Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study.

Background: Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented. Materials and methods: Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review. Results: Median patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%-38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred. Conclusion: Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1-positive prostate cancer, and its side effect profile was favorable. ClinicalTrials.gov Identifier: NCT02054806.

Regression of melanoma metastases following treatment with the n-bisphosphonate zoledronate and localised radiotherapy.

We report a case of regression of pulmonary and bony metastases in a patient with malignant melanoma following palliative treatment with systemic zoledronate and localised radiotherapy to the bone. Zoledronate is a potent new bisphosphonate used for the treatment of metabolic bone diseases including bone metastases due to its inhibitory effect on osteoclasts. In the context of metastatic cancer zoledronate is routinely used to improve bone pain and reduce the frequency of skeletal events. There is also an increasing body of evidence suggesting that bisphosphonates exhibit anti-tumour properties. Bisphosphonates are able to activate Vgamma9Vdelta2 gamma-delta T cells which can be key players in the immune defence against malignant cells. Furthermore bisphosphonates have direct anti-proliferative, anti-metastatic and pro-apoptotic effects on tumour cells. These actions, together with their low side effect profile, may prove to be useful therapeutic tools in the treatment of cancer even in the absence of bone metastases. On the basis of this case report we here review the current literature on present preclinical and clinical studies using bisphosphonates for the treatment of cancer.

Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones.

The semaphorin receptor, neuropilin-1 (NP-1), was first identified in Xenopus as the A5 antigen and is expressed abundantly in developing retinal ganglion cells (RGCs). Here we show that growth cones acquire responsiveness to semaphorin 3A (Sema 3A) with age and that the onset of responsiveness correlates with the appearance of NP-1 immunoreactivity. Growth cones from "old" (stage 35/36) retinal explants collapse rapidly (5-10 min) in response to Sema 3A and turn away from a gradient of Sema 3A, whereas "young" growth cones (stage 24) are insensitive to Sema 3A. Moreover, transfection of full-length NP-1 into young neurons confers premature Sema 3A sensitivity. When young neurons are aged in culture they develop Sema 3A sensitivity in parallel with those in vivo, suggesting that an intrinsic mechanism of NP-1 regulation mediates this age-dependent change. Sema 3A-induced collapse is transient, and after recovery approximately 30% of growth cones extend new branches within 1 hr, implicating Sema 3A as a branching factor. Pharmacological inhibitors were used to investigate whether these three Sema 3A-induced behaviors (collapse, turning, and branching) use distinct second messenger signaling pathways. All three behaviors were found to be mediated via cGMP. In situ hybridization shows that Sema 3A is expressed in the tectum and at the anterior boundary of the optic tract where axons bend caudally, suggesting that Sema 3A/NP-1 interactions play a role in guiding axons in the optic tract and in stimulating terminal branching in the tectum.

Tumor recurrence and tumor-related mortality in endometrial cancer: Analysis in 276 patients.

BACKGROUND: In this manuscript, we assessed tumor recurrence and tumor-related mortality in a clinical series of endometrial cancer patients. MATERIALS AND METHODS: A retrospective evaluation of 276 patients (mean age 64 years) with histologically confirmed endometrial cancer treated at a single hospital in Madrid (Spain) was conducted. The median follow-up was estimated using the inverse Kaplan-Meier method. RESULTS: Salient findings were endometrioid carcinoma (84.8% of cases), grade G1 (48.9%) and stages IB (35.1%) and IC (23.2%). Myometrial infiltration >50% was documented in 31.2% of cases and lymphovascular space invasion in 11.9%. After surgery, 52.5% of patients were classified into the low risk group, 21.4% into the intermediate risk group and 26.1% into the high risk group. Tumor recurrence occurred in 14.5% of patients, with an estimated median follow-up of 45 months (95% confidence interval (CI): 41.2-48.8), locoregional recurrence in 42.5% and distant recurrences in 57.5%. Furthermore, 40% of tumor recurrences developed during the first year after primary treatment and 90% over the first 3 years of follow-up. The tumor-related mortality rate was 15.9%. The estimated median follow-up was 46 months (95% CI: 43.0-49.0). Furthermore, 5.07% of death because of tumor developed during the first year after primary treatment and 13.77% over the first 3 years of follow-up. CONCLUSION: The rates of tumor-related death and tumor recurrence in endometrial cancer patients are low, with the highest percentages occurring within 3 years of primary treatment. Most of the recurrences occur outside the pelvis.

Use of topical FK506 in a corneal graft rejection model in Lewis rats.

