Non-malignant Diseases Research Articles

Safety and Efficacy of High-Dose Memory CD45RO+ Donor Lymphocyte Infusion in Pediatric Recipients after Hematopoietic Stem Cell Transplantation

Memory T selected cells (CD45RA-/RO+) as donor lymphocyte infusion are less capable of producing alloreactivity and graft versus host disease (GvHD) compared with naïve T cells. The objective of this study was to evaluate the safety and efficacy of high-dose memory (CD45RA-/RO+) donor lymphocyte infusion (mDLI) after allogeneic hematopoietic cell transplantation (HCT). Indications for mDLI were “as needed” and “as prophylactic regimen.” Sixty-one children diagnosed with malignant (82%) and non-malignant diseases (18%) received 241 mDLIs. Patients received a median of three infusions (range 1‒13) of mDLI with a median infused dose of 1.35 × 107/kg CD45RO+ containing 8.96 × 106/kg CD3+CD45RO+ and 3.81 × 103/kg CD3+CD45RA+. De novo GvHD developed in 7 patients following 4% of the mDLI infusions. Among patients with GvHD before mDLI, this condition worsened following 6 infusions (11%) in the 3 patients with grade II–IV acute GvHD. A decrease in cytomegalovirus viral load followed 65% of mDLI infusions. Two-year overall survival (OS) for the total cohort was 64% (95% CI 57%‒72%). For patients receiving prophylactic mDLI, the two-year non-relapse mortality was 10% (95% CI 9%‒11%). In summary, high-dose mDLI is feasible and safe, with a relatively low risk of severe GvHD even in patients with active GvHD. Importantly, mDLI was associated with positive effects, including enhanced control of CMV viremia.

Diagnostic value of serum fibrin degradation complex DR-70 combined with conventional tumor biomarkers in colorectal cancer.

Most patients with colorectal cancer (CRC) show no early symptoms, and tumor markers have low sensitivity and specificity. We therefore investigated the ability of serum fibrin degradation complex DR-70 plus traditional tumor markers to diagnose CRC. We retrospectively screened patients with CRC or non-malignant colorectal diseases, as well as healthy individuals, for inclusion in this study. The individuals' clinical characteristics were recorded, and serum samples were collected. Expression levels of DR-70 and conventional tumor markers were measured by enzyme-linked immunosorbent assay and electrochemiluminescence. DR-70 levels differed significantly among patients with CRC, patients with benign colorectal diseases, and healthy individuals. Receiver operating characteristic curve analysis identified DR-70 as a conventional tumor marker with the highest sensitivity and the second-highest specificity after carcinoembryonic antigen. This study identified DR-70 as a reliable marker for the detection, differentiation, and progression of CRC, with good sensitivity and specificity. DR-70 measurement could greatly improve the efficacy of CRC diagnosis when used together with other tumor markers.

Perioperative efficacy of laparoscopic duodenal-preserving pancreatic head resection

