrastructural study of the thymus demonstrates a profound depletion of small thymocytes, especially in the inner cortex where they normally represent the greater part of the cell population. The thymic weight, and the cortico-medullary ratio as measured by histometry, decrease significantly. These findings are similar to those observed following steroid administration. However, whereas after steroid treatment restitution of the normal complement of thymocytes occurs within 7–10 days, in the present model the thymic weight and corticomedullary ratio remain at the low levels observed on days 1 and 3 until after day 24 following DMBA administration. A block in the regenerative process is confirmed by the results of morphometrical analysis of the thymocyte nuclear area in the cortex. On day 1 and 3 after DMBA the mean thymocyte nuclear area is reduced in the outer cortex and increased in the inner cortex, because of the selective destruction of small thymocytes and the migration of the corticoresistant blast thymocytes towards the medulla. Subsequently, until after day 24 the mean nuclear area of the thymocytes is significantly higher in the outer and in the inner cortex of treated rats than in the corresponding parts of the cortex of control rats. This aspect of the cortex is characteristic of the early phase of the regenerative process, i.e. of day 2 or 3 after steroids administration.It can be assumed that in this experimental model the thymic changes are due not only to the raised cortisol level but also to a direct effect of DMBA on the thymus, which is probably an inhibition of DNA synthesis in cells in the S phase of the mitotic cycle, i.e. in the replication of DNA. It also seems possible that a causal relationship exists between inhibition of DNA synthesis in proliferating organs like the thymus, and the carcinogenic activity of DMBA.