Hypomethylating Agents and Venetoclax for Acute Myeloid Leukemia Relapsed After Hematopoietic Stem Cell Transplant.

BACKGROUND: Hypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. PATIENTS AND METHODS: We retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. RESULTS: CR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. CONCLUSION: These data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.

Neoadjuvant platinum-based chemotherapy and lymphadenectomy for penile cancer: an international, multi-institutional, real-world study.

INTRODUCTION: This study investigated the efficacy and safety of neoadjuvant chemotherapy for locally advance penile squamous cell carcinoma for which current evidence is lacking. METHODS: Included patients had locally advanced penile squamous cell carcinoma with clinical lymph node metastasis treated with at least 1 dose of neoadjuvant chemotherapy prior to planned consolidative lymphadenectomy. Objective response rates were assessed using Response Evaluation Criteria in Solid Tumors v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan-Meier method. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events v5.0. RESULTS: A total of 209 patients received neoadjuvant chemotherapy for locally advanced and clinically node-positive penile squamous cell carcinoma. The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 treatment-related adverse events occurred in 35 (17%) patients, and no treatment-related mortality was observed. Of the patients, 201 (97%) completed planned consolidative lymphadenectomy. During follow-up, 106 (52.7%) patients expired, with a median overall survival of 37.0 months (95% confidence interval [CI] = 23.8 to 50.1 months) and median progression-free survival of 26.0 months (95% CI = 11.7 to 40.2 months). Objective response rate was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to neoadjuvant chemotherapy had a longer median overall survival (73.0 vs 17.0 months, P < .01) compared with those who did not. The lymph node pathologic complete response rate was 24.8% in the cohort. CONCLUSION: Neoadjuvant chemotherapy with lymphadenectomy for locally advanced penile squamous cell carcinoma is well tolerated and active to reduce the disease burden and improve long-term survival outcomes.

15 years of patient-reported outcomes in clinical trials leading to GU cancer drug approvals: a systematic review on the quality of data reporting and analysis.

Background: Standardized, high-quality PRO data reporting is crucial for patient centered care in the field of oncology, especially in clinical trials that establish standard of care. This study evaluated PRO endpoint design, conduct and reporting methods in FDA approved drugs for GU malignancies. Methods: A systematic review of the FDA archives identified GU cancer drug approvals from Feb 2007 to July 2022. ClinicalTrials.gov and PubMed were used to retrieve relevant data. PRO data was screened, and analytic tools, interpretation methods in the published papers and study protocols were reviewed. Compliance with PRO reporting standards were assessed using PRO Endpoint Analysis Score (PROEAS), a 24-point scoring scale from Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium (SISAQOL). Findings: We assessed 40 trial protocols with 27,011 participants, resulting in 14 renal cell cancer (RCC), 16 prostate cancer (PC), and 10 urothelial cancer (UC) approvals. PRO data was published for 27 trials, with 23 PRO publications (85%) focusing solely on PRO data, while 4 (15%) included PRO data in the original paper. Median time between primary clinical and secondary paper with PRO data was 10.5 months (range: 9-25 months). PROs were not planned as primary endpoints for any study but 14 (52%) reported them as secondary, 10 (37%) as exploratory outcomes, and 3 (11%) lacked any clarity on PRO data as endpoint. Mean PROEAS score of all GU cancers was 11.10 (range: 6-15), RCC (11.86, range: 6-15), UC (11.50, range: 9-14), and PC (10.56, range: 6-15). None met all the SISAQOL recommendations. Interpretation: Low overall PROEAS score and delays in PRO data publication in GU cancer drug trials conducted in the past decade emphasize the need for improvement in quality of design and conduct of PRO endpoint in future trials and accelerated publication of PRO endpoints, using standardized analysis, and prespecified hypothesis driven endpoint. These improvements are essential for facilitating interpretation and application of PRO study findings to define patient care. Funding: None.

Multiplex Immunofluorescence Captures Progressive Immune Exhaustion with Advancing Penile Squamous Cell Cancer Stage.