PURPOSE: To evaluate the immunosuppressive effect of topical FK506 on allograft corneal rejection in rats. METHODS: Lewis rats were used as recipients and Fisher rats as corneal graft donors. In Experiment 1, all rats received intraperitoneally FK506 (0.3 mg/kg per day) for 7 days to ensure equal baseline parameters. The rats then were assigned randomly to treatment with topical 0.3% FK506 or vehicle alone. In another set of experiments, rats were treated only with topical treatment. The grafts were inspected by clinical evaluation. Corneas obtained at the time of maximum rejection were used for histology and immunohistochemistry. RESULTS: The selected combination of rat strains caused 100% graft rejection in untreated animals within 2 weeks after the penetrating keratoplasty. In the treated animals, rejection was delayed until the end of topical therapy. One third of corneal grafts remained clear until day 30. Histologic and immunohistochemical studies confirmed the clinical evaluations. Untreated rat corneas had a large number of infiltrating helper-inducer T cells, macrophages, interleukin-2 receptor-expressing cells, and Ia-antigen-expressing cells. At the same timepoint, topically treated corneas showed a limited inflammatory response characterized by a 2/3 reduction in the number of infiltrating helper and cytotoxic cells, and a five-fold decrease in the expression of class I and class II major histocompatibility antigens. CONCLUSIONS: Topical FK506 treatment is an effective way of preventing corneal graft rejection in the Lewis rat corneal graft model. It shows promise as a drug to prevent corneal graft rejection in humans.

Immunohistochemistry of Terrien's and Mooren's corneal degeneration.

Lamellar keratoplasty specimens from a patient with Terrien's marginal degeneration and a patient with Mooren's ulcer were compared using routine histopathologic and immunohistochemical staining with an avidin-biotin-peroxidase complex. Less than 25% of the resident cells in the Terrien's marginal degeneration specimen expressed major histocompatibility class II antigens compared with 75% to 100% of the resident cells in the Mooren's ulcer specimen. The ratio of CD4 cells (T-helper/inducer) to CD8 cells (T-suppressor/cytotoxic cells) in the Terrien's marginal degeneration specimen was almost 1:1 compared with 24:1 in the Mooren's ulcer specimen. In addition, less than 5% of the infiltrating cells from the Terrien's marginal degeneration specimen stained positive for CD22 (B cells), compared with 25% to 50% from the Mooren's ulcer specimen. These data may help explain why Terrien's marginal degeneration runs a more benign course than does Mooren's ulcer and provides a rationale for the use of immunosuppressive drugs to treat Mooren's ulcer.

Prevalence of pain in the Spanish population: telephone survey in 5000 homes.

Pain has become the most common accompanying symptom in patients seeking medical advice, and it is one of the main issues in public health. In Spain, there are no reliable data about the impact of pain in general population. The aim of the study was to estimate the prevalence of acute and chronic pain in the Spanish general population. An epidemiological observational population-based cross-sectional study was carried out by means of a telephone survey. Multistep stratified quota-adjusted sampling was performed with people aged 18-95 years. A computer-assisted questionnaire was administered, covering physical pain symptoms, site, frequency, perceived cause, therapeutic measures and interference with daily life activities. There were 11,980 useful contacts, with 5000 effective interviews (42% of useful sample). Of the interviewees, 29.6% (95% confidence interval, 28.3-30.8%) reported having had pain the day before (women, 37.6%; men, 20.9%) and 43.2% the week before. Most common pain sites were lower extremities (22.7%) and back (cervical and lumbar levels) (21.5%), followed by head (20.5%). Frequency of pain increased with age, reaching 42.6% for people older than 65 years. Among people complaining of pain during the last day or week, duration of symptoms was higher than 3 months in 54% (chronic pain), representing 23.4% of the Spanish general population; most common causes of chronic pain were arthritis, rheumatism and migraine. Regarding treatment, 61.7% of people complaining of pain said they were taking drugs. Source of drug treatment advice was a physician or a nurse in 66.4% of cases and self-prescription in 29%. It is concluded that pain, particularly chronic pain, has a high prevalence in the Spanish general population and a significant impact on occupational and social relationships.

Combined use of cyclosporine and ketoconazole in the treatment of endogenous uveitis.

Ten patients with endogenous uveitis were in clinical remission attributable to treatment with cyclosporine and prednisone. After the cyclosporine dose was reduced by two thirds, these patients were randomly assigned to treatment with or without ketoconazole, a potent inhibitor of cytochrome P-450, in a double-masked placebo-controlled study. The dose was reduced over three days. During a three-month follow-up, no patients treated with ketoconazole had a relapse of uveitis, while four of six (66%) control subjects had a flare-up. Toxicity in the ketoconazole-treated group was limited to a transient decrease in glomerular filtration rate (20% from baseline) at one month in two of six (33%) patients. Renal function was stabilized by further reduction of the cyclosporine dose.

Retinal toxicity in human immunodeficiency virus-infected children treated with 2',3'-dideoxyinosine.

