Refined hepatic grading system in chronic graft-versus-host disease improves prognostic risk stratification of long-term outcomes.

OBJECTIVES: Hepatic grading systems for categorizing severity in chronic graft-versus-host disease (cGvHD) were determined arbitrarily, leading us to initiate the present study to provide objective evidence for the determination of optimal cutoff values and devise a hepatic grading system to predict prognosis. METHODS: Of 842 patients who received allogeneic hematopoietic stem transplant (HCT), 336 patients diagnosed with cGvHD were evaluated for overall survival (OS) and non-relapse mortality (NRM) after cGVHD development. Multiple statistical parameters were evaluated to define optimal cutoff values of liver profile, including negative predictive value (NPV), positive predictive value (PPV), accuracy, and p-values as measures of risk stratification power. RESULTS: We found that alkaline phosphatase (ALP) ≥ 146 IU/L (NPV: 83.4%; PPV: 32.8%; accuracy: 52.7%) and bilirubin ≥ 14 µmol/L (NPV: 81.8%; PPV: 39.4%; accuracy 68.1%) significantly correlated with OS. We developed a refined hepatic cGvHD grading score (RHS), stratifying patients into a low-RHS group with RHS score 0, OS at 3 years (n = 162) to 80.5%, compared to high-RHS group with score 1-2 (n = 172) 62.7%. Regarding NRM, score 0 segregated NRM at 3 years to 11.9%, compared with score 1-2 19.6%, P = .1. CONCLUSIONS: Refined hepatic score is promising for stratifying patients with cGVHD and liver involvement according to long-term outcomes.

Combination of the Centre for International Blood and Marrow Transplant Registry Risk Score and the Global Severity Score Enhances Prognostic Risk Stratification in Patients Receiving Frontline Therapy for Chronic Graft-versus-Host Disease.

The Centre for International Blood and Marrow Transplant Registry (CIBMTR) score has been shown to be prognostic for overall survival (OS) and nonrelapse mortality (NRM) but has been shown in several single-center studies to classify a large proportion of patients with chronic graft-versus-host disease (cGVHD) in the lower risk groups (RG1 to RG2), thereby limiting its prognostic utility for those patients. We evaluate the CIBMTR score, the Global Severity Score (GSS), and a novel risk score developed to improve on the limitations of the CIBMTR with respect to clinically relevant outcomes, including failure-free survival (FFS), in patients receiving frontline systemic treatment for cGVHD. We identified 277 patients between 2002 and 2012 at the Princess Margaret Cancer Centre in Toronto, Canada, who developed cGVHD and were treated with at least 1 line of systemic therapy. cGVHD was graded by GSS, and patients were stratified by CIBMTR. We evaluated OS, NRM, relapse, and FFS within GSS grade groups, as well as CIBMTR RGs, and used a novel prognostic risk score. The median FFS duration was 164 days in the severe GSS group versus 238 days in the moderate-grade group and 304 days in mild-grade group (P= .001). The median FFS duration was 501 days in CIBMTR RG1 versus 291 days in RG2 and 166 days in RG3 to RG6 (P = .003). A novel risk score combining the GSS and CIBMTR scores was prognostic of OS, NRM, and FFS and was able to subdivide patients with cGVHD in CIBMTR RG1 to RG2 into distinct prognostic risk categories. The CIBMTR risk score and the GSS are well correlated with FFS, OS, and NRM following frontline systemic treatment for cGVHD. A new risk score model combining the CIBMTR risk score and the GSS could enhance risk stratification in the lower CIBMTR risk groups.

Incidence and Risk Factors for Nontuberculous Mycobacterial Infection after Allogeneic Hematopoietic Cell Transplantation.

Allogenic hematopoietic stem cell transplant (HCT) recipients are at risk of many infections. Nontuberculous mycobacteria (NTM) are increasingly recognized as clinically significant pathogens in this population. We investigated the incidence and risk factors for NTM infection after allogeneic HCT. This retrospective cohort study included all patients with allogeneic HCT at our institution during 2001 to 2013. Patients who developed significant NTM infection (NTM disease) were identified. Multivariable modeling was used to identify risk factors for NTM disease, and a risk score model was constructed to identify high-risk patients. Of 1097 allogeneic HCT patients, 45 (4.1%) had NTM isolated and 30 (2.7%) had NTM disease (28 [93.3%] exclusively pulmonary, 2 [6.7%] pulmonary plus another site). Incidence of NTM infection by competing risk analysis was 2.8% at 5 years (95% CI, 1.9% to 4.0%). The median time to diagnosis was 343 days (range, 19 to 1967). In Fine-Gray proportional hazards modeling, only global severity of chronic graft-versus-host disease (cGVHD) (HR, 1.99; 95% CI, 1.12 to 3.53; P = .019,) and cytomegalovirus (CMV) viremia (HR, 5.77; 95% CI, 1.71 to 19.45; P = .004) were significantly associated with NTM disease. Using these variables a risk score was calculated: 1 point for CMV viremia or moderate cGVHD and 2 points for severe cGVHD. The score divided patients into low risk (0 to 1 points, n = 820 [77.3%], 3-year NTM risk 1.2%), intermediate risk (2 points, n = 161 [15.4%], 3-year NTM risk 7.1%), and high risk (3 points, n = 56 [5.4%], 3-year NTM risk 14.3%). NTM disease after allogeneic HCT is common. Severe cGVHD and CMV viremia are associated with increased risk, permitting risk stratification.

Distinctive clinical characteristics and favorable outcomes in patients with large granular lymphocytosis after allo-HCT: 12-year follow-up data.

An increase in large granular lymphocytes (LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo-HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow-up for the occurrence of LGL lymphocytosis after allo-HCT. The 3-year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo-HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival (OS 86.6% vs 44.7% at 3 years), lower non-relapse mortality (NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time-dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo-HCT.

The association of adjuvant therapy with survival at the population level following pancreatic adenocarcinoma resection.

BACKGROUND: Using a retrospective observational cohort approach, the overall survival (OS) following curative-intent resection of pancreatic adenocarcinoma (PC) was defined at the population level according to adjuvant treatment, and predictors of OS were identified. METHODS: Patients undergoing resection of PC in the province of Ontario between 2005 and 2010 were identified using the provincial cancer registry, and linked to databases that include all treatments received and outcomes experienced in the province. Pathology reports were abstracted for staging and margin status. Patients were identified as having received chemotherapy (CT), chemoradiation therapy (CRT), or no adjuvant treatment (NAT). Kaplan-Meier survival analysis of patients surviving ≥ 6 months was performed, and predictors of OS identified by log-rank test. Cox multivariable analysis was used to define independent predictors of OS. RESULTS: Among the 473 patients undergoing PC resection, the median survival was 17.8 months; for the 397 who survived ≥ 6 months following surgery, the 5-year OS for the CT, CRT, and NAT groups was 21%, 16%, and 17%, respectively (p = 0.584). Lymph node-negative patients demonstrated improved OS associated with chemotherapy on multivariable analysis (HR = 2.20, 95% CI = 1.25-3.83 for NAT vs. CT). CONCLUSIONS: Following PC resection, only patients with negative lymph nodes demonstrated improved OS associated with adjuvant chemotherapy.

Incidence, risk factors, and long-term outcomes of sclerotic graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Sclerotic chronic graft-versus-host disease (sclGVHD) is associated with significant morbidity and a poor quality of life. We reviewed 502 patients diagnosed with chronic GVHD and analyzed the incidence and risk factors of sclGVHD and long-term outcomes and immunosuppressive therapy (IST) cessation in patients with sclGVHD. With a median onset at 18 months the cumulative incidence of sclGVHD was estimated at 22.6% at 5 years (95% confidence interval, 18.6% to 26.8%). Univariate and multivariate analysis identified 2 risk factors for sclGVHD: non-T cell depletion (hazard ratio [HR] 9.09, P < .001) and peripheral blood stem cell (HR 3.87, P < .001). Overall survival (OS) at 5 years was significantly better in the sclGVHD group (88.1%) compared with the non-sclGVHD group (62.7%; P < .001), as were nonrelapse mortality (7.3% versus 21.5% at 5 years) and relapse rates (9.1% versus 19.3% at 5 years). There was no difference in the rate of IST cessation at 5 years (44.8% versus 49.9%, P = .312), but there was a trend of longer IST duration in the sclGVHD group compared with the non-sclGVHD group (median 71.6 months versus 62.9 months). In conclusion, T cell depletion and graft source affect the risk of sclGVHD. SclGVHD did not adversely affect long-term outcomes or IST duration.