Objective: To compare the perioperative outcomes of laparoscopic duodenal-preserving pancreatic head resection(LDPPHR) with laparoscopic pancreaticoduodenectomy(LPD) in the treatment of borderline and benign diseases of the pancreatic head. Methods: This is a retrospective cohort study. Perioperative data from 87 patients with non-malignant pancreatic head diseases who underwent LDPPHR or LPD were retrospectively collected in the Department of Biliary-Pancreatic Surgery,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology from January 2020 to December 2022. There were 49 male and 38 female patients with an age (M(IQR)) of 57.0(16.5) years (range: 20 to 75 years). Forty patients underwent LDPPHR and 47 patients underwent LPD. Quantitative data following a normal distribution were compared using Student's t-test, while quantitative data not following a normal distribution were compared using the Mann-Whitney U test. Comparisons of categorical or ordinal variables were made using χ2 test or Fisher's exact test. Logistic regression analysis was used to estimate the risk factors associated with the rate of complications. Results: There were no statistically significant differences between the LDPPHR group and the LPD group in terms of reoperation rate,total hospital stay duration,postoperative hospital stay duration,90-day mortality rate,30-day and 90-day readmission rates,and 2-year tumor recurrence rate (all P>0.05). The complication rate was higher in the LDPPHR group compared to the LPD group (80.0%(32/40) vs. 51.1%(24/47), χ2=7.89,P=0.005),but there was no difference in the rate of Clavien-Dindo classification of surgical complications ≥Ⅲ between the two groups (10.0%(4/40) vs. 12.8%(6/47), χ2<0.01, P=0.947). Additionally,the rate of delayed gastric emptying (DGE) was higher in the LDPPHR group compared to the LPD group (χ2=10.79,P=0.001),but there was no statistically significant difference in the rate of B,C grade DGE between the two groups (χ2=0.48, P=0.487). There were no statistically significant differences in the rates of postoperative pancreatic fistula,bile leakage,post-pancreatectomy hemorrhage,intra-abdominal infection,and pulmonary infection between the two groups (all P>0.05). The results of the univariate logistic regression analysis showed that LDPPHR (compared to LPD, OR=3.83, 95%CI: 1.46 to 10.04, Z=2.73,P=0.006) and preoperative biliary stent placement (compared to non-use of biliary stent, OR=5.30, 95%CI: 1.13 to 25.00, Z=2.11, P=0.035) were risk factors for the complication rate,but neither was an independent risk factor for complication rate (all P>0.05). Conclusion: The preliminary results suggest that LDPPHR can achieve perioperative safety and effectiveness comparable to LPD.

Improving Cancer Probability Estimation in Nondiagnostic Bronchoscopies: A Meta-analysis

BackgroundIn patients with peripheral pulmonary lesions (PPL), non-diagnostic bronchoscopy, results are not uncommon. The conventional approach to estimate the probability of cancer (pCA) following bronchoscopies relies on dichotomous test assumptions, utilizing prevalence, sensitivity, and specificity to determine negative predictive value (NPV). However, bronchoscopy is a multi-disease test, raising concerns about the accuracy of dichotomous methodologies. Research QuestionBy how much does calculating pCA using a dichotomous approach (pCAdichotomous) underestimate the true pCA when applied to multi-disease tests like bronchoscopy for the diagnosis of PPL? MethodsMeta-analysis of cohort studies involving radial-EBUS for PPL. PRISMA guidelines were followed, constructing 2×2 contingency tables for calculating pCAdichotomous. For the multi-disease test approach, 3×3 contingency tables for calculating pCAmulti-disease using the likelihood ratio method for non-diagnostic results LR(T0) was used. Observed malignancy rates in patients with non-diagnostic results were compared to pCAdichotomous and pCAmulti-disease. ResultsIn 46 studies (7506 patients), malignancy was the underlying diagnosis in 76%, another specific disease in 13%, and non-specific fibrosis/scar in 10%. The percentage of patients with non-diagnostic results who had malignancy matched pCAmulti-disease across all studies. In contrast, pCAdichotomous consistently underestimated cancer risk (median difference: 0.12, 25th−75th percentile: 0.06−0.23), particularly in studies with a higher prevalence of non-malignant disease. The pooled LR(T0) was 0.46 (95% CI 0.40−0.52, I2 76%, p<0.001), and correlated with the prevalence of non-malignant diseases (p=0.001). InterpretationConventional dichotomous methods for estimating pCA after non-diagnostic bronchoscopies underestimate the likelihood of malignancy. Physicians should opt for the multi-disease test approach when interpreting bronchoscopy results.

Evaluation of dried blood spots for Epstein–Barr virus nucleic acid testing

Epstein–Barr virus (EBV) is a ubiquitous and oncogenic virus that is associated with various malignancies and non-malignant diseases and EBV DNA detection is widely used for the diagnosis and prognosis prediction for these diseases. The dried blood spots (DBS) sampling method holds great potential as an alternative to venous blood samples in geographically remote areas, for individuals with disabilities, or for newborn blood collection. Therefore, the objective of this study was to assess the viability of detecting EBV DNA load from DBS. Matched whole blood and DBS samples were collected for EBV DNA extraction and quantification detection. EBV DNA detection in DBS presented a specificity of 100 %. At different EBV DNA viral load in whole blood, the sensitivity of EBV DNA detection in DBS was 38.78 % (≥1 copies/mL), 43.18 % (≥500 copies/mL), 58.63 % (≥1000 copies/mL), 71.43 % (≥2000 copies/mL), 82.35 % (≥4000 copies/mL), and 92.86 % (≥5000 copies/mL), respectively. These results indicated that the sensitivity of EBV DNA detection in DBS increased with elevating viral load. Moreover, there was good correlation between EBV DNA levels measured in whole blood and DBS, and on average, the viral load measured in whole blood was about 6-fold higher than in DBS. Our research firstly demonstrated the feasibility of using DBS for qualitative and semi-quantitative detection of EBV DNA for diagnosis and surveillance of EBV-related diseases.