To assess the safety and antiretroviral activity of 2',3'-dideoxyinosine, we enrolled 43 children with symptomatic (Centers for Disease Control class P-2) human immunodeficiency virus infection in a Phase I-II study and monitored them prospectively for the development of ocular complications secondary to HIV infection or drug toxicity. Follow-up ranged from 12 to 103 weeks with a median follow-up of 71 weeks. Three of 43 children (7.0%) developed peripheral atrophy of the retinal pigment epithelium during treatment with 2',3'-dideoxyinosine. The two children with the most severe retinal atrophy were enrolled in the study at the highest dosage studied (540 mg/m2/day). In contrast to findings in children, no retinal atrophy in HIV-infected adults treated with 2',3'-dideoxyinosine has been evident to date.

Non-everted oxygenated rat intestinal segments as a measure of neutral detergent fiber effects on iron absorption.

Iron absorption in the presence of varying amounts and sizes of dietary fiber was measured. A method using non-everted rat intestinal segments perfused in oxygen was refined. Neutral detergent fiber (NDF), a component of dietary fiber, was extracted from cooked pinto bean (Phaseolus vulgaris). The NDF did not affect iron absorption in intestinal segments from iron replete rats. However, 4 and 6 mg of NDF/ml significantly decreased iron absorption in the intestinal segments from anemic rats. NDF with a smaller particle size of 0.125 mm increased iron absorption relative to that absorbed with 0.180 mm particles. Histological examination validated using non-everted intestinal segments perfused with oxygen as a method for studying dietary effects on iron absorption. Segments which are not everted are less prone to damage. Perfusion with oxygen maintained metabolic activity in the tissue during the experiment.

Organ donation and family decision-making within the Spanish donation system.

This study analyses the variables associated with the decisions made by families of potential organ donors to give or deny consent for the extraction of organs. Different indicators were recorded in 68 cases of family interview for petition of consent carried out in 13 Spanish hospitals. Those variables showing the strongest relation with family decision (donation/refusal of consent) are knowledge shown by the family about the deceased's wishes with regard to donation (p<0.001), family relationship climate (p<0.01), expression of family's satisfaction level with medical attention received (p<0.01) and number of relatives present at the consent request interview (p<0.01). Logistic regression on family decision with considered variables correctly predicted relatives' final choice in 98.4% of cases. In turn, multivariate exploratory analysis highlights a potential association between the expression of the deceased's wishes and several concurrent variables in the process (satisfaction with personal treatment and medical attention received, emotional reactions in the interviews of notification of death and consent request). It also shows that patterns of reaction and family participation in this process may vary according to the sex of the deceased relative. Results suggest that both educational efforts devoted to promoting a positive attitude toward donation in the general population and the training of health professionals involved in the generation of organs may be key factors in reducing organ shortage.

Ocular complications of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with AIDS.

Recent reports suggest that acquired immunodeficiency syndrome (AIDS) patients are at higher risk of developing mucocutaneous reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome (SJS). Resultant dry eye may be further exacerbated by human immunodeficiency virus (HIV) related lacrimal gland dysfunction and lead to a chronic keratoconjunctivitis. We report one patient with AIDS and toxic epidermal necrolysis and two patients with AIDS and SJS who developed severe dry eye misdiagnosed as infectious keratoconjunctivitis. Cicatrizing mucocutaneous reactions should be suspected in AIDS patients and the dry eye treated to control symptoms and prevent complications.

An unusual cause and treatment of decelerations in fetal heart rate.

Decelerations of severe degree were detected during the monitoring of fetal heart rate at term. Decelerations continued despite the usual maneuvers in patient's position. Examination by ultrasound revealed that a loop of umbilical cord was held and squeezed in the fetal fist. The oxytocin infusion stimulated strong and frequent fetal movements which caused the fetal grip on umbilical cord to release and FHR decelerations to disappear. Induced labor progressed rapidly and within 5 h a healthy term infant was delivered.

[Spanish public opinion concerning organ donation and transplantation]. / La opinión pública española ante la donación y el trasplante de órganos.

BACKGROUND: Information, beliefs, attitudes and the motivations of the Spanish population regarding organ donation and transplantation were studied to facilitate possible programs directed at the promotion of organ donation. METHODS: The Psychosocial Aspects of Donation Questionnaire (PADQ) was applied by personal interview to a representative sample of the Spanish population (n = 1,288). RESULTS: Sixty-five percent of the population was found to be in favor of donating their own organs while only 6.1% had an organ donation card. The main reasons inducing those questioned to be donors were solidarity (47%) and reciprocity (29%). The fundamental reasons hindering donation were not knowing how to be a donor (34%) and the fear of the possibility of an only apparent death (24%). Ninety-three percent would donate the organs of a dead relative if they knew that this person was in favor of donating. Only 52% would donate if they did not know the will of the departed relative. The younger subjects with a higher level of education, higher socioeconomic status, and better informed evaluated donation and transplantation favorably and those with direct experience showed a more favorable inclination to the donation of their own organs. CONCLUSIONS: Educational programs directed at the population should provide information on the efficacy and the profitability of transplantation presenting real cases and emphasizing the quality of life obtained by the receptors. Incentives to organ donation should be directed at reasons of solidarity and reciprocity. Family debate of the matter should be promoted as should the establishment of clear and accessible procedures for the obtaining of a donor card and thereafter the communication of the holders as to their decision to their respective relatives.

