Disease-related Causes Research Articles

Access barriers to anti-CD19+ CAR T-cell therapy for NHL across a community transplant and cellular therapy network

AbstractWe analyzed access barriers to anti-CD19+ chimeric antigen receptor T cells (CARTs) for non-Hodgkin lymphoma (NHL) within a community-based transplant and cell therapy network registry. A total of 357 intended recipients of US Food and Drug Administration–approved anti-CD19+ CARTs were identified during the study period (2018-2022). Results showed that the median age at referral was 61 years; referral years were 2018 (4%), 2019 (14%), 2020 (18%), 2021 (26%), and 2022 (38%). Diagnoses included diffuse large B cell (69%), follicular (13%), follicular/large (7%), mantle cell (4%), or other (7%). CART products infused were axicabtagene ciloleucel (62%), Tisa-cel (16%), Brexu-cel (13%), and lisocabtagene maraleucel (9%). One hundred eighty-two patients received infusion with CARTs. The median durations between referral to consultation, consultation to apheresis, and collection to infusion were 11, 107, and 32 days, respectively. The median duration from consultation to CART infusion declined steadily from 207 days in 2019 to 108 days in 2022 (P < .0001). A total of 124 patients (41%) did not receive CART, mostly from disease progression (34%) or poor health (15%). Multivariable logistic regression showed no significant differences in demographic, financial, or social determinants compared with those receiving CART. Notably, the proportion of ineligible patients declined from 53% in 2018 to 2020 to 34% by 2021 to 2022 (P = .001). In conclusion, 41% of community patients were unable to access timely CART therapy for NHL, mostly related to attrition from disease-related causes, whereas the overall time to infusion exceeded 4 months. Time to infusion and the proportion receiving CARTs improved over time. Reducing time to apheresis, early referral, and careful attention to salvage/bridging strategies are necessary.

A Pilot Study of Age Estimation and Cause of Death: Insights into Skeletal Aging

Background/Objectives: Forensic anthropological age estimations are often limited by a lack of diversity in reference samples, imprecision, and, for certain populations, inaccuracy. This study aims to explore the relationship between health, as indicated by cause of death, and skeletal age estimation, with the goal of determining whether including health information can improve accuracy and precision in age estimation. Methods: Skeletal age data were collected from the Maxwell Museum Documented Skeletal Collection using the Lovejoy et al. method for the auricular surface and the Suchey-Brooks method for the pubic symphysis. All individuals had a known cause of death, which was categorized into two broad groups: disease-related and trauma-related. Cause of death category served as a proxy for health status. Results: Individuals who died from disease-related causes often fell within the upper end of the age ranges for both the auricular surface and pubic symphysis methods. In contrast, those who died from trauma-related causes tended to fall within the lower end of these age ranges. Conclusions: These results indicate that incorporating factors such as health into existing forensic age estimation methods could enhance the precision of age estimates, particularly by addressing the influence of environmental and lifestyle factors on skeletal aging.

Gain of chromosome 8q and high expression of EZH2 may predict poor prognosis in Chinese patients with uveal melanoma

PurposeTo explore risk factors predicting poor prognosis of uveal melanoma in a Chinese population, with specific emphasis on monosomy 3, 8q gain, and EZH2 staining. MethodsEighty-nine patients with uveal melanoma from 2012 to 2021 were reviewed. Clinical and pathological records were collected and analyzed. Immunohistochemical staining of EZH2, monosomy 3 and 8q gain were respectively conducted in 45, 54, and 57 cases. Survival was evaluated by Kaplan–Meier analysis and log-rank test. Cox proportional hazard regressions were employed to predict risk factors of distant metastasis. ResultsThe median follow-up was 44 months. Altogether, 16 % of patients developed distant metastases and died from disease-related causes. Disease-specific survival at one and three years was 96.6 % and 88.4 % while distant metastasis rates were 7.9 % and 12 %. Univariate Cox regression analysis revealed that age (HR: 1.04), tumor largest basal diameter (HR: 1.21), tumor thickness (HR: 1.21), ciliary body involvement (HR: 3.50), AJCC stage (HR: 5.68), epithelioid cell type (HR: 7.71), 8q gain (HR: 7.48), and high expression of EZH2 (HR: 6.09) were associated with distant metastasis. 8q gain was associated with epithelioid cell type and thicker tumor while EZH2 was correlated with epithelioid cell type. Monosomy 3 lacked a significant correlation with other factors. ConclusionEZH2 and 8q gain could be taken into consideration when calculating poor prognosis in Chinese patients with uveal melanoma. Monosomy 3 showed no significance in distant metastasis, but this may be due to a small sample size.

Survival Analysis of Elderly Patients With Laryngeal Cancer After Total Laryngectomy: A Retrospective Cohort Study.

Objective This study investigates the overall survival (OS) of elderly patients who underwent total laryngectomy for laryngeal cancer (LC) and examines the impact of tumor-node-metastasis (TNM) staging on survival rates. Methods A retrospective cohort study utilized data from the Otorhinolaryngology Clinic at the University Hospital of Patras, including 75 elderly patients (>65 years) who underwent total laryngectomy for LC between 2000 and 2015. Survival analysis was performed using the Kaplan-Meier estimator, with comparisons made using the Log-rank test. Statistical significance was defined as the p-value being less than or equal to 0.05. Results Over the 16-year period, new LC cases were predominantly male (97.3%) with a mean age of 73.88 years (range: 65-89 years). Most patients were smokers (96%) and alcohol users (54.7%). Histologically, 18.7% of tumors were classified as poorly differentiated, 65.3% as moderately differentiated and 16% as well differentiated. Post-surgical TNM staging indicated 10.7% stage II, 37.3% stage III and 52% stage IV, primarily located in the glottis (62.7%) and followed by supraglottis (34.7%). All patients underwent total laryngectomy, with 69.3% and 37.3% receiving neck dissection and adjuvant therapy (chemotherapy or radiotherapy), respectively. During follow-up, 39 patients died, with 74.3% due to disease-related causes. Five-year OS rates were 44.6%, with variations by stage (stage II: 62.5%, stage III: 55.8%, stage IV: 32.4%; p=0.039) and age (65-75 years: 51.7%, >75 years: 34.7%; p=0.039). Conclusions TNM staging of the laryngeal cancer significantly influences the overall survival of elderly patients undergoing total laryngectomy for LC. Early diagnosis of the disease is crucial for patient survival.

Nevus comedonicus of glans with unusual morphology due to manipulation.

Nevus comedonicus, an uncommon skin condition, was originally termed "comedo nevus" by Kofmann in 1895. It is characterized by the clusters of pits-containing black keratinous plugs resembling blackheads. Conventionally, nevus comedonicus manifests at birth (in 50% of cases) or during the first decade of life. The commonly affected areas include the head, neck, chest, upper, and lower limbs, with patterns ranging from unilateral, bilateral, linear, interrupted, segmental, to blaschkoid. While genital nevus comedonicus is rare, some cases have been reported. In this report, we present a case of nevus comedonicus on the glans, underscoring the importance of considering nonsexually transmitted disease-related causes for genital lesions.

Mortality related to sickle cell disease and COVID-19 in Brazil, 2020.

The ability to cause death is the definitive measure of an infectious disease severity, particularly one caused by a novel pathogen like severe acute respiratory syndrome-CoV-2 (COVID-19). This study describes sickle cell disease-related mortality issues during the COVID-19 pandemic in Brazil. The provisional 2020 mortality data originated from the public databases of the Mortality Information System and were investigated using the multiple-cause-of-death methodology. In 2020, 688 sickle cell disease-related deaths occurred, of which 422 (61.3%) had an underlying cause of death and 266 (38.7%) had an associated cause of death. Furthermore, 98 COVID-19-related deaths occurred, of which 78 were underlying cause of death among sickle cell disease associated (non-underlying) cause of death. Sickle cell disease-related deaths occurred mostly among young adults aged 25-49 years. COVID-19 deaths occurred at ages older than among sickle cell disease-related deaths. Majority of deaths happened in the southeast (42.3%) and northeast regions (34.0%), while COVID-19 deaths prevailed in the northeast region (42.9%). Regarding overall deaths, the leading underlying cause of death was sickle cell disease itself, followed by infectious and parasitic diseases (14.8%), owing to COVID-19 deaths, and diseases of the circulatory system (8.9%). Next, in males, diseases of the digestive system (4.8%) occurred, while, in females, maternal deaths succeeded, included in the chapter on pregnancy, childbirth, and the puerperium, accounting for 5.9% of female deaths. The leading overall associated (non-underlying) cause of deaths were septicemias (29.4%), followed by respiratory failure (20.9%), pneumonias (18.3%), and renal failure (14.7%). In Brazil, COVID-19 deaths produced trend changes in sickle cell disease-related causes of death, age at death, and regional distribution of deaths in 2020.

