Efficacy of CARVYKTI in CARTITUDE-4 versus other conventional treatment regimens for lenalidomide-refractory multiple myeloma using inverse probability of treatment weighting.

Aim: The phase III randomized controlled trial (RCT) CARTITUDE-4 (NCT04181827) demonstrated superiority of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) over daratumumab, pomalidomide and dexamethasone (DPd) and pomalidomide, bortezomib and dexamethasone (PVd) for relapsed/refractory multiple myeloma (RRMM) patients who have received one to three prior line(s) of therapy (LOT[s]) including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide. These analyses estimate the relative efficacy between cilta-cel and other common treatment regimens, for which no direct comparative evidence is available. Materials & methods: Patient data were available from the CARTITUDE-4, CASTOR, CANDOR and APOLLO RCTs. Imbalances between cohorts on key patient characteristics were adjusted for using inverse probability of treatment weighting (IPTW). Relative efficacies were estimated with response rate ratios (RRs) and 95% confidence intervals (CIs) for overall response rate (ORR), very good partial response or better rate (≥VGPR) and complete response or better rate (≥CR), and with hazard ratios (HRs) and 95% CIs for progression-free survival (PFS). Sensitivity analyses using different analytical methods and additional covariates were explored. Results: Key characteristics were well balanced across cohorts after IPTW. Cilta-cel showed statistically significant benefit in PFS (HRs: 0.11-0.51), ≥VGPR (RRs: 1.51-5.13) and ≥CR (RRs: 2.90-35.24) versus all comparators, and statistically significant improvements in ORR over most comparator regimens (RRs: 1.22-1.90). Results were consistent across sensitivity analyses. Conclusion: Cilta-cel demonstrated benefit over other common treatment regimens, highlighting its potential to become a new standard of care option for lenalidomide-refractory RRMM patients with one to three prior LOT(s). These comparisons help to demonstrate the improved efficacy of cilta-cel in countries where the standard of care may differ from DPd/PVd.

Comparative efficacy of ciltacabtagene autoleucel versus idecabtagene vicleucel in the treatment of patients with relapsed or refractory multiple myeloma previously treated with 2-4 prior lines of therapy: a matching-adjusted indirect comparison.

OBJECTIVE: To estimate the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma (RRMM) treated with 2-4 prior lines of therapy. METHODS: Matching adjusted indirect comparison (MAICs) were performed using individual patient-level data (IPD) for cilta-cel from CARTITUDE-1 and CARTITUDE-4 and published aggregated data for ide-cel from KarMMa-3. Cilta-cel patients who met inclusion criteria from KarMMa-3 were selected, and outcomes were compared against data for ide-cel using simulated IPD derived from aggregate-level data from KarMMa-3. Patient characteristics were adjusted by reweighting cilta-cel IPD to match the distribution of prognostic factors in KarMMa-3. Comparative efficacy was estimated for response outcomes using a weighted logistic regression analysis and for progression-free survival using a weighted Cox proportional hazards model. RESULTS: Patients treated with cilta-cel were 1.2 times more likely to achieve overall response (relative response ratio [RR]: 1.18 [95% confidence interval: 1.03-1.34]; p = 0.04), 1.3 times more likely to achieve very good partial response or better (RR: 1.34 [1.15-1.57]; p = 0.003), and 1.9 times more likely to achieve complete response or better (RR: 1.91 [1.54-2.37]; p < 0.0001) versus ide-cel patients from KarMMa-3. Cilta-cel was associated with a significant 49% reduction in risk of disease progression or death versus ide-cel (hazard ratio: 0.51 [95% confidence interval: 0.31, 0.84]; p = 0.0078). CONCLUSION: For patients with triple-class exposed RRMM treated with 2-4 prior lines of treatment, cilta-cel was found to provide superior clinical benefit over ide-cel in terms of response and progression-free survival.

Plain language summary of the CARTITUDE-4 study of ciltacabtagene autoleucel for the treatment of people with relapsed or refractory multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a phase 3 clinical trial called CARTITUDE-4. This trial compared the anti-cancer therapy ciltacabtagene autoleucel (or cilta-cel) with standard therapies in people who have multiple myeloma, a cancer that affects specific kinds of blood cells called plasma cells. The people in the study had been treated with 1 to 3 previous treatments for multiple myeloma, including a common anti-myeloma treatment called lenalidomide, but their multiple myeloma did not get better. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED?: About half of the 419 participants in this study received cilta-cel, while the other half received standard therapies, or therapies that are commonly used to treat multiple myeloma. Participants who received cilta-cel had a type of immune cell called T cells collected from their blood and genetically modified to recognize a specific protein found on myeloma cells. These modified T cells, which comprise cilta-cel, were then infused back into the bloodstream. WHAT WERE THE RESULTS OF THE STUDY?: After approximately 1 year in the study, more participants were alive without their cancer getting worse in the cilta-cel group (76%) than in the standard therapies group (49%). The most common side effects in both groups were infections and low blood cell counts. Cytokine release syndrome (a potentially serious side effect caused by overactivation of the immune system) was common but mostly mild. Neurotoxicities (including immune effector cell-associated neurotoxicity syndrome, which can cause symptoms such as headaches, changes in consciousness, and difficulty with memory, attention, speaking, or understanding others) were less common and were reported in 20.5% of participants treated with cilta-cel. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: In CARTITUDE-4, more participants treated with cilta-cel showed improvements and were alive with control of their disease 12 months after receiving cilta-cel compared with participants who received standard therapies.Clinical Trial Registration: NCT04181827 (CARTITUDE-4) (ClinicalTrials.gov).

Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory. AREAS COVERED: We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6). EXPERT OPINION: CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma.

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).

High-throughput optofluidic screening of single B cells identifies novel cross-reactive antibodies as inhibitors of uPAR with antibody-dependent effector functions.

The urokinase-type plasminogen activator receptor (uPAR) is an essential regulator for cell signaling in tumor cell proliferation, adhesion, and metastasis. The ubiquitous nature of uPAR in many aggressive cancer types makes uPAR an attractive target for immunotherapy. Here, we present a rapid and successful workflow for developing cross-reactive anti-uPAR recombinant antibodies (rAbs) using high-throughput optofluidic screening of single B-cells from human uPAR-immunized mice. A total of 80 human and cynomolgus uPAR cross-reactive plasma cells were identified, and selected mouse VH/VL domains were linked to the trastuzumab (Herceptin®) constant domains for the expression of mouse-human chimeric antibodies. The resulting rAbs were characterized by their tumor-cell recognition, binding activity, and cell adhesion inhibition on triple-negative breast cancer cells. In addition, the rAbs were shown to enact antibody-dependent cellular cytotoxicity (ADCC) in the presence of either human natural killer cells or peripheral blood mononuclear cells, and were evaluated for the potential use of uPAR-targeting antibody-drug conjugates (ADCs). Three lead antibodies (11857, 8163, and 3159) were evaluated for their therapeutic efficacy in vivo and were shown to suppress tumor growth. Finally, the binding epitopes of the lead antibodies were characterized, providing information on their unique binding modes to uPAR. Altogether, the strategy identified unique cross-reactive antibodies with ADCC, ADC, and functional inhibitory effects by targeting cell-surface uPAR, that can be tested in safety studies and serve as potential immunotherapeutics.

Post-operative tension spinal subdural extra-arachnoid hygroma of the lumbar spine: case series, literature review, and recommendations for clinical management.

OBJECTIVE: Case series presentation and literature review of patient group suffering from symptomatic tension subdural extra-arachnoid hygroma following decompressive surgery for degenerative lumbar stenosis or disc disease. The purpose was to better understand this rare post-operative complication with a pathognomic radiological sign to help recommend optimal strategies for clinical management. METHODS: Retrospective case series comprising seven cases from one tertiary Neurosurgical centre spanning a 10-year period from 2011 to 2021. Patients included were those known to have undergone a spinal procedure and subsequently to have developed a symptomatic spinal subdural extra-arachnoid hygroma (SSEH). A literature review was conducted using PubMed, MEDLINE and EMBASE (keywords 'subdural hygroma', 'lumbar CSF hygroma', 'extra arachnoid hygroma', 'extra-arachnoid CSF collection', 'CSF tension hygroma', 'lumbar extra arachnoid hygroma', 'lumbar spinal hygroma', 'post-operating spinal hygroma', 'post-operative spinal CSF collection') and through reading references cited in relevant articles. Articles involving post-operative SSEH following lumbar spinal surgery were included. RESULTS: Rare complication with only five other cases in the literature. Dural breach described intra-operatively in only 5 of 12 total cases from our series and the literature. 5 patients in our series were managed surgically with 2 being managed conservatively. All patients in our series improved symptomatically and radiologically following surgical or conservative management. CONCLUSIONS: This is a rare post-lumbar surgery complication that can cause rapidly deteriorating lower limb and sphincteric function. Surgical management with wide durotomy and arachnoid marsupialisation can lead to reversal of neurological deterioration and excellent clinical results. A delayed presentation with pseudomeningocele formation may be managed conservatively if neurology is stable or improving. It is a condition that it is important for the clinician to recognise in order to instigate appropriate management in a time-dependent fashion.

Rapidly Progressive Granulomatous Amoebic Encephalitis in a Diabetic Individual.

We present a case of rapidly progressive granulomatous amoebic encephalitis caused by Balamuthia mandrillaris in an individual with diabetes mellitus. Our patient presented with occipital headache, blurry vision, confusion, and gait imbalance of one week's duration. Brain imaging revealed numerous peripheral ring-enhancing lesions concerning malignancy. Brain biopsy was consistent with Balamuthia mandrillaris infection. He passed away 45 days after presentation despite being treated with a five-drug regimen. This case highlights the importance of considering amoebic brain infections, especially with ring-enhancing lesions on imaging. There are opportunities to design modalities for rapid diagnosis and better treatment.

Perioperative Blood Loss after Preoperative Prostatic Artery Embolization in Patients Undergoing Simple Prostatectomy: A Propensity Score‒Matched Study.

PURPOSE: To assess perioperative blood loss following prostatic artery embolization (PAE) before surgery in patients undergoing simple prostatectomy. METHODS: A retrospective chart review was used to identify 63 patients (mean age, 65.3 ± 8.0 years) with prostatic hypertrophy and severe lower urinary tract symptoms who underwent prostatectomy from September 2014 to December 2019, 18 (28.5%) of whom underwent PAE before surgery. Demographic data, pertinent laboratory results, procedural or operative information, hospital course details, and pathology reports were obtained. A 2:1 propensity score‒matching analysis was performed to compare intraoperative blood loss in patients who underwent prostatectomy alone with intraoperative blood loss in those who first underwent bilateral PAE before surgery. RESULTS: Sixteen (89%) of the 18 patients underwent bilateral PAE before surgery. Thirty-two patients who underwent prostatectomy without embolization before surgery were selected for the 2:1 propensity score‒matched analysis based on age, race, surgery type, prostate gland size, and comorbidities. The mean estimated blood loss (EBL) for prostatectomy alone was 545 ± 380 mL (mean ± standard deviation). There was a statistically significant reduction in the EBL for patients who underwent bilateral PAE (303 ± 227 mL, P < .01). The operative time was also significantly decreased for patients who underwent PAE before surgery (P < .05). For patients who underwent PAE, there were no complications related to the procedure. CONCLUSIONS: Bilateral PAE before surgery appears to be safe and may be effective in reducing perioperative bleeding and operative time.

Bilateral facial cutaneous angiomyolipomas: First case in the literature and a possible correlation with human immunodeficiency virus.

Angiomyolipomas (AMLs) are benign tumors consisting of smooth muscle-like cells, adipocyte-like cells, and epithelioid cells. They are usually renal in origin, and extrarenal AMLs are rare. Cutaneous AMLs are even more rare. We present a case of 65 year old female, with no underlying genetic condition, who developed bilateral facial cutaneous AMLs. To the best of our knowledge, this is the first case in the literature. In addition, we investigate and suggest a correlation between human immunodeficiency virus and AMLs.

Gallbladder Hydatid Cyst: A Review on Clinical Features, Investigations and Current Management.

BACKGROUND: Gallbladder hydatid cyst (GBHC) is highly uncommon with an incidence of 0.3-0.4% of all atypically located hydatid cysts. Our personal experience of one case of primary GBHC (PGBHC) managed laparoscopically motivated this systematic review. This study aimed to analyze the demographic characteristics, types [whether primary GBHC (PGBHC) or secondary GBHC (SGBHC)], clinical presentation, laboratory investigations, imaging studies, operative procedure, hospital stay, follow-up and recurrence. METHODS: A systematic review was performed using preferred reporting items for systematic reviews and meta-analyses guidelines. RESULTS: Twenty studies, including 22 cases plus one more case managed by us, were included in the review. For PGBHC, the mean age was 48.61 years while for SGBHC it was 47.9 years. PGBHC was more common in females (69.23%) while SGBHC was more common in males (55.55%). Overall, GBHC was more common in females (56.52%). The most common presentation overall was abdominal pain (100%) followed by nausea/vomiting (43.47%). The other common symptoms were nausea/vomiting (61.53%) and Murphy's sign (38.46%) in PGBHC, but jaundice (50%) and fever (30%) in SGBHC. In PGBHC, 50% patients had normal liver function while this was deranged in 66.66% patients with SGBHC. Serology was positive in 50% of PGBHC and 100% in SGBHC. Ultrasonography was positive in 50%, while CT-scan showed 70%. CT-scan was better at detection of SGBHC (100%). The most common operation was open cholecystectomy (78.26%) either isolated or combined. Isolated open cholecystectomy was commonly done in PGBHC (69.23%). Overall, only 56.52% of patients received albendazole, but no recurrence was reported. The average hospital stay was 7.25 days and follow-up ranged from 1 month to 10 years. CONCLUSION: GBHC mostly affects females with abdominal pain being the most common symptom. Ultrasonography is expedient though CT-scan is more sensitive. Albendazole monotherapy has questionable value. Open cholecystectomy is the most common operation. However, laparoscopy is safe in experienced hands.

Readability Assessment of Internet-based Patient Education Materials Related to Treatment Options for Benign Prostatic Hyperplasia.

RATIONALE AND OBJECTIVES: To assess the current readability levels for online Internet-Based Patient Education Materials (IPEMs) related to treatment options for benign prostatic hyperplasia, including transurethral resection of prostate (TURP) and prostate artery embolization (PAE). MATERIALS AND METHODS: Using the Google search engine we identified 40 IPEMs pertaining to TURP and PAE. Readability analysis was performed using the following algorithms: Flesch Reading Ease Score (FRES), Flesch-Kincaid Grade Formula (FKGL), Simple Measure of Gobbledygook (SMOG), and the Gunning Frequency of Gobbledygook (GFOG). Scores are categorized by difficulty (FRES) and grade level (FKGL, SMOG, GFOG). RESULTS: Only 7.5% (3/40) websites met the United States Department of Health and Human Services recommendation of a sixth grade or lower comprehension levels, with FRES scores in the "fairly easy" category. Comparison of TURP to PAE groups showed that TURP readability scores with respect FRES and FKGL were significantly easier to read. According to SMOG and GFOG analysis there was no difference between the two groups by grade level, which demonstrated an average at the 12th grade reading level. Subgroup analysis of IPEM type, categorized as Health Networks (12), University Hospitals (14), Clinical Practices (6), and Miscellaneous (8), found no difference in reading level across all scoring systems. CONCLUSION: Currently available IPEMs pertaining to benign prostatic hyperplasia treatment options are written at a level that is too difficult for the average American to understand. Physicians and health networks should take United States Department of Health and Human Services recommendations into consideration when designing IPEMs to optimize accessibility of health information to improve patient compliance and outcomes.

Zebras in Foreskin Dermatopathology: A Review.

OBJECTIVES: The aim of the study was to review uncommon foreskin dermatopathology conditions clinically and pathologically. METHODS: A database search of PubMed and Google Scholar were extracted between March 1, 2009, and March 1, 2019, using the search terms "foreskin," "prepuce," "penis," "pathology," "dermatology," and "rare." The search was limited to "humans" and "dermatopathology." Full article texts were reviewed. Reference lists were screened for additional articles. Patient details (diagnosis, dermatopathology, treatment, and follow-up if available) were extracted. We excluded articles written in the non-English language, unusual variants of common conditions, and cases of common dermatologic conditions. RESULTS: A list of 369 articles was identified and another screening identified 30 articles for rare foreskin pathologies. Those are divided into categories based on the following etiologies: (a) benign, including congenital (e.g., aposthia), infectious (graft versus host disease and histoplasma), autoimmune (Crohn's disease and pyoderma gangrenosum), and benign neoplasms (neurofibroma, apocrine hidrocystoma, verruciform xanthoma, porokeratosis, penile cutaneous horn, localized amyloidosis) and (b) malignancies, including primary (myeloid sarcoma, basal cell carcinoma, Kaposi's sarcoma, mucosal-associated lymphoid tissue lymphoma), and metastasis. CONCLUSIONS: We reviewed and discussed unusual benign and malignant dermatopathology conditions that can affect the foreskin.

Comparison of in chemico skin sensitization methods and development of an in chemico skin photosensitization assay.

Chemical substances that induce an allergic response in skin upon contact are called skin allergens or sensitizers, while chemical substances that elicit an allergic response only in presence of light are called photoallergens or photo sensitizers. The Direct Peptide Reactivity Assay (DPRA, OECD N° 442C, 2015) and the Amino Acid Derivative Reactivity Assay (ADRA) are in chemico assays used to discriminate between allergens and non-allergens. The DPRA and the ADRA, respectively, monitor the depletion of model peptides and modified amino acids induced by crosslinking with test chemicals. In the current study we compared these two assays and analyzed their suitability to predict skin sensitization potential of several chemical substances.  In order to study the combined effect of a chemical compound and UV light, we modified DPRA (photo-DPRA) as well as ADRA (photo-ADRA) by introduction of a photo-irradiation parameter. Analysis using photo-DPRA and photo-ADRA correctly distinguished known photoallergens from non-photoallergens. Upon irradiation, photoallergens selectively showed higher depletion of model peptides or modified amino acids. Thus, photo-DPRA and/or photo-ADRA can serve as non-animal in vitro methods for the identification and assessment of photoallergens/ photosensitizers.

Transfacet and Transpedicular Posterior Approaches to Thoracic Disc Herniations: Consecutive Case Series of 24 Patients.

OBJECTIVE: Various approaches are advocated for symptomatic thoracic disc herniation (TDH). The aim of this series is to demonstrate the feasibility, safety, and results of posterior transfacet or transpedicular approaches for excision of all types of extradural TDH. We report a consecutive series of patients undergoing posterior approach surgery for TDH. METHODS: Twenty-four patients (17 women, 7 men) underwent surgery at 25 disc levels. Mean age was 56.3 years (range, 23-79 years). A posterior transfacet or transpedicular approach was used. Patients presented with myelopathy (n = 21, 88%), radiculopathy (n = 8, 33%), sphincter dysfunction (n = 16, 67%), and axial back pain (n = 10, 43%). Preoperative imaging revealed 7 (30%) central, 14 (61%) calcified, and 10 (43%) large disc herniations. The mean follow-up period was 6.0 months (range, 2-36 months). RESULTS: Eighteen patients underwent unilateral approach surgery (5 transfacet and 13 transfacet plus transpedicular), and 7 patients required bilateral approach laminectomy for unilateral (n = 4) or bilateral (n = 3) discectomy. One patient required unplanned reoperation for resection of residual disc. Average operative time was 95 minutes (range, 40-175 minutes). Mean hospital stay was 4.9 days (range, 2-35 days). There were no major complications. Postoperative Frankel scores were maintained or improved in all patients at last review. CONCLUSIONS: TDH including large central calcified discs can be safely removed through posterior transfacet or transpedicular approaches with reduced morbidity in comparison with more invasive anterior approaches. Careful microsurgical technique and use of specialized instruments are important for successful excision of TDH from a posterior approach.

Enzyme-containing spin membranes for rapid digestion and characterization of single proteins.

Proteolytic digestion is an important step in characterizing protein sequences and post-translational modifications (PTMs) using mass spectrometry (MS). This study uses pepsin- or trypsin-containing spin membranes for rapid digestion of single proteins or simple protein mixtures prior to ultrahigh-resolution Orbitrap MS analysis. Centrifugation of 100 µL of pretreated protein solutions through the functionalized membranes requires less than 1 min and conveniently digests proteins into large peptides that aid in confirming specific protein sequence variations and PTMs. Peptic and tryptic peptides from spin digestion of apomyoglobin and four commercial monoclonal antibodies (mAbs) typically cover 100% of the protein sequences in direct infusion MS analysis. Increasing the spin rate leads to a higher fraction of large peptic peptides for apomyoglobin, and MS analysis of peptic and tryptic peptides reveals mAb PTMs such as N-terminal pyroglutamate formation, C-terminal lysine clipping and glycosylation. Relative to overnight in-solution digestion of mAbs, spin digestion yields higher sequence coverages. Spin-membrane digestion followed by infusion MS readily differentiates a mAb to the Ebola virus from a related antibody that differs by addition of a single amino acid.

A rare case of pulmonary toxoplasmosis in a patient with undifferentiated inflammatory arthritis on chronic methotrexate and corticosteroid therapy.

Pulmonary toxoplasmosis is a serious pulmonary condition caused by the protozoan Toxoplasma gondii It typically affects immunocompromised patients presenting acutely with cough, fever, myalgias, arthralgias and lymphadenopathy, and chronically with persistent cough and dyspnoea. Because of its protean features, it can mimic many more common lung conditions in the immunocompromised patient, including atypical pneumonia, Pneumocystis pneumonia and interstitial lung disease. In this article, we present the case of a 55-year-old woman who presented to our hospital with persistent dyspnoea and cough, initially suspected to have an arthritis-related interstitial lung disease. She received a final diagnosis of pulmonary toxoplasmosis after lung biopsy demonstrated Toxoplasma cysts, later confirmed by serology. Treatment with trimethoprim-sulfamethoxazole resulted in significant improvement of her respiratory symptoms after 3 months.

A review for clinicians: Prostate cancer and the antineoplastic properties of metformin.

OBJECTIVES: Metformin has numerous antineoplastic effects including an AMP-activated protein kinase-dependent mechanism, AMP-activated protein kinase-independent mechanisms, alteration of insulin and insulin-like growth factor signaling pathways, and suppression of androgen signaling pathways that trigger prostate cancer growth and proliferation. In contrast to other malignancies that are associated with increased incidence among patients with obesity and type II diabetes mellitus (T2DM), epidemiological studies suggest that obesity and T2DM may impart a protective effect on prostate cancer incidence by creating a set of metabolic conditions that lower androgen levels. METHODS AND MATERIALS: The PubMed and Web of Science databases were searched using the terms "prostate cancer," "metformin," "antineoplastic," "antitumorigenic," and "diabetes" up to the first week of August 2016. Articles regarding metformin's antineoplastic properties on prostate cancer were reviewed. RESULTS: Treating T2DM with metformin may reverse the metabolic conditions that suppress androgen levels, thereby enabling higher levels of androgens to stimulate prostate growth, proliferation, and tumorigenesis. Thus, the antineoplastic properties of metformin may not be appreciable in the early stages of prostate cancer development because metformin corrects for the metabolic conditions of T2DM that impart a protective effect on prostate cancer. These findings, although inconclusive, do not support the use of metformin as a preventive agent for prostate cancer. However, the future appears bright for metformin as either a monotherapy or an adjunct to androgen deprivation therapy, external-beam radiation therapy, prostatectomy, or chemotherapy. Support for this includes meta-analyses that suggest a mortality benefit to patients with prostate cancer on metformin, a clinical trial that demonstrates metformin leads to significant improvement in metabolic syndrome parameters for patients with prostate cancer on androgen deprivation therapy, and a clinical trial that shows metformin has modest activity in the treatment of some patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. CONCLUSIONS: This review summarizes the literature regarding the antineoplastic mechanisms, clinical implications, and future trajectory of clinical research for metformin in prostate cancer.

The Open Approach to Severe Stent Encrustation: A Consecutive Case Series.

Urologists rely heavily on indwelling ureteral stents to manage urinary tract obstruction secondary to calculi, malignancy, stricture, congenital anomalies, or edematous response to operative procedures (Borboroglu and Kane, 2000). The use of a ureteral stent is a temporary intervention and requires removal to prevent potential complications. However, patient noncompliance with follow-up may lead to encrustation of the ureteral stent. Given the widespread use of indwelling ureteral stents in urologic practice, the issue of encrustation secondary to a retained stent is a significant clinical challenge.