Validation of the Spanish version of the Glasgow Dyspepsia Severity Score.

OBJECTIVE: To translate, adapt and validate the Spanish version of the Glasgow Dyspepsia Severity Score (GDSS). METHOD: The translation into Spanish and the adaptation of the scale was carried out by specialized medical translators. The comprehensibility of the translated scale was assessed by two independent observers and by the research team. GDSS includes eight items and was filled out once by 40 healthy subjects (control group) and twice by 131 patients with functional dyspepsia. After the first measurement, patients were prescribed a H2 blocker (roxatidine) for 2 months. A second evaluation was carried out 6 months after the beginning of the treatment. RESULTS: The comprehensibility of the questionnaire was good. It showed acceptable internal consistency both for the control group (0.6) and for the patients at the inclusion visit (0.6) and good consistency for the patients at the 6 month follow-up evaluation (0.8). After treatment, the overall score decreased almost to half (p < 0.0001) in the patients, thus confirming the effectiveness of the treatment 4 months after its discontinuation, although their score was still higher than the score of the control group (p < 0.001). CONCLUSIONS: Results suggest the usefulness of including the GDSS scale in the dyspeptic symptoms recording protocols, since it allow to estimate, with appropriate objectivity and in an easy and quickly way, the degree of impairment due to dyspeptic symptoms, as well as the perception of well-being and the effectiveness of a given therapy.

Criteria used by general practitioners in prescribing prokinetic or antisecretory drugs in patients with functional dyspepsia.

OBJECTIVE: To analyze the clinical factors considered by general practitioners for the prescription of prokinetic or antisecretory drugs in patients with functional dyspepsia (FD), and to assess therapeutic outcomes and factors predicting effectiveness. DESIGN: Multicentric, prospective and observational study. PATIENTS: 1,021 patients with FD were included. One hundred and thirty-two (132) were excluded from the analysis because they were taking ASA or NSAID. Patients were classified according to their predominant symptoms as reflux, ulcer, dysmotility or non-specific. At the physician discretion, treatment with alkali drugs was prescribed to 38 patients, prokinetic drugs to 574, antisecretory drugs to 123 and a combined therapy to 154. One month later, patient self-perception of symptomatic improvement was evaluated in patients treated with prokinetic drugs and antisecretory drugs. RESULTS: 85% of the patients reported symptomatic improvement after one month of treatment. Patients with non-specific FD had lower improvement rates regardless of the drug used (prokinetic or antisecretory) (77%) compared to all the other types (p = 0.03). Prescription of prokinetics was associated to female gender (OR: 0.43; 95% CI: 0.28-0.66) and early satiety (OR: 2.5; 95% CI: 1.6-4.1). A longer symptomatic evolution (OR 0.92: 95% CI: 0.88-0.97) was the only independent predictive factor of a poor response to prokinetic drugs. CONCLUSIONS: Among patients with FD attended by general practitioners, female gender and early satiety symptom were associated to the prescription of prokinetic drugs. Early symptomatic effectiveness rates for prokinetic or antisecretory drugs alike were high (85%). Patients with non-specific dyspepsia or long symptomatic evolution showed less favorable symptomatic response to prokinetic drugs.

Identification of unknown ocular pathogens in clinically suspected eye infections using ribosomal RNA gene sequence analysis.

DNA sequence-based identification of pathogens from ocular samples of patients with clinically suspected eye infections was accomplished using 16S and internal transcribed spacer (ITS) ribosomal RNA gene sequence analysis. PCR was positive for 24 of 99 samples tested. Both culture and 16S rDNA sequence analysis identified Pseudomonas aeruginosa, streptococci and Enterobacteriaceae. Isolates misidentified as Burkholderia cepacia by biochemical tests were identified as Ralstonia mannitolilytica by 16S rDNA sequence analysis. Sequence analysis identified the following microorganisms from 19 culture-negative samples: Haemophilus influenzae, Sphingomonas sp., Klebsiella pneumoniae, Staphylococcus haemolyticus, Morganella morganii, Mycobacterium sp., Chryseobacterium sp., Pseudomonas saccharophila (Xanthomonas) and the fungus, Phaeoacremonium inflatipes.