Tumor Grade and Molecular Characteristics Associated with Survival in Sporadic Medullary Thyroid Carcinoma.

Background: The International Medullary Thyroid Carcinoma Grading System (IMTCGS) divides medullary thyroid carcinoma (MTC) into two categories, high- and low-grade tumors, which has a profound impact on patient outcomes. The aim of this study was to explore the association between IMTCGS grading, clinical data, and molecular status in sporadic MTC. Methods: A retrospective cohort study was performed on consecutive sporadic MTCs from patients undergoing initial surgery between January 2000 and January 2022 at the Padua Endocrine Surgery Unit. Clinical, pathological, and follow-up data were collected, tumors were graded, and somatic mutations of RET and RAS genes were analyzed. Patient outcomes were based on Ct levels and MTC-related deaths. Survival analyses were carried out employing the Kaplan-Meier method and the log-rank test. A Cox proportional hazard regression model was employed for multivariable survival analysis with the following covariates: somatic RET mutation, MTC stage at diagnosis, sex, age at diagnosis, and IMTCGS grade. Results: We included 141 consecutive sporadic MTCs. The median follow-up was 80.0 months (interquartile ranges: 41.5-122.5 months). Seventeen patients (12.1%) died from disease-related causes. 107/141 (76.9%) were classified as low-grade tumors, 32/141 (23.1%) as high-grade. Patients carrying a RET mutation had more aggressive features and shorter disease-specific survival (DSS) (p = 0.001) and were more frequently classified high-grade than low-grade MTC (p < 0.001). At multivariable survival analysis, only IMTCGS grading was independently associated with DSS (hazard ratio 8.8 [confidence interval: 2.7-28.3], p = 0.005). RET mutations, in particular RET-M918T, were more frequent in high-grade than in low-grade MTC (68.8% vs. 29.4% mutated in RET, 46.9% vs. 12.7% mutated in RET-M918T; p < 0.001). None of the high-grade tumors was mutated in the RAS gene, but the mutation was present in 11.8% of low-grade tumors. Conclusions: IMTCGS grading was associated with DSS independently of other clinical, pathological, and molecular factors. Moreover, MTC grading was associated with RET and RAS patterns, which explains, at least in part, the molecular basis of the aggressive behavior of high-grade MTC.

Comparable Outcomes of Relapsed Acute Lymphoblastic Leukemia in Adolescents and Young Adults (AYA) Patients Treated with Pediatric-Inspired Chemotherapy (R3 protocol) Versus Adult-Based Salvage (FA) Protocol

Background Although the survival rate of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved by using pediatric-based treatment protocols, those who experience a relapse still have poor outcomes when treated with adult chemotherapy salvage-regimens, which have traditionally included high doses of Ara-C. The long-term survival rate for patients treated with these salvage-regimens is less than 10%. Salvage treatment with blinatumomab for adults with relapsed B-cell ALL results in a complete remission (CR) rate of 34%, a median survival of 7.7 months, and an overall survival (OS) of less than 30% at 18 months. In contrast, the ALLR3 protocol for relapsed ALL in patients up to the age of 18 years achieved a CR rate of 97% and an overall survival rate of 72%. Therefore, this study aims to compare the outcomes of AYA patients treated with pediatric-inspired regimen (R3 regimen) to those treated with adult-based regimen (FA (Fludarabine/Cytarabine) protocol). Methods The R3 protocol treated 17 AYA patients with relapsed Philadelphia-negative ALL, aged between 14 to 40 years old, who had received first-line therapy. Patients who achieved CR underwent allogenic transplant. The protocol included vincristine, mitoxantrone, asparaginase, dexamethasone, and intrathecal methotrexate. In comparison, 60 patients were treated with FA protocol, with patients achieved CR proceeded to allogeneic stem cell transplantation. Relapses were classified as very early (&amp;lt; 18 months from diagnosis), early (&amp;gt;18 months from diagnosis and &amp;lt;6 months from the end of therapy), and late (&amp;gt;6 months from the end of therapy). Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Results The two arms had comparable characteristics. The median age in the R3 arm was 16 years (range: 14-40 years) compared to 22 years (range: 18-32 years) in the FA protocol arm. In the R3 arm, 88.2% of patients had B-cell ALL, while in the FA protocol arm, 92.2% had B-cell ALL. CNS involvement was seen in 28.8% and 17.6% of cases in the R3 and FA protocol arms, respectively. Relapses were classified as very early, early, or late in 2 (12%), 5 (29%), and 7 (41%) of cases in the R3 arm and were mostly late (25.2%) in the FA protocol arm. Relapses in the R3 arm were isolated bone marrow (BM), isolated extramedullary (EMD), or combined BM and EMD in 14 (82%), 1 (6%), and 2 (12%) cases, respectively, while EMD was around three times higher (16.9%) in the FA arm. The overall CR rate was 60% at the end of R3 induction, with negative MRD (&amp;lt;10 −4 cells) in 47.1% of patients. The overall CR rate was higher in the FA arm (76.3%), but the difference with the R3 arm was not statistically significant (p-value 0.1). The disease was refractory to subsequent salvage therapy in 42% of cases in both arms. About half of the patients who responded to R3 proceeded to allogeneic stem cell transplant (52.3%), while 78% of the patients post-FA underwent transplantation. Eight patients died (47%) in R3 arm, but only one patient died due to treatment-related sepsis, while the other seven patients died due to disease-related causes. At a median follow-up of 4 years, OS was 53% in the R3 arm compared to 30.8% in the FA arm, but the difference was not significant (p-value=0.8). The post-FA mortality was mainly due to infections (15.3% in FA vs. 5.9% in R3). Conclusion Pediatric-inspired protocols that have shown significant benefits in the front-line setting for ALL in the AYA population did not demonstrate a significant difference when compared to traditional adult-based salvage chemotherapy regimens in relapsed disease.