Identification of Core Techniques That Enhance Genome Editing of Human T Cells Expressing Synthetic Antigen Receptors.

Genome editing technologies have seen remarkable progress in recent years, enabling precise regulation of exogenous and endogenous genes. These advances have been extensively applied to the engineering of human T lymphocytes, leading to the development of practice changing therapies for patients with cancer and the promise of synthetic immune cell therapies for a variety of nonmalignant diseases. Many distinct conceptual and technical approaches have been used to edit T-cell genomes, however targeted assessments of which techniques are most effective for manufacturing, gene editing, and transgene expression are rarely reported. Through extensive comparative evaluation, we identified methods that most effectively enhance engineering of research-scale and preclinical T-cell products at critical stages of manufacturing.

Prospects and Potential for Chimerism Analysis after Allogeneic Hematopoietic Stem Cell Transplantation.

Chimerism analysis after allogeneic hematopoietic stem cell transplantation serves to confirm engraftment, indicate relapse of hematologic malignancy, and attribute graft failure to either immune rejection or poor graft function. Short tandem repeat PCR (STR-PCR) is the prevailing method, followed by quantitative real-time PCR (qPCR), with detection limits of 1-5% and 0.1%, respectively. Chimerism assays using digital PCR or next-generation sequencing, both of which are more sensitive than STR-PCR, are increasingly used. Stable mixed chimerism is usually not associated with poor outcomes in non-malignant diseases, but recipient chimerism may foretell relapse of hematologic malignancies, so higher detection sensitivity may be beneficial in such cases. Thus, the need for and the type of intervention, e.g., immunosuppression regimen, donor lymphocyte infusion, and/or salvage second transplantation, should be guided by donor chimerism in the context of the feature and/or residual malignant cells of the disease to be treated.

Association between Long-Term Exposure to PM2.5 Inorganic Chemical Compositions and Cardiopulmonary Mortality: A 22-Year Cohort Study in Northern China.

Particulate matter with diameters ≤2.5 μm (PM2.5) has been identified as a significant air pollutant contributing to premature mortality. Nevertheless, the specific compositions within PM2.5 that play the most crucial role remain unclear, especially in areas with high pollution concentrations. This study aims to investigate the individual and joint mortality risks associated with PM2.5 inorganic chemical compositions and identify primary contributors. In 1998, we conducted a prospective cohort study in four northern Chinese cities (Tianjin, Shenyang, Taiyuan, and Rizhao). Satellite-based machine learning models calculated PM2.5 inorganic chemical compositions, including sulfate (SO4 2-), nitrate (NO3 -), ammonium (NH4 +), and chloride (Cl-). A time-varying Cox proportional hazards model was applied to analyze associations between these compositions and cardiorespiratory mortality, encompassing nonaccidental causes, cardiovascular diseases (CVDs), nonmalignant respiratory diseases (RDs), and lung cancer. The quantile-based g-computation model evaluated joint exposure effects and relative contributions of the compositions. Stratified analysis was used to identify vulnerable subpopulations. During 785,807 person-years of follow-up, 5812 (15.5%) deaths occurred from nonaccidental causes, including 2932 (7.8%) from all CVDs, 479 (1.3%) from nonmalignant RDs, and 552 (1.4%) from lung cancer. Every interquartile range (IQR) increase in SO4 2- was associated with mortality from nonaccidental causes (hazard ratio: 1.860; 95% confidence interval: 1.809, 1.911), CVDs (1.909; 1.836, 1.985), nonmalignant RDs (2.178; 1.975, 2.403), and lung cancer (1.773; 1.624, 1.937). In the joint exposure model, a simultaneous rise of one IQR in all four compositions increased the risk of cardiorespiratory mortality by at least 36.3%, with long-term exposure to SO4 2- contributing the most to nonaccidental and cardiopulmonary deaths. Individuals with higher incomes and lower education levels were found to be more vulnerable. Long-term exposure to higher levels of PM2.5 inorganic compositions was associated with significantly increased cardiopulmonary mortality, with SO4 2- potentially being the primary contributor. These findings offer insights into how PM2.5 sources impact health, aiding the development of more effective governance measures.

Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses

AbstractEpstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies and causes significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1307 publicly available EBV genomes from cancer, nonmalignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included, to our knowledge, the first natural killer (NK)/T-cell lymphoma (NKTCL) EBV genomes reported outside of East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than to cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8-fold to 21.9-fold increased risk. We also observed frequent variations in EBV genomes that affected peptide sequences previously reported to bind common major histocompatibility complex alleles. Finally, we found several nonsynonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.

Immunotherapy with genetically engineered T cells holds promise for the treatment of nonmalignant diseases in the dog.

The ability to genetically redirect the antigenic specificity of T cells using chimeric antigen receptors (CAR) has led to unprecedented durable clinical remissions in human patients with relapsed/refractory hematological malignancies. This remarkable advance in successful immune cell engineering has now led to investigations into the application of CAR-T-cell technology to treat nonmalignant diseases. The use of CAR-T cells to target and eliminate specific cell subsets involved in the pathogenesis of autoimmunity, fibrosis, senescence, and infectious disease represents a new direction for adoptive cell therapies. While the use of CAR-T cells for nonmalignant disease is still in its infancy, early reports of dramatic clinical responses to CAR-T cells targeting CD19+ B cells in patients with severe autoimmune disease raise the possibility that this approach could lead to durable remissions, eliminating the need for ongoing conventional immunosuppressive therapies. Excitingly, nonmalignant disease processes that may be addressed by CAR-T-cell therapy in humans also occur in our canine populations. Given that technologies for developing canine CAR constructs are now available, robust protocols have been described for generating canine CAR-T cells, and experience is being gathered with their clinical use in oncology, it is anticipated that CAR-T cells will soon enter the veterinary clinics for the treatment of debilitating nonmalignant diseases. Here, we provide a broad overview of CAR-T-cell therapies for nonmalignant diseases and extrapolate these advances into the veterinary space, highlighting areas in which canine CAR-T cells are poised to enter the clinics for the treatment of nonmalignant disease.

An analysis of post-operative thromboembolic events in patients diagnosed with gastro-esophageal cancer.

e16123 Background: Venous thromboembolism (VTE) commonly manifests as a postoperative complication of gastroesophageal cancer (GEC) surgery. However, guidelines seldom differentiate preventive approaches for postoperative VTE based on cancer types. Furthermore, there is a lack of research evaluating factors associated with the risk of thrombosis for patients diagnosed with GEC who undergo surgery. Herein, we aim to determine the incidence of VTE after GEC surgery and the clinical characteristics of the patients associated with VTE events. Methods: We retrospectively reviewed the charts of patients diagnosed with GEC and underwent gastrectomy/esophagectomy at Cleveland Clinic, OH, and Weston, FL, between 2005 and 2022. Patients who had non-malignant diseases or did not undergo invasive surgery were excluded. Of the 437 patients who underwent GEC surgery, only 375 met the inclusion criteria. Patients who developed a VTE event diagnosed by imaging studies within one year of GEC surgery were considered positive for the event. DVT prophylaxis (DDPX) was defined as the administration of anticoagulants, such as heparin and enoxaparin. The average length of DVT prophylaxis was 7 days. The chi-square test was used to assess the significant differences among the groups based on VTE status. Results: In this cohort of 375 patients, 54 (14.4%) patients experienced VTE. 43 patients (79.60%) who experienced a VTE event received DDPX, whereas 10 patients (18.50%) with VTE did not receive DDPX. Of the 321 patients who did not develop VTE, 251 patients (78.20%) received DDPX, while 66 patients (20.60%) did not receive DDPX. DDPX administration in both cohorts was not significantly different (p 0.868). Notably, 36 (66.7%) of the patients developed VTE events within 30 days following GEC surgery, with a subsequent significant decrease in VTE incidence beyond this timeframe (9.3%, 7.4%, 11.1%, and 5.5% in the 30-60-, 60-90, 90–180, and 180-365-day intervals, respectively, p &lt; 0.001). Among the patients who presented with gastrointestinal stromal and neuroendocrine tumors (7.50%), none of the patients developed a VTE event. Nevertheless, 19.35% of the 31 patients diagnosed with squamous cell carcinoma had a VTE within one year of GEC. Patients with Stage IV disease had a higher risk of VTE compared to lower-stage disease (25.95%, p 0.032). However, factors such as BMI, smoking status, type of surgery, treatment regimens, and ECOG score were not significantly associated with VTE. Conclusions: Patients diagnosed with GEC who underwent surgical intervention demonstrated a significant propensity for VTE, particularly within 30 days post-surgery. The rate of VTE incidence was not significantly different among the DPPX and non-DPPX cohorts, which could be attributed to the short duration of anticoagulation. Further studies are warranted to investigate the optimal duration of DDPX.