Penile squamous cell carcinoma (PSCC) is a rare and deadly malignancy. Therapeutic advances have been stifled by a poor understanding of disease biology. Specifically, the immune microenvironment is an underexplored component in PSCC and the activity of immune checkpoint inhibitors observed in a subset of patients suggests immune escape may play an important role in tumorigenesis. Herein, we explored for the first time the immune microenvironment of 57 men with PSCC and how it varies with the presence of human papillomavirus (HPV) infection and across tumor stages using multiplex immunofluorescence of key immune cell markers. We observed an increase in the density of immune effector cells in node-negative tumors and a progressive rise in inhibitory immune players such as type 2 macrophages and upregulation of the PD-L1 checkpoint in men with N1 and N2-3 disease. There were no differences in immune cell densities with HPV status.

The Prognostic Role of Human Papillomavirus and p16 Status in Penile Squamous Cell Carcinoma-A Systematic Review.

PSCC is a rare cancer, with approximately half of all cases related to HPV. While HPV and p16 IHC testing have proven their prognostic value for oropharyngeal cancer, this is not yet established for PSCC. The current level of evidence exploring the relation between PSCC and HPV is moderate, so we conducted a systematic review following PRISMA guidelines to evaluate the prognostic role of HPV and p16 IHC in PSCC clinical outcomes. We searched the PubMed, Embase, and Cochrane databases and identified 34 relevant studies that met our inclusion criteria. Of these, 33 were retrospective cohort studies, and one was a cross-sectional study. Nine studies reported that HPV-positive and p16-positive PSCC had better overall survival (OS) and disease-free survival (DFS). This study highlights the need for a meta-analysis to determine the role of routine HPV status or p16 staining testing as part of the initial diagnosis and staging of PSCC patients worldwide.

Static Respiratory System Compliance as a Predictor of Extubation Failure in Patients with Acute Respiratory Failure.

PURPOSE: Ventilator weaning protocols rely in part on objective indices to best predict extubation failure in the critically ill. We investigated static respiratory system compliance (RC) as a predictor of extubation failure, in comparison to extubation readiness using rapid shallow breathing index (RSBI). MATERIAL AND METHODS: This was a cross-sectional, multi-institutional study of mechanically ventilated patients admitted between 12/01/2017 and 12/01/2019. All patients older than 18 years with a documented spontaneous breathing trial and extubation trial were included. RC and RSBI were calculated prior to the extubation trial. The primary outcome was extubation failure-defined as need for reintubation within 72 h from time of extubation. RESULTS: Of the 2263 patients, 55.8% were males with a mean age of 68 years. The population consisted mostly of Caucasians (73%) and African Americans (20.4%). 274 (12.1%) patients required reintubation within 72 h. On multivariate logistic regression after adjusting for age, sex, body mass index (BMI), admission Sequential Organ Failure Assessment (SOFA) score, number of ventilator days, and the P/F ratio on the day of extubation, RC remained the strongest predictor for extubation failure at 24 h (aOR 1.45; 95% CI 1.00-2.10) and 72 h (aOR 1.58; 95% CI 1.15-2.17). There was no significant association between RSBI and extubation failure at 24 (aOR 1.00; 95% CI 0.99-1.01) or at 72 h (aOR 1.00; 95% CI 0.99-1.01). CONCLUSION: RC measured on the day of extubation is a promising physiological discriminant to potentially risk stratify patients with acute respiratory failure for extubation readiness. We recommend further validation studies in prospective cohorts.

A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer.

Background: We hypothesize that cancer survival can be improved through adapting treatment strategies to cancer evolutionary dynamics and conducted a phase 1b study in metastatic castration sensitive prostate cancer (mCSPC). Methods: Men with asymptomatic mCSPC were enrolled and proceeded with a treatment break after achieving > 75% PSA decline with LHRH analog plus an NHA. ADT was restarted at the time of PSA or radiographic progression and held again after achieving >50% PSA decline. This on-off cycling of ADT continued until on treatment imaging progression. Results: At data cut off in August 2022, only 2 of the 16 evaluable patients were off study due to imaging progression at 28 months from first dose of LHRH analog for mCSPC. Two additional patients showed PSA progression at 12.4 and 20.5 months and remain on trial. Since none of the 16 patients developed imaging progression at 12 months, the study succeeded in its primary objective of feasibility. The secondary endpoints of median time to PSA progression and median time to radiographic progression have not been reached at a median follow up of 26 months. Conclusions: It is feasible to use an individual's PSA response and testosterone levels to guide intermittent ADT in mCSPC.

Evidence showing lipotoxicity worsens outcomes in covid-19 patients and insights about the underlying mechanisms.

We compared three hospitalized patient cohorts and conducted mechanistic studies to determine if lipotoxicity worsens COVID-19. Cohort-1 (n = 30) compared COVID-19 patients dismissed home to those requiring intensive-care unit (ICU) transfer. Cohort-2 (n = 116) compared critically ill ICU patients with and without COVID-19. Cohort-3 (n = 3969) studied hypoalbuminemia and hypocalcemia's impact on COVID-19 mortality. Patients requiring ICU transfer had higher serum albumin unbound linoleic acid (LA). Unbound fatty acids and LA were elevated in ICU transfers, COVID-19 ICU patients and ICU non-survivors. COVID-19 ICU patients (cohort-2) had greater serum lipase, damage-associated molecular patterns (DAMPs), cytokines, hypocalcemia, hypoalbuminemia, organ failure and thrombotic events. Hypocalcemia and hypoalbuminemia independently associated with COVID-19 mortality in cohort-3. Experimentally, LA reacted with albumin, calcium and induced hypocalcemia, hypoalbuminemia in mice. Endothelial cells took up unbound LA, which depolarized their mitochondria. In mice, unbound LA increased DAMPs, cytokines, causing endothelial injury, organ failure and thrombosis. Therefore, excessive unbound LA in the circulation may worsen COVID-19 outcomes.

Venous thromboembolism prophylaxis in hospitalized sickle cell disease and sickle cell trait patients.

INTRODUCTION: Sickle trait (Hb SA) or sickle disease (Hb SS) carries increased risk of venous thromboembolism (VTE). Hb SS patients are young and lack common comorbid conditions that qualify them for VTE prophylaxis (VTEP). METHODS: Retrospective, multicenter analysis of Hb SS/Hb SA adult patients between January 2013 and December 2018. RESULTS: There were 803 Hb SA (525 patients) and 1020 Hb SS admissions (262 patients). VTEP use was similar between Hb SA and controls (42% vs. 46%; p-value = .06) and Hb SS and controls (45% vs. 42%; p-value = .13). Hb SS/Hb SA patients more frequently received more than half of prescribed doses of VTEP. In multivariate analysis, increasing age and longer hospitalizations were positive predictors. Odds of VTEP use varied with treatment site for Hb SS patients, whereas comorbid conditions, admission hemoglobin and platelet count were not predictive. By contrast, in Hb SA patients, comorbid conditions, higher admission hemoglobin, and higher admission platelet counts raised the odds of VTEP being offered. CONCLUSIONS: VTEP is underused in Hb SS/Hb SA patients. There may be a trend toward offering more VTEP in Hb SS disease, but not in Hb SA patients, where VTEP prescribing is driven by comorbid conditions rather than genotype. Patient compliance does not appear to play a major role, but intercenter variability suggests provider education may improve VTEP use.

Clinical Applications of Liquid Biopsy in Prostate Cancer: From Screening to Predictive Biomarker.

Prostate cancer (PC) remains the most common malignancy and the second most common cause of cancer death in men. As a result of highly variable biological behavior and development of resistance to available agents under therapeutic pressure, optimal management is often unclear. Traditional surgical biopsies, even when augmented by genomic studies, may fail to provide adequate guidance for clinical decisions as these can only provide a snapshot of a dynamic process. Additionally, surgical biopsies are cumbersome to perform repeatedly and often involve risk. Liquid biopsies (LB) are defined as the analysis of either corpuscular (circulating tumor cells, extracellular vesicles) or molecular (circulating DNA or RNA) tumor-derived material. LB could more precisely identify clinically relevant alterations that characterize the metastatic potential of tumors, predict response to specific treatments or actively monitor for the emergence of resistance. These tests can potentially be repeated as often as deemed necessary and can detect real-time response to treatment with minimal inconvenience to the patient. In the current review, we consider common clinical scenarios to describe available LB assays in PC as a platform to explore existing evidence for their use in guiding decision making and to discuss current limitations to their adoption in the clinic.

Extubation Failure in Critically Ill COVID-19 Patients: Risk Factors and Impact on In-Hospital Mortality.

PURPOSE: We sought to identify clinical factors that predict extubation failure (reintubation) and its prognostic implications in critically ill COVID-19 patients. MATERIALS AND METHODS: Retrospective, multi-center cohort study of hospitalized COVID-19 patients. Multivariate competing risk models were employed to explore the rate of reintubation and its determining factors. RESULTS: Two hundred eighty-one extubated patients were included (mean age, 61.0 years [±13.9]; 54.8% male). Reintubation occurred in 93 (33.1%). In multivariate analysis accounting for death, reintubation risk increased with age (hazard ratio [HR] 1.04 per 1-year increase, 95% confidence interval [CI] 1.02 -1.06), vasopressors (HR 1.84, 95% CI 1.04-3.60), renal replacement (HR 2.01, 95% CI 1.22-3.29), maximum PEEP (HR 1.07 per 1-unit increase, 95% CI 1.02 -1.12), paralytics (HR 1.48, 95% CI 1.08-2.25) and requiring more than nasal cannula immediately post-extubation (HR 2.19, 95% CI 1.37-3.50). Reintubation was associated with higher mortality (36.6% vs 2.1%; P < 0.0001) and risk of inpatient death after adjusting for multiple factors (HR 23.2, 95% CI 6.45-83.33). Prone ventilation, corticosteroids, anticoagulation, remdesivir and tocilizumab did not impact the risk of reintubation or death. CONCLUSIONS: Up to 1 in 3 critically ill COVID-19 patients required reintubation. Older age, paralytics, high PEEP, need for greater respiratory support following extubation and non-pulmonary organ failure predicted reintubation. Extubation failure strongly predicted adverse outcomes.

Gradient changes in bioprosthetic valve thrombosis: duration of anticoagulation and strategies to improve detection.

OBJECTIVE: Bioprosthetic valve thrombosis (BPVT) is increasingly recognised as a major cause of prosthetic dysfunction in the first years postimplantation. How early abnormal gradients can be detected prior to diagnosis and how fast they normalise with anticoagulant therapy is unknown. We set forth to (1) evaluate patterns of increase in gradients prior to BPVT diagnosis and (2) characterise time-course of response to anticoagulation. METHODS: Patients treated with warfarin for BPVT (1999-2019) with clinically significant reduction of mean gradients (≥25%) were identified retrospectively. Recovery was defined as gradient decrease ≥50%, to postimplantation or to normal-range gradients per position, model and size. Time-to-BPVT (implantation-BPVT diagnosis), potential diagnostic delay (first abnormal gradient by position, model and size-BPVT diagnosis) and time-to-recovery (BPVT diagnosis-complete resolution) were recorded. RESULTS: 77 patients were identified; 32 (42%) aortic (23 surgical-12 porcine, 11 pericardial; 9 transcatheter); 24 (31%) mitral; 21 (27%) tricuspid. Median time-to-BPVT was 24, 21 and 10 months, respectively. Potential diagnostic delay was median 21 months for aortic, 4 months for mitral, but 0 for tricuspid. Recovery was significantly faster in mitral than aortic (median 2.5 vs 4.8 months, p=0.038) and tricuspid (median 5.9 months, p=0.025) positions. Porcine aortic valves responded faster than pericardial aortic valves (median 2.9 vs 20.3 months, p=0.004). CONCLUSION: Gradients start to increase months before the clinical BPVT diagnosis. Recovery is faster in mitral and surgical aortic porcine valves; a longer warfarin trial seems indicated in tricuspid and surgical aortic pericardial valves.

Inferior Vena Cava Filter Retrieval Trends: A Single-Center Experience.

Recognition of the adverse events of inferior vena cava filters (VCFs) has prompted the Food and Drug Administration (FDA) to issue safety warnings (2010 and 2014), advocating for removal, once the risk of pulmonary embolism has abated. Despite an initial increase in retrieval rates, these remain low (25-30% at 1 year in 2014). We retrospectively investigated retrieval trends in adults with VCFs placed between 2015 and 2018 at a single institution. The rate of retrievable VCF removal accounting for the competing risk of death was the main outcome. There were 494 VCFs placed (305 retrievable). The cumulative incidence of retrieval remained low (21% at 1 year), even after the second FDA warning (2014). Patients who resumed anticoagulation (AC) at any time were more likely to have retrieval (hazard ratio [HR] = 3.6, p < 0.01) and had higher retrieval rates at every time point (31.4 vs. 7.6% at 1 year). Advanced age (HR = 0.98 per year, p = 0.004), stroke (HR = 0.28, p = 0.028), and active malignancy (HR = 0.42, p = 0.006) predicted nonretrieval. Device-related complications were infrequent (<1%) but thrombotic complications occurred early and were more common for nonretrieved VCFs (17 vs. 12%, p = 0.29). Revision of guidelines to recommend active surveillance for the ability to tolerate AC in the immediate postimplantation period may improve retrieval rates.

Safety of apixaban compared to warfarin in hemodialysis patients: Do antiplatelets make a difference?

BACKGROUND: Data on the safety of apixaban compared to warfarin in hemodialysis (HD) patients are accumulating, but the impact of concomitant antiplatelet use is unknown. OBJECTIVES: Compare hemorrhagic risk and impact of antiplatelets in HD patients receiving oral anticoagulants (OAC). METHODS: Retrospective, multi-center study of HD patients started on OAC inpatient over 5 years. RESULTS: 707 patients were included: 563 received warfarin, and 144 received apixaban. 197 had bleeding, most in the warfarin group (173 [30.1%] vs 24 [16.7%] in the apixaban group), P-value < .01). However, with concomitant antiplatelet use, frequencies were similar (31.4% vs 25.0%; P-value = .292). Cumulative incidence using bleeding as event of interest and death as competing risk showed higher rates of bleeding with warfarin. In a multivariate model, apixaban was associated with a lower hemorrhagic risk (hazard ratio [HR] 0.55 [95% confidence interval {CI} 0.35-0.86}). Apixaban showed lower hemorrhagic risk alone (HR 0.24, 95% CI 0.10-0.55) and similar risk when administered with antiplatelets (HR 0.93, 95% CI 0.55-1.56). CONCLUSIONS: Apixaban is associated with less bleeding in HD patients compared to warfarin, but concomitant antiplatelet use may negate the safety advantage. Prospective trials are warranted to determine the impact of antiplatelets on apixaban safety.

Association of anticoagulation dose and survival in hospitalized COVID-19 patients: A retrospective propensity score-weighted analysis.

BACKGROUND: Hypercoagulability may contribute to COVID-19 pathogenicity. The role of anticoagulation (AC) at therapeutic (tAC) or prophylactic doses (pAC) is unclear. OBJECTIVES: We evaluated the impact on survival of different AC doses in COVID-19 patients. METHODS: Retrospective, multi-center cohort study of consecutive COVID-19 patients hospitalized between March 13 and May 5, 2020. RESULTS: A total of 3480 patients were included (mean age, 64.5 years [17.0]; 51.5% female; 52.1% black and 40.6% white). 18.5% (n = 642) required intensive care unit (ICU) stay. 60.9% received pAC (n = 2121), 28.7% received ≥3 days of tAC (n = 998), and 10.4% (n = 361) received no AC. Propensity score (PS) weighted Kaplan-Meier plot demonstrated different 25-day survival probability in the tAC and pAC groups (57.5% vs 50.7%). In a PS-weighted multivariate proportional hazards model, AC was associated with reduced risk of death at prophylactic (hazard ratio [HR] 0.35 [95% confidence interval {CI} 0.22-0.54]) and therapeutic doses (HR 0.14 [95% CI 0.05-0.23]) compared to no AC. Major bleeding occurred more frequently in tAC patients (81 [8.1%]) compared to no AC (20 [5.5%]) or pAC (46 [2.2%]) subjects. CONCLUSIONS: Higher doses of AC were associated with lower mortality in hospitalized COVID-19 patients. Prospective evaluation of efficacy and risk of AC in COVID-19 is warranted.

Therapeutic Anticoagulation Delays Death in COVID-19 Patients: Cross-Sectional Analysis of a Prospective Cohort.

A hypercoagulable state has been described in coronavirus disease 2019 (COVID-19) patients. Others have reported a survival advantage with prophylactic anticoagulation (pAC) and therapeutic anticoagulation (tAC), but these retrospective analyses have important limitations such as confounding by indication. We studied the impact of tAC and pAC compared with no anticoagulation (AC) on time to death in COVID-19. We performed a cross-sectional analysis of 127 deceased COVID-19 patients and compared time to death in those who received tAC ( n = 67), pAC ( n = 47), and no AC ( n = 13). Median time to death was longer with higher doses of AC (11 days for tAC, 8 days for pAC, and 4 days for no AC, p < 0.001). In multivariate analysis, AC was associated with longer time to death, both at prophylactic (hazard ratio [HR] = 0.29; 95% confidence interval [CI]: 0.15 to 0.58; p < 0.001) and therapeutic doses (HR = 0.15; 95% CI: 0.07 to 0.32; p < 0.001) compared with no AC. Bleeding rates were similar among tAC and remaining patients (19 vs. 18%; p = 0.877). In deceased COVID-19 patients, AC was associated with a delay in death in a dose-dependent manner. Randomized trials are required to prospectively investigate the benefit and safety of higher doses of AC in this population.

Unusual behaviour of an unusual tumour: calcitriol-induced hypercalcaemia in metastatic oesophageal neuroendocrine carcinoma.

Hypercalcaemia in malignancy is most commonly caused by paraneoplastic secretion of parathyroid hormone-related protein or osteolytic metastases. Very rarely (<1% of cases), the mechanism behind increased serum calcium is increased production of calcitriol (1,25-dihydroxyvitamin D) and even rarer is the occurrence of this phenomenon in solid malignancies, with few such instances reported in the literature. We present a case of a neuroendocrine malignancy originating in the oesophagus associated with calcitriol-induced hypercalcaemia, a phenomenon that has not been previously described. We review the pathophysiology of calcitriol-induced hypercalcaemia and previously reported cases of solid tumours with this presentation.

Long-Term Outcomes of Anticoagulation for Bioprosthetic Valve Thrombosis.

BACKGROUND: Early in the prevention and treatment of bioprosthetic valve thrombosis (BPVT), anticoagulation is effective, but the long-term outcome after BPVT is unknown. OBJECTIVES: The goal of this study was to assess the long-term outcomes of patients with BPVT treated with anticoagulation. METHODS: This analysis was a matched cohort study of patients treated with warfarin for suspected BPVT at the Mayo Clinic between 1999 and 2017. RESULTS: A total of 83 patients treated with warfarin for suspected BPVT (age 57 ± 18 years; 45 men [54%]) were matched to 166 control subjects; matching was performed according to age, sex, year of implantation, and prosthesis type and position. Echocardiography normalized in 62 patients (75%) within 3 months (interquartile range [IQR]: 1.5 to 6 months) of anticoagulation; 21 patients (25%) did not respond to warfarin. Median follow-up after diagnosis was 34 months (IQR: 17 to 54 months). There was no difference in the primary composite endpoint between the patients with BPVT and the matched control subjects (log-rank test, p = 0.79), but the former did have a significantly higher rate of major bleeding (12% vs. 2%; p < 0.0001). BPVT recurred (re-BPVT) in 14 (23%) responders after a median of 23 months (IQR: 11 to 39 months); all but one re-BPVT patient responded to anticoagulant therapy. Patients with BPVT had a higher probability of valve re-replacement (68% vs. 24% at 10 years' post-BPVT; log-rank test, p < 0.001). CONCLUSIONS: BPVT was associated with re-BPVT and early prosthetic degeneration in a significant number of patients. Indefinite warfarin anticoagulation should be considered after a confirmed BPVT episode, but this strategy must be balanced against an increased risk of bleeding.

Diffuse large B-cell lymphoma of the vagina in pregnancy.

A 28-year-old primigravida was evaluated for complaints of difficulty urinating and pelvic pain of 6-weeks duration. She denied fever, night sweats, weight loss or fatigue. Pelvic ultrasonography revealed a single fetal pole with cardiac activity and a 7 cm mass in the anterior vagina which encased the urethra. The diagnosis of diffuse large B-cell lymphoma germinal centre type was made on analysis of biopsied pelvic mass. Whole body MRI revealed the disease was limited to the vagina. The patient received six cycles of Rituximab-cyclophosphamide, doxorubicin, vincristine and prednisone with significant improvement in her symptoms. Serial ultrasounds over the subsequent months showed appropriate development of the fetus. Whole body MRI after treatment showed decreased size and decreased signal of the primary pelvic mass compatible with favourable treatment response. Challenges in the management of this rare presentation of lymphoma are discussed.

Prognostic Importance and Predictors of Survival in Isolated Tricuspid Regurgitation: A Growing Problem.

OBJECTIVE: To define mortality associated with isolated tricuspid regurgitation (TR) and identify risk factors associated with decreased survival. PATIENTS AND METHODS: We conducted a retrospective cohort study of residents of southeastern Minnesota with moderate-severe or more severe isolated TR diagnosed between January 1, 2005, and April 15, 2015. Isolated TR was defined as TR in the absence of left-sided heart disease or pulmonary hypertension. Patients with an ejection fraction of less than 50%, right ventricular systolic pressure greater than 45 mm Hg, moderate or more severe left-sided valve disease, congenital cardiac anomalies, previous valve operation, tricuspid stenosis, flail leaflet, carcinoid, and rheumatic disease were excluded. Five-year survival was compared with age- and sex-matched Minnesota census bureau data. Multivariate regression was used to identify variables associated with mortality. RESULTS: Over a 10-year period, 289 patients with isolated TR were identified. The mean ± SD age was 79.2±10.6 years, 70.6% (204) were women, atrial fibrillation was present in 74.0% (214), and 24.6% (71) had an intracardiac device. By 5 years after diagnosis, 51.5% had been hospitalized for heart failure. Observed 5-year mortality was 47.8% compared with 36.3% in the census data (P=.005). After adjusting for age and other comorbidities, multivariate regression identified a dilated inferior vena cava (≥2.1 cm) without respiratory variation on echocardiography (hazard ratio, 1.93; 95% CI, 1.13-3.31; P=.02) and creatinine level greater than 1.6 mg/dL (hazard ratio, 1.8; 95% CI, 1.16-2.8; P=.009) as associated with increased mortality. CONCLUSION: Patients with isolated TR are frequently hospitalized for heart failure and experience excess mortality. Elevated right atrial pressure and renal dysfunction are associated with mortality. This poor outcome may have implications for timing of intervention.