Demographic and Clinical Characteristics of Persons With Spinal Cord Injury in Bangladesh: Database for the International Spinal Cord Injury Community Survey 2023.

The study aims to explore the demographic and clinical characteristics of persons with spinal cord injury (SCI) in Bangladesh. A total of 3035 persons with SCI spanning from 2018 to 2022 were included in this cross-sectional study. Information about demographic and clinical variables was obtained from the medical records and verified through telephone calls to ensure accuracy and consistency. Approximately half (48.30%) of the study participants were located in Dhaka Division. The average age of persons with SCI was 38.3 years, with a standard deviation of 15.9 years, and the largest proportion (33.4%) fell within the age range of 18-30 years. Males outnumbered females by nearly 2.5 times. In the study, 59.6% had suffered traumatic injuries, whereas 40.4% had SCI attributable to disease-related causes; 58.1% were diagnosed with tetraplegia and 40.1% with paraplegia. Fall from height (42.1%) and road traffic trauma (27%) were the most common causes of traumatic injuries. Degenerative myelopathy (41.1%) was the most frequent cause of non-traumatic SCI, followed by tumors (27.7%) and tuberculosis (TB; 14.8%). Both traumatic (58.3%) and degenerative (56.7%) causes of SCI commonly affected the cervical spine, whereas TB (24.4%) and tumors (47.5%) had a higher incidence of affecting the dorsal spine. In the absence of a registry or national database for patients with SCI in Bangladesh, this study would serve as representative data for future studies.

Clinicopathologic and Immunophenotypic Classification of Invasive Lobular Carcinoma with Histiocytoid Features.

Histiocytoid lobular breast carcinoma is a rare subtype of invasive lobular carcinoma characterized by relatively bland, uniform nuclei, single small eosinophilic nucleolus, and ample granular cytoplasm. These cancers are typically triple negative, show frequent androgen receptor (AR) positivity, and are therefore theorized to represent a variant of apocrine differentiation in invasive lobular carcinoma. Anecdotal evidence suggests that these tumors have excellent outcomes, though some studies suggest a variable clinical outcome. Inclusion criteria included women with a histologic diagnosis of invasive lobular carcinoma with histiocytoid features, regardless of immunohistochemical profile, diagnosed at our institution between 2008 and 2021 with additional tissue still available for ancillary studies. We reviewed patients meeting these criteria and investigated hematoxylin and eosin-stained slides and a panel of immunohistochemical stains (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 [HER2], AR, endothelial growth factor receptor, and keratin 5/6), as well as outcomes including survival and metastatic disease. Overall, 12 eligible patients were identified. The classical immunophenotype (triple negative with AR positivity) was noted in 4 out of 12 tumors. The majority of the remaining tumors (7 out of 12) showed a luminal B immunohistochemical profile, while 1 out of 12 was HER2-enriched. No patients in the cohort died from disease-related causes and 2 out of 12 presented with distant metastatic disease during their disease course. Histiocytoid lobular breast carcinoma is a morphologic variant of lobular carcinoma with apocrine features that shows a variable immunohistochemical profile and variable clinical behavior. Further subclassification and stricter diagnostic criteria may be helpful in the distinction between truly indolent tumors and those with more aggressive clinical features.

A clinical case of acute anabolic steroid-induced toxic hepatitis

Drug-induced liver injury (DILI) can be considered in cases of acute hepatitis by the exclusion of any disease-related causes. For several decades, anabolic steroids have been considered not only as drugs for treatment of diseases such as hypogonadism, sarcopenia, hypotrophy in cancer patients, aplastic anemia, etc., but also as risk factor for acute liver failure, that can lead to liver cancer, and even sudden death. Anabolic steroids are known to be increasingly used not only for legitimate medical uses, but also for enhance physical performance and promote muscle growth for ideal body shape. The article presents a clinical case of acute drug-induced hepatitis after 2 months of using stanozolol, a synthetic testosterone derivative, in a 25-year-old previously healthy man. Thorough etiological investigations ruled out other causes of DILI. The man was treated at the in-patient department and discharged with improvement, but it took several months for the disappearance of hepatic cytolytic and cholestatic changes. Clinicians should be aware of the risk for toxic drug-induced hepatitis in male bodybuilders and collect a thorough history of the patient’s intake of nutritional supplements that may contain androgen derivatives.

Catch-Up Growth in Infants and Young Children With Faltering Growth: Expert Opinion to Guide General Clinicians.

Faltering growth (FG) is a problem regularly seen by clinicians in infants and young children (<2 years of age). It can occur due to non-disease-related and disease-related causes and is associated with a wide range of adverse outcomes, including shorter-term effects such as impaired immune responses and increased length of hospital stay, and longer-term consequences, including an impact on schooling and cognitive achievements, short stature, and socioeconomic outcomes. It is essential to detect FG, address underlying causes and support catch-up growth where this is indicated. However, anecdotal reports suggest misplaced fear of promoting accelerated (too rapid) growth may deter some clinicians from adequately addressing FG. An invited international group of experts in pediatric nutrition and growth reviewed the available evidence and guidelines on FG resulting from disease-related and non-disease-related effects on nutritional status in healthy term and small for gestational age infants and children up to the age of 2 years in low-, middle-, and high-income countries. Using a modified Delphi process, we developed practical consensus recommendations to provide clarity and practical recommendations for general clinicians on how FG should be defined in different young child populations at risk, how FG should be assessed and managed, and the role of catch-up growth after a period of FG. We also suggested areas where further research is needed to answer remaining questions on this important issue.

The burden of gastrointestinal diseases in Japan, 1990-2019, and projections for 2035.

Disease burden estimation allows clinicians and policymakers to plan for future healthcare needs. Although advances have been made in gastroenterology, as Japan has an aging population, disease burden assessment is important. We aimed to report gastrointestinal disease burden in Japan since 1990 and project changes through to 2035. This descriptive study examined the crude and age-standardized rates of prevalence, mortality, and disability-adjusted life years (DALYs) of 22 gastrointestinal diseases between 1990 and 2019. We used data from the Global Burden of Disease study 2019. We calculated the expected disease burden of gastrointestinal diseases by 2035 using an autoregressive integrated moving average. Since 1990, cancer has accounted for most gastrointestinal disease-related causes of mortality and DALYs in Japan (77.1% and 71.2% in 1990, 79.2% and 73.7% in 2019, respectively). Although cancer-associated age-standardized mortality rates and DALYs have shown a decreasing trend, the crude rates have increased, suggesting that an aging society has a significant impact on the disease burden in Japan. Therefore, the overall gastrointestinal disease burden is expected to increase by 2035. Noncancerous chronic diseases with a high burden included cirrhosis, biliary disease, ileus, gastroesophageal reflux disorder, hernia, inflammatory bowel disease, enteric infections, and vascular intestinal disorders. In cirrhosis, the DALYs for hepatitis C decreased and the prevalence of non-alcoholic steatohepatitis increased. In the super-aging Japanese society, the burden of gastrointestinal diseases is expected to increase in the coming years. Colorectal, gastric, pancreatic, and liver cancers are the focus of early detection and treatment.

Assessment of COVID-19 as the Underlying Cause of Death Among Children and Young People Aged 0 to 19 Years in the US

COVID-19 was the underlying cause of death for more than 940 000 individuals in the US, including at least 1289 children and young people (CYP) aged 0 to 19 years, with at least 821 CYP deaths occurring in the 1-year period from August 1, 2021, to July 31, 2022. Because deaths among US CYP are rare, the mortality burden of COVID-19 in CYP is best understood in the context of all other causes of CYP death. To determine whether COVID-19 is a leading (top 10) cause of death in CYP in the US. This national population-level cross-sectional epidemiological analysis for the years 2019 to 2022 used data from the US Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research (WONDER) database on underlying cause of death in the US to identify the ranking of COVID-19 relative to other causes of death among individuals aged 0 to 19 years. COVID-19 deaths were considered in 12-month periods between April 1, 2020, and August 31, 2022, compared with deaths from leading non-COVID-19 causes in 2019, 2020, and 2021. Cause of death rankings by total number of deaths, crude rates per 100 000 population, and percentage of all causes of death, using the National Center for Health Statistics 113 Selected Causes of Death, for ages 0 to 19 and by age groupings (<1 year, 1-4 years, 5-9 years, 10-14 years, 15-19 years). There were 821 COVID-19 deaths among individuals aged 0 to 19 years during the study period, resulting in a crude death rate of 1.0 per 100 000 population overall; 4.3 per 100 000 for those younger than 1 year; 0.6 per 100 000 for those aged 1 to 4 years; 0.4 per 100 000 for those aged 5 to 9 years; 0.5 per 100 000 for those aged 10 to 14 years; and 1.8 per 100 000 for those aged 15 to 19 years. COVID-19 mortality in the time period of August 1, 2021, to July 31, 2022, was among the 10 leading causes of death in CYP aged 0 to 19 years in the US, ranking eighth among all causes of deaths, fifth in disease-related causes of deaths (excluding unintentional injuries, assault, and suicide), and first in deaths caused by infectious or respiratory diseases when compared with 2019. COVID-19 deaths constituted 2% of all causes of death in this age group. The findings of this study suggest that COVID-19 was a leading cause of death in CYP. It caused substantially more deaths in CYP annually than any vaccine-preventable disease historically in the recent period before vaccines became available. Various factors, including underreporting and not accounting for COVID-19's role as a contributing cause of death from other diseases, mean that these estimates may understate the true mortality burden of COVID-19. The findings of this study underscore the public health relevance of COVID-19 to CYP. In the likely future context of sustained SARS-CoV-2 circulation, appropriate pharmaceutical and nonpharmaceutical interventions (eg, vaccines, ventilation, air cleaning) will continue to play an important role in limiting transmission of the virus and mitigating severe disease in CYP.

Overall and complication-free survival in a large cohort of patients with β-thalassemia major followed over 50 years.

We report data on survival and complications for a longitudinal cohort of 709 transfusion-dependent β-thalassemia major patients (51.1% males) born between 1970 and 1997 and followed through 2020 at seven major centers in Italy. Overall survival probability at 30 years was 83.6% (95%CI: 78.5-89.1) in the oldest birth cohort (1970-1974) compared with 93.3% (95%CI: 88.6-98.3) in the youngest birth cohort (1985-1997) (p=0.073). Females showed better survival than males (p=0.022). There were a total of 93 deaths at a median age of 23.2 years with the most frequent disease-related causes being heart disease (n=53), bone marrow transplant (BMT) complication (n=10), infection (n=8), liver disease (n=4), cancer (n=3), thromboembolism (n=2) and severe anemia (n=1). There was a steady decline in the number of deaths due to heart disease from the year 2000 onwards and no death from BMT was observed after the year 2010. A progressive decrease in the median age of BMT was observed in younger birth cohorts (p < 0.001). A total of 480 (67.7%) patients developed ≥1 complication. Patients in younger birth cohorts demonstrated better complication-free survival (p < 0.001) which was comparable between sexes (p=0.230). Independent risk factors for death in multivariate analysis included heart disease (HR: 4.63, 95%CI: 1.78-12.1, p=0.002), serum ferritin >1000 ng/mL (HR: 15.5, 95%CI: 3.52-68.2, p < 0.001), male sex (HR: 2.75, 95%CI: 0.89-8.45, p=0.078), and splenectomy (HR: 6.97, 95%CI: 0.90-54.0, p < 0.063). Survival in patients with β-thalassemia major continues to improve with adequate access to care, best practice sharing, continued research, and collaboration between centers.

Death in detention in the Northern part of Tunisia: a 15-year study (2005–2019)

PurposeThis study aims to analyze the pattern of deaths in detention in Northern Tunisia as well as the causes of death.Design/methodology/approachThe authors conducted a cross-sectional retrospective study including all the casualties of death in detention examined in the legal medicine Department in the main teaching hospital from 2005 to 2019. The department covers 10 out of the 11 governorates of Northern Tunisia and 13 prisons.FindingsOf a total of 197 casualties, only 2 were females. The mean age was 45.39 ± 14.43 years. A known medical history was reported in 63.5%, mainly cardiovascular disease, mental health disorders and diabetes. Half of the deaths occurred at the hospital. A total of 53 victims spent less than one year in custody before their death. Most deaths occurred due to disease-related causes (78.7%; n = 155); among these, 69 victims died from cardiovascular disease. Suicide accounted for 3.6% of the casualties and homicides for four cases.Research limitations/implicationsSeveral missing data regarding the details of the detention circumstances as well as the absence in some cases of the toxicological and histopathology analysis results, which could bias the study findings.Practical implicationsDeath in detention in Northern Tunisia involved mainly males between their 30s and their 50s who died mainly from cardiovascular or pulmonary disease. These results underscore the importance of empowering the penitentiary health system.Originality/valueTo the best of the authors’ knowledge, this study is one of largest studies with regard to the number of decedents and the number of prisons from the Arab countries allowing to draw a pattern of casualties of death in prison.

Malignant germ cell tumors in men aged 50 years and over are associated with adverse pathologic features and higher stage at presentation

BackgroundGerm cell tumors (GCT) are the most common malignancy in men in the third and fourth decades of life. The occurrence of malignant GCT in men aged 50 years or over is rare, and their histopathologic characteristics and outcome is insufficiently characterized in the medical literature. Hence, we report the histopathologic features and clinical outcome of malignant GCTs in men aged ≥50 years at our institution. DesignWe performed a retrospective search of our database from 2005 to 2021 to identify men aged 50 years or older with malignant GCT. Cases of spermatocytic tumor were excluded. Clinical and histopathologic features of the tumors were reviewed. ResultsForty-seven cases were identified, showing a sharp decline in incidence over the age of 65. Thirty-nine (83 %) tumors were testicular while eight (17 %) were non-testicular in presentation. Cases included 26 (55 %) seminomas, 15 (32 %) non-seminoma/mixed malignant GCT, and 5 (11 %) regressed testicular germ cell tumors. The most common component in mixed malignant GCTs was embryonal carcinoma (77 %), followed by seminoma and yolk sac tumor (62 % each). Germ cell neoplasia in situ (GCNIS) accompanied 57 % of the cases. Aggressive pathologic features, including lymphovascular invasion, retroperitoneal/lymph node involvement and higher stage at presentation, were identified in a significant proportion of cases (36/47, 77 %). Clinical follow up showed six patients (14 %) died of disease-related causes. ConclusionOur findings expand and corroborate the previously reported data on malignant GCT in older men. Unique characteristics include tendency for higher stage at presentation with adverse pathologic features and more aggressive clinical course.

Improved Survival of Adolescents and Young Adults (AYA) Patients Aged 14-40 Years with First Relapse of Acute Lymphoblastic Leukemia Using Pediatric-Inspired Chemotherapy Salvage Protocol (R3 induction protocol)

Background: Although survival of adolescent and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved using pediatric-inspired protocols, the outcomes of those who relapse remain poor using adult chemotherapy salvage-regimens that have historically incorporated high dose Ara-C based regimen, with long term-survival of less than 10%. The CR rate with blinatumomab for salvage in adult ALL is 34% with a median survival of 7.7 months, with an OS of less than 30% at 18 months. In contrast, pediatric salvage regimens have historically been based on multi-agent therapy and have reported superior outcomes. The ALLR3 protocol for relapsed ALL in patients up to the age of 18 years reported a CR rate of 97% and an overall survival of 72%. We therefore aimed to analyze the outcomes of young adolescents and adults treated on the R3 regimen +/- blinatumomab. Methods: Seventeen AYA patients with Philadelphia-negative ALL aged between 14 and 40 years who relapsed after first-line therapy and treated with ALLR3-protocol were identified. Relapses were classed as very early (<18 months from diagnosis) early (>18m from diagnosis and <6 months from end of therapy) and late (>6 months from end of therapy). The protocol consisted of vincristine (1.5mg/m2 IV D3,10,17,24); mitoxantrone ( 10mg/m2 IV d1 &2); PEG-asparaginase (1000 u/m2 IV d3 & 17); dexamethasone (10mg/m2 BID day d1-5 and d15-20); and intrathecal methotrexate (12mg d1 & d8) were identified. Patient aged 30-40 years received L-Asparaginase instead of PEG-Asparaginase, and 8mg/m2 of dexamethasone instead of 10mg/m2. Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Patients who achieved minimal residual disease (MRD) negative CR proceeded with an allogeneic transplant. MRD-positive patients received blinatumomab followed by a transplant. Results: The median age at relapse was 16 years (14-40 years), 88.2% of patients were B-cell ALL and 11.8% were T-cell ALL. Most patient had standard cytogenetics on presentation (76.5%) and were CNS negative (82.4%). Relapses were very early, early or late in 2 (12%) , 5 (29%) , and 7 (41%) of cases, respectively. Relapses were isolated bone marrow (BM), isolated extramedullary (EMD) or combined BM and EMD in 14 (82%),1 (6%) and 2(12%) cases, respectively. Overall complete remission (CR) rate was 60% at the end of R3 induction; CR with negative minimal residual disease (MRD negative, <10−4 cells) at the end of R3-induction was achieved in 47.1% of patients, while 11.8% of patients had CR with positive MRD (≥10−4 cells) who received Blinatumumab thereafter with eradication of MRD. Refractory disease was seen in 41.2% of patients. Almost all patients who responded to R3 proceeded to allogeneic stem cell transplant (88.8%). Eight patients died (47%), but only one patient died because of treatment-related sepsis, while the other 7 patients died because of disease-related causes. At a median follow up of 4 years, OS was 47.3%. Conclusion: Compared to traditional adult-based chemotherapy regimens and antibody therapies used in relapsed ALL, the use of pediatric-inspired protocol (R3) in relapsed AYA-ALL patients showed favorable response rates and overall survival. Further trials are required of pediatric inspired salvage regimens, preferably incorporating antibody therapies in adult patients, especially in 1st relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinicopathologic features and biologic behavior of canine splenic nodules with stromal, histiocytic and lymphoid components.

The term fibrohistiocytic nodule has been discouraged in favor of specific pathologic entities, including complex nodular hyperplasia, splenic stromal sarcoma and histiocytic sarcoma. Nevertheless, the diagnosis of splenic lesions with mixed stromal, histiocytic and lymphoid components still remains a challenge due to lack of straightforward histologic criteria. Misestimation of the biologic behavior of these lesions may lead to detrimental consequences on the clinical management of patients. In this study, we retrospectively evaluated the clinicopathologic features and outcome of canine splenic nodular lesions with mixed components, to identify prognostic factors and histologic criteria of malignancy. Thirty-seven cases were included. Immunohistochemistry did not allow for further subclassification. Nine (24.3%) dogs died from disease-related causes after a median of 234 days (range, 48–1,247). One-, 2- and 3-year disease-specific survival rates were 80, 60, and 43%, respectively. When considering nodules with stromal cell atypia and at least one of mitotic count ≥9, presence of karyomegaly/multinucleated cells and lymphoid component <40%, half of these dogs died of disease-related causes with a median disease-specific survival time of 548 days (95% CI, 0-1216). In the remaining dogs, no disease-related death was reported (P < 0.001). Canine splenic nodular lesions with mixed stromal, histiocytic and lymphoid components and histologic criteria of malignancy may behave aggressively, leading to distant metastasis and death. In the absence of further criteria aiding their classification, and to better characterize their biologic behavior, we encourage the distinction of these complex splenic tumors from conventional sarcomas and histiocytic sarcomas.

Clinical case of distal arthrogryposis in combination with epilepsy due to an unbalanced translocation

The clinical case of a patient with congenital contractures of the lower and upper limbs, face, seizures, facial dysmorphias, motor disorders and psychomotor development delay is presented. The proband with Freeman–Sheldon syndrome had no mutations in genes associated with distal arthrogryposis. Chromosomal microarray analysis revealed terminal duplication of the long arm of chromosome 9 and terminal microdeletions of the short arm of chromosome 20 – 46,XX.arr[hg38]9q33.3q34.3 (127016168_138124666) x3,20p13 (259113_1003183)x1 in the de novo status. This clinical observation demonstrates an opportunity of using innovative molecular cytogenetic technologies in the search for disease-related genetic causes in the absence of mutations detected by whole exome sequencing.