Bismuth-based quadruple therapy versus standard triple therapy for the eradication of Helicobacter pylori in Belgium: a multicentre, non-blinded randomized, prospective study.

Helicobacter pylori (Hp) infection predisposes to malignant and non-malignant diseases warranting eradication. In Belgium, resistance rates for clarithromycin demonstrate regional variations making the use of standard triple therapy (STT) borderline acceptable. According to a recent Belgian survey, STT and bismuth-based quadruple therapy (BQT), are equally frequent prescribed as first line treatment for treatment naïve Hp positive patients. This study aims to evaluate the eradication rates (ER) of BQT versus STT. Multicentre, non-blinded randomized, prospective study comparing ER in treatment-naïve Hp positive patients. ER were compared by intention to treat (ITT) and per protocol (PP) analysis. Overall 250 patients were included (STT 126, BQT 124). Seventeen patients were lost to follow-up (6,8%). No significant difference in ER between BQT and STT was observed in ITT (73% vs 68%, p= 0,54) neither in PP analysis (81% vs 75%, p= 0,33). Side effects and endoscopic findings were comparable between groups. Post-hoc analysis showed no differences according to gender or site allocation. The numerical advantage of BQT did not translate in a significant improvement of ER when compared with STT. These results question the cost-effectiveness of BQT, while confirming the suboptimal eradication rates on STT. A nationwide monitoring of resistance patterns, maximal investments in treatment adherence as well as a detailed follow-up of the changing treatment landscape are mandatory to continuously optimise Hp ER in Belgium.

Narrative review of occupational exposures and noncommunicable diseases.

Within the scope of the Exposome Project for Health and Occupational Research on applying the exposome concept to working life health, we aimed to provide a broad overview of the status of knowledge on occupational exposures and associated health effects across multiple noncommunicable diseases (NCDs) to help inform research priorities. We conducted a narrative review of occupational risk factors that can be considered to have "consistent evidence for an association," or where there is "limited/inadequate evidence for an association" for 6 NCD groups: nonmalignant respiratory diseases; neurodegenerative diseases; cardiovascular/metabolic diseases; mental disorders; musculoskeletal diseases; and cancer. The assessment was done in expert sessions, primarily based on systematic reviews, supplemented with narrative reviews, reports, and original studies. Subsequently, knowledge gaps were identified, e.g. based on missing information on exposure-response relationships, gender differences, critical time-windows, interactions, and inadequate study quality. We identified over 200 occupational exposures with consistent or limited/inadequate evidence for associations with one or more of 60+ NCDs. Various exposures were identified as possible risk factors for multiple outcomes. Examples are diesel engine exhaust and cadmium, with consistent evidence for lung cancer, but limited/inadequate evidence for other cancer sites, respiratory, neurodegenerative, and cardiovascular diseases. Other examples are physically heavy work, shift work, and decision latitude/job control. For associations with limited/inadequate evidence, new studies are needed to confirm the association. For risk factors with consistent evidence, improvements in study design, exposure assessment, and case definition could lead to a better understanding of the association and help inform health-based threshold levels. By providing an overview of knowledge gaps in the associations between occupational exposures and their health effects, our narrative review will help setting priorities in occupational health research. Future epidemiological studies should prioritize to include large sample sizes, assess exposures prior to disease onset, and quantify exposures. Potential sources of biases and confounding need to be identified and accounted for in both original studies and systematic reviews.