Predicting Early Graft Dysfunction and Mortality After Liver Transplant Using the De Ritis Ratio.

BACKGROUND: Predicting complications after liver transplantation (LT) remains challenging. We propose incorporating the De Ritis ratio (DRR), a widely known parameter of liver dysfunction, into current or future scoring models to predict early allograft dysfunction (EAD) and mortality after LT. METHODS: A retrospective chart review was conducted on 132 adults receiving a deceased donor LT from April 2015 to March 2020 and their matching donors. Donor variables, postoperative liver function, and DRR were correlated with the occurrence of EAD, post-transplant complications expressed by the Clavien-Dindo score, and 30-day mortality as outcome variables. RESULTS: Early allograft dysfunction was observed in 26.5% of patients and 7.6% of patients who died within 30 days after transplant. Recipients were more likely to experience EAD when receiving grafts from donation after circulatory death (P = .04), donor risk index (DRI) >2 (P = .006), ischemic injury at time-zero biopsy (P = .02), longer secondary warm ischemia time (P < .05), or higher Clavien-Dindo scores (IIIb-V; P < .001). The DRI, total bilirubin, and DRR on postoperative day 5 yielded significant associations with the primary outcomes and were used to develop the Gala-Lopez score using a weighted scoring model. This accurately predicted EAD, high Clavien-Dindo, and 30-day mortality in 75%, 81%, and 64% of patients. CONCLUSION: Including recipient and donor variables in predictive models, and for the first time DRR, as a constituent, should be regarded to predict EAD, severe complications, and 30-day mortality post-LT. Further studies will be required to validate the present findings and their applicability when using normothermic regional and machine perfusion technologies.

The gendered ovary: whole body effects of oophorectomy.

Since oophorectomy in healthy women predates the commercialization of BRCA mutations screens, genomics cannot explain entirely why physicians and cancer specialists recommend this procedure for women at risk. Rather, one must situate the development of reproductive cancer genomics within a broader sociocultural context in which researchers bring to bear habits of mind about women, reproduction and motherhood. (Happe, 2006, p. 173)

Population-Level Symptom Assessment Following Pancreaticoduodenectomy for Adenocarcinoma.

Importance: Postoperative morbidity associated with pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) remains as high as 70%. However, to our knowledge, few studies have examined quality of life in this patient population. Objective: To identify symptom burden and trajectories and factors associated with high symptom burden following PD for PA. Design, Setting, and Participants: This population-based cohort study of patients undergoing PD for PA diagnosed between 2009 and 2015 linked population-level administrative health care data to routinely prospectively collected Edmonton Symptom Assessment System (ESAS) scores from 2009 to 2015, with a data analysis undertaken in 2018. Exposures: Baseline characteristics, including age, sex, income quintile, rurality, immigration status, and comorbidity burden, as well as treatment characteristics, including year of surgery and receipt of chemotherapy. Main Outcome and Measures: The outcome of interest was moderate to severe symptoms (defined as ESAS ≥4) for anxiety, depression, drowsiness, lack of appetite, nausea, pain, shortness of breath, tiredness, and impaired well-being. The monthly prevalence of moderate to severe symptoms was presented graphically for each symptom. Multivariable regression models identified factors associated with the reporting of moderate to severe symptoms. Results: We analyzed 6058 individual symptom assessments among 615 patients with PA who underwent resection (285 women [46.3%]) with ESAS data. Tiredness (443 [72%]), impaired well-being (418 [68%]), and lack of appetite (400 [65%]) were most commonly reported as moderate to severe. The proportion of patients with moderate to severe symptoms was highest immediately after surgery (range, 14%-66% per symptom) and decreased over time, stabilizing around 3 months (range, 8%-42% per symptom). Female sex, higher comorbidity, and lower income were associated with a higher risk of reporting moderate to severe symptoms. Receipt of adjuvant chemotherapy was not associated with the risk of moderate to severe symptoms. Conclusions and Relevance: There is a high prevalence of symptoms following PD for PA, with improvement over the first 3 months following surgery. In what to our knowledge is the largest cohort reporting on symptom burden for this population, we have identified factors associated with symptom severity. These findings will aid in managing patients' perioperative expectations and designing strategies to improve targeted symptom management.

Influência do nistagmo espontâneo de olhos fechados na vectonistagmografia computadorizada em pacientes com vestibulopatias periféricas crônicas / Influence of spontaneous nystagmus with eyes closed on computerized vestibular exam of patients with chronic peripheral

Introdução: O nistagmo espontâneo de olhos fechados (NEOF) pode modificar os resultados obtidos durante algumas provas do exame vestibular, levando a conclusões errôneas. Objetivo: Caracterizar os pacientes e o tipo de influência do NEOF nas provas da vectonistagmografia digital. Método: Estudo retrospectivo baseado no levantamento de prontuários de pacientes com presença de NEOF à vectonistagmografia digital, atendidos no Ambulatório de Equilibriometria da UNIFESP-EPM, nos anos de 2000 a 2007. Foram realizadas comparações entre gêneros, idades, direção, velocidade angular do NEOF, conclusão do exame vestibular e sua influência nos resultados da prova calórica. Resultados: Encontramos 73,7% população do sexo feminino; média etária de 55,08 anos; prevalência do NEOF horizontais e velocidade angular menor do que 7o/s em 86,7%. 59% da amostra apresentaram algum tipo de influência causado pelo NEOF na prova calórica como: inversão, hiporreflexia, hiper-reflexia, preponderância direcional do nistagmo (PDN) e preponderância labiríntica (PL) alteradas. As conclusões mais prevalentes foram Exame Vestibular Normal (EVN) e síndrome vestibular periférica irritativa bilateral (SVPIB). 38,7% realizaram prova calórica gelada e desses casos foi possível chegar a uma conclusão em 79%. Conclusão: O NEOF mais comum foi do tipo horizontal, com VACL menor do que 7o/s, influenciando na maioria dos exames e somente nos resultados da prova calórica a ar, com inversão do nistagmo pós-calórico, hiper-reflexia e hiporreflexia, PDN e PL alteradas; as conclusões mais prevalentes foram EVN e SVPIB; e a prova calórica gelada retirou a influência do NEOF na maioria dos indivíduos, possibilitando chegar a uma conclusão final.

Introduction: The spontaneous nystagmus with eyes closed (NEOF) can modify the results obtained during some evidence of vestibular, leading to erroneous conclusions. Objective: To characterize the patients and the type of influence on the evidence of NEOF vectonystagmography digital. Method: Retrospective study based on survey charts of patients with the presence of NEOF vectonystagmography digital, in the Outpatient Equilibriometria UNIFESP-EPM, in the years 2000 to 2007. Comparisons were made between genders, ages, direction, angular velocity of NEOF, completion of entrance examination and its influence on the results of caloric testing. Results: We found 73.7% of the population was female, mean age of 55.08 years; NEOF prevalence of horizontal and angular velocity smaller than 7o/s in 86.7%. 59% had some kind of influence caused by the caloric test NEOF as inversion, hyporeflexia, hyperreflexia, nystagmus directional preponderance (NDP) and labyrinthine preponderance (LP) changed. The most prevalent findings were normal vestibular tests (EVN) and bilateral irritative peripheral vestibular syndrome (BIPVS). 38.7% caloric ice and realized these cases it was possible to reach a conclusion in 79%. Conclusion: The NEOF most common was the horizontal type, with VACL less than 7o/s, influencing the majority of examinations and only the results of caloric testing the air, with reversal of post-caloric nystagmus, hyperreflexia and hyporeflexia, NDP and PL altered; the findings were more prevalent and BIPVS EVN, and the caloric test the influence of ice withdrew NEOF in most individuals, enabling to reach a final conclusion.