Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Microbial diversity and biomarker analysis of modern freshwater microbialites from Laguna Bacalar, Mexico.

Laguna Bacalar is a sulfate-rich freshwater lake on the Yucatan Peninsula that hosts large microbialites. High sulfate concentrations distinguish Laguna Bacalar from other freshwater microbialite sites such as Pavilion Lake and Alchichica, Mexico, as well as from other aqueous features on the Yucatan Peninsula. While cyanobacterial populations have been described here previously, this study offers a more complete characterization of the microbial populations and corresponding biogeochemical cycling using a three-pronged geobiological approach of microscopy, high-throughput DNA sequencing, and lipid biomarker analyses. We identify and compare diverse microbial communities of Alphaproteobacteria, Deltaproteobacteria, and Gammaproteobacteria that vary with location along a bank-to-bank transect across the lake, within microbialites, and within a neighboring mangrove root agglomeration. In particular, sulfate-reducing bacteria are extremely common and diverse, constituting 7%-19% of phylogenetic diversity within the microbialites, and are hypothesized to significantly influence carbonate precipitation. In contrast, Cyanobacteria account for less than 1% of phylogenetic diversity. The distribution of lipid biomarkers reflects these changes in microbial ecology, providing meaningful biosignatures for the microbes in this system. Polysaturated short-chain fatty acids characteristic of cyanobacteria account for <3% of total abundance in Laguna Bacalar microbialites. By contrast, even short-chain and monounsaturated short-chain fatty acids attributable to both Cyanobacteria and many other organisms including types of Alphaproteobacteria and Gammaproteobacteria constitute 43%-69% and 17%-25%, respectively, of total abundance in microbialites. While cyanobacteria are the largest and most visible microbes within these microbialites and dominate the mangrove root agglomeration, it is clear that their smaller, metabolically diverse associates are responsible for significant biogeochemical cycling in this microbialite system.

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and methods: We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results: Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

Iron-mineral accretion from acid mine drainage and its application in passive treatment.

This study demonstrates substantial removal of iron (Fe) from acid mine drainage (pH ≈3) in a passive vertical flow reactor (VFR) with an equivalent footprint of 154 m(2) per L/s mine water and residence times of >23 h. Average Fe removal rate was 67% with a high of 85% over the 10-month trial. The fraction of Fe passing a 0.22 µm filter (referred to here as Fe-filt) was seen to be removed in the VFR even when Fe(II) was absent, indicating that the contribution of microbial Fe(II) oxidation and precipitation was not the dominant removal mechanism in the VFR. Removal rates of Fe-filt in the VFR were up to 70% in residence times as low as 8 h compared with laboratory experiments where much smaller changes in Fe-filt were observed over 60 h. Centrifugation indicated that 80-90% of the influent Fe had particle sizes <35 nm. Together with analyses and geochemical modelling, this suggests that the Fe-filt fraction exists as either truly aqueous (but oversaturated) Fe(III) or nanoparticulate Fe(III) and that this metastability persists. When the water was contacted with VFR sludge, the Fe-filt fraction was destabilized, leading to an appreciably higher removal of this fraction. Heterogeneous precipitation and/or aggregation of nanoparticulate Fe(III) precipitates are considered predominant removal mechanisms. Microbial analyses of the mine water revealed the abundance of extracellular polymeric substance-generating Fe-oxidizing bacterium 'Ferrovum myxofaciens', which may aid the removal of iron and explain the unusual appearance and physical properties of the sludge.

Establishing likelihood ratios for patterned garment comparisons from seam measurement data.

It is often challenging to ascribe an objective measure of confidence for identifications based on surveillance imagery from a crime scene. The present work seeks to address this deficiency in the case of garment comparison evidence by developing a quantitative method for establishing a conservative lower bound on the likelihood ratio (LR) for identifications involving patterned garments. The method is based on statistical analysis of pattern offset measurements taken from a sample of garments of the same type (manufacturer, style, and size) as the seized evidence. The developed analysis framework was demonstrated on different types of garments over a range of modeled surveillance imaging scenarios with variable image quality; the lower bounds on the LRs ranged from approximately 10-1 to over 400-1. The statistical model was tested and validated through a large-scale empirical study involving both simulated and human observer-performed garment comparisons.

Circumferential mucosectomy with stapled proctopexy is a safe, effective outpatient alternative for the treatment of symptomatic prolapsing hemorrhoids in the elderly.

BACKGROUND: Circumferential mucosectomy with stapled proctopexy (CMSP) was first introduced in 1993 as a less painful and highly effective alternative to traditional operative hemorrhoidectomy. Although CMSP has many advantages over traditional hemorrhoidectomy, some authorities and insurers continue to regard it as an inpatient procedure and others have been slow to adopt this progressive technique. This study documents the safe and effective outpatient nature of this procedure. METHODS: From December 2001 through August 2002, 33 patients with mucosal prolapse and prolapsing internal hemorrhoids were treated using circumferential mucosectomy with stapled proctopexy as outpatients at an ambulatory surgery center. Fourteen (42%) patients were treated using local anesthesia with intravenous sedation, 18 (55%) chose spinal anesthesia, and general anesthesia was used in one patient. Patients were evaluated postoperatively by telephone at 1 and 2 weeks, and seen in clinic at 4 weeks. RESULTS: One patient (3%) required an emergency department visit for minor postoperative bleeding. None of our elderly patients required emergency department evaluation and none reported significant complications. Four patients (13%) required urinary catheter placement prior to discharge from the surgery center due to urinary retention. One patient (3%) developed an uncomplicated urinary tract infection, which resolved with antibiotic treatment. Two patients were seen earlier than 4 weeks at the surgeon's request; one was immunocompromised from chemotherapy for metastatic carcinoid, and one reported persistent pain during initial telephone follow-up. No complications were identified in either patient, and no additional complications have been noted to date. CONCLUSIONS: CMSP is a safe, effective, time-efficient procedure for patients with mucosal prolapse and prolapsing hemorrhoids that can be performed safely in the ambulatory surgery center setting. Age is not a limiting factor in selecting patients for this safe outpatient procedure.

Formation of iodinin by a strain of Acidithiobacillus ferrooxidans grown on elemental sulfur.

The presence of the pigment iodinin, an Acidithiobacillus ferrooxidans culture metabolite, was demonstrated after growth of bacteria on elemental sulfur. The structure of iodinin was confirmed by X-ray structure analysis; its physiological role is discussed.

Reduction of ferric iron by acidophilic heterotrophic bacteria: evidence for constitutive and inducible enzyme systems in Acidiphilium spp.

AIMS: To compare the abilities of two obligately acidophilic heterotrophic bacteria, Acidiphilium acidophilum and Acidiphilium SJH, to reduce ferric iron to ferrous when grown under different culture conditions. METHODS AND RESULTS: Bacteria were grown in batch culture, under different aeration status, and in the presence of either ferrous or ferric iron. The specific rates of ferric iron reduction by fermenter-grown Acidiphilium SJH were unaffected by dissolved oxygen (DO) concentrations, while iron reduction by A. acidophilum was highly dependent on DO concentrations in the growth media. The ionic form of iron present (ferrous or ferric) had a minimal effect on the abilities of harvested cells to reduce ferric iron. Whole cell protein profiles of Acidiphilium SJH were very similar, regardless of the DO status of the growth medium, while additional proteins were present in A. acidophilum grown microaerobically compared with aerobically-grown cells. CONCLUSIONS: The dissimilatory reduction of ferric iron is constitutive in Acidiphilium SJH while it is inducible in A. acidophilum. SIGNIFICANCE AND IMPACT OF THE STUDY: Ferric iron reduction by Acidiphilium spp. may occur in oxygen-containing as well as anoxic acidic environments. This will detract from the effectiveness of bioremediation systems where removal of iron from polluted waters is mediated via oxidation and precipitation of the metal.

Isolation and phylogenetic characterization of acidophilic microorganisms indigenous to acidic drainage waters at an abandoned Norwegian copper mine.

The biodiversity of culturable acidophilic microbes in three acidic (pH 2.7-3.7), metal-rich waters at an abandoned subarctic copper mine in central Norway was assessed. Acidophilic bacteria were isolated by plating on selective solid media, and dominant isolates were identified from their physiological characteristics and 16S rRNA gene sequences. The dominant iron-oxidizing acidophile in all three waters was an Acidithiobacillus ferrooxidans-like eubacterium, which shared 98% 16S rDNA identity with the type strain. A strain of Leptospirillum ferrooxidans was obtained from one of the waters after enrichment in pyrite medium, but this iron oxidizer was below detectable levels in the acidic waters themselves. In two sites, there were up to six distinct heterotrophic acidophiles, present at 10(3) ml(-1). These included Acidiphilium-like isolates (one closely related to Acidiphilium rubrum, a second to Acidiphilium cryptum and a third apparently novel isolate), an Acidocella-like isolate (96% 16S rDNA identity to Acidocella facilis) and a bacterium that shared 94.5% 16S rDNA identity to Acidisphaera rubrifaciens. The other numerically significant heterotrophic isolate was not apparently related to any known acidophile, with the closest match (96% 16S rDNA sequence identity) to an acetogen, Frateuria aurantia. The results indicated that the biodiversity of acidophilic bacteria, especially heterotrophs, in acidic mine waters may be much greater than previously recognized.

Cryosurgery and needle ablation of renal lesions.

Laparoscopic renal cryoablation is a minimally invasive alternative for treating renal tumors utilizing narrow probes cooled with a compressed gas such as argon or carbon dioxide. At this time, cryotherapy has shown the most promise as an alternative to partial nephrectomy as a nephron-sparing treatment for renal tumors. Radiofrequency ablation employs needle electrodes placed percutaneously directly into renal lesions to deliver energy, creating high temperatures leading to cell death. High-intensity focused ultrasound is a noninvasive technique in which focused ultrasound energy is applied to cause cell death within the focal zone. Microwave thermotherapy uses small applicators to deliver microwave energy to tissues, resulting in the generation of heat. Although RF, HIFU, and microwave thermotherapy show promise as energy sources for tumor ablation, they are in the early stages of development. Little is known about their acute and chronic histologic effects and long-term efficacy as a treatment for malignant disease. Further work is needed to develop cryosurgery and needle ablation in order to delineate what role these techniques will ultimately play in the management of RCC.

A microbiological survey of Montserrat Island hydrothermal biotopes.

In March 1996, a survey of hydrothermal sites on the island of Montserrat was carried out. Six sites (Galway's Soufrière. Gages Upper and Lower Soufrières, Hot Water Pond, Hot River, and Tar River Soufrière) were mapped and sampled for chemical, ATP, and microbial analyses. The hydrothermal Soufrière sites on the slopes of the active Chances Peak volcano exhibited temperatures up to almost 100 degrees C and were generally either mildly acidic at pH 5-7 or strongly acidic at pH 1.5-3, but with some hot streams and pools of low redox potential at pH 7-8. Hot Water Pond sites, comprising a series of heated pools near the western shoreline of the island. were neutral and saline, consistent with subsurface heating of entrained seawater. Biological activity shown by ATP analyses was greatest in near-neutral pH samples and generally decreased as acidity increased. A variety of heterotrophic and chemolithotrophic thermophilic organisms were isolated or observed in enrichment cultures. Most of the bacteria that were obtained in pure culture were familiar acidophiles and neutrophiles, but novel, iron-oxidizing species of Sulfobacillus were revealed. These species included the first mesophilic iron-oxidizing Sulfobacillus strains to be isolated and a strain with a higher maximum growth temperature (65 degrees C) than the previously described moderately thermophilic Sulfobacillus species.

Interactive software for generation and visualization of structured findings in radiology reports.

OBJECTIVE: Our objectives were to develop a user-friendly graphic interface for a module that integrates traditional radiology reporting, natural language processing, and editing capabilities; to facilitate the structuring of radiology reports as part of routine clinical practice; to use a commercial speech recognition module for online transcription; and to implement the module in a hardware-independent environment. CONCLUSION: After implementation, the module was tested with 150 chest radiology reports by two radiologists and assessed for ease of use and accuracy. Overall, accuracy was close to 90% and user satisfaction was high. When radiology reports are structured as a part of routine clinical practice, it is possible to accomplish intelligent indexing and retrieval to facilitate teaching and research.

Teleradiology as a foundation for an enterprise-wide health care delivery system.

An effective, integrated telemedicine system has been developed that allows (a) teleconsultation between local primary health care providers (primary care physicians and general radiologists) and remote imaging subspecialists and (b) active patient participation related to his or her medical condition and patient education. The initial stage of system development was a traditional teleradiology consultation service between general radiologists and specialists; this established system was expanded to include primary care physicians and patients. The system was developed by using a well-defined process model, resulting in three integrated modules: a patient module, a primary health care provider module, and a specialist module. A middle agent layer enables tailoring and customization of the modules for each specific user type. Implementation by using Java and the Common Object Request Broker Architecture standard facilitates platform independence and interoperability. The system supports (a) teleconsultation between a local primary health care provider and an imaging subspecialist regardless of geographic location and (b) patient education and online scheduling. The developed system can potentially form a foundation for an enterprise-wide health care delivery system. In such a system, the role of radiologist specialists is enhanced from that of a diagnostician to the management of a patient's process of care.

A medical digital library to support scenario and user-tailored information retrieval.

Current large-scale information sources are designed to support general queries and lack the ability to support scenario-specific information navigation, gathering, and presentation. As a result, users are often unable to obtain desired specific information within a well-defined subject area. Today's information systems do not provide efficient content navigation, incremental appropriate matching, or content correlation. We are developing the following innovative technologies to remedy these problems: 1) scenario-based proxies, enabling the gathering and filtering of information customized for users within a pre-defined domain; 2) context-sensitive navigation and matching, providing approximate matching and similarity links when an exact match to a user's request is unavailable; 3) content correlation of documents, creating semantic links between documents and information sources; and 4) user models for customizing retrieved information and result presentation. A digital medical library is currently being constructed using these technologies to provide customized information for the user. The technologies are general in nature and can provide custom and scenario-specific information in many other domains (e.g., crisis management).