Intraoperative Ionizing Radiation Exposure Awareness and Associated Morbidity in Neurosurgery: A Nationwide Survey

Neurosurgeons often use radiation to visualize blood vessels and implants intraoperatively. However, high exposure to radiation increases one's cancer risk. This study aims to investigate intraoperative ionizing radiation exposure awareness and associated morbidity among neurosurgeons. An anonymized 30-question survey about their intraoperative radiation exposure, protective measures, radiation knowledge, and any conditions that can arise from protracted radiation exposure was disseminated to 3344 American Association of Neurological Surgeons members. A total of 227 (6.8%) neurosurgeons completed the survey. Most neurosurgeons (61, 27%) performed 2-4 surgeries per week necessitating radiation (61, 27%), did not use a dosimeter (134, 59%), and wore a lead apron (89%) and a thyroid shield (75%). Only 7 (3%) of respondents could correctly identify the safety limit for occupational radiation. One hundred and thirty-four (59%) respondents correctly identified the relationship between distance and radiation dose reduction. Two hundred and thirteen (94%) neurosurgeons reported concern about occupational radiation exposure. No significant association was found between occupational radiation exposure and the rate of cataracts, combined cancer, and skin cancer. Multivariate logistic regression adjusting for age and cancer history found that the likelihood of developing leukemia (P= 0.02) and nonmalignant thyroid nodular disease (P= 0.01) is positively associated with increased total occupational radiation exposure. There is a need for improved radiation safety awareness among neurosurgeons, especially in the context of rising usage of minimally invasive surgery. This can allow for a greater understanding of radiation-associated risks among neurosurgeons and guide the implementation of safer practices.

Diagnostic potential of protein serum biomarkers for distinguishing small and non-small cell lung cancer in patients with suspicious lung lesions

Background Biomarkers play a role in identifying, managing, and predicting cancer outcomes. In lung cancer, they are used at various time points. Doubts remain regarding their accuracy for differential diagnosis and histological subtyping. A diagnostic test study was conducted. It included malignant lesions and controls with benign lesions. Before lung biopsy, all patients had the following biomarkers measured in serum (Pro-GRP,NSE,CYFRA21-1,SCC-Ag,CEA). Methods The predictive capacity of serum biomarkers was evaluated to discriminate between lung cancer and benign pathology. The accuracy was also assessed for distinguishing between SCLC and NSCLC and explored their ability to perform histological subtyping. Results 93 patients were included, 60 with lung cancer, 33 with benign pathology. Pro-GRP and NSE were elevated in SCLC compared with NSCLC or nonmalignant disease. The most accurate for differentiating between malignant and benign pathology were CEA and CYFRA21-1. Pro-GRP had a poor predictive capacity for distinguishing NSCLC from SCLC. However, combined with CEA and CYFRA21-1, performance improved. For SCLC, the diagnostic capacity of Pro-GRP increased by combining with biomarkers, such as NSE/CYFRA21–1. Conclusions Biomarkers lacked the sensitivity and specificity for independent differential diagnosis or histological subtyping. However, the observed patterns in biomarker levels associated with specific histological subtypes suggest potential utility in a multi-biomarker approach or in conjunction with other diagnostic tools. This insight could guide future research to improve diagnostic accuracy and personalized treatment strategies in lung cancer.

Reproductive Strategies for Declining Fertility: Fertility Preservation

There is a global trend of declining fertility among people of childbearing age and mankind is confronted with great challenges of fertility problems. As a result, fertility preservation technology has emerged. Fertility preservation involves interventions and procedures aimed at preserving the patients' chances of having children when their fertility may have been impaired by their medical conditions or the treatments thereof, for example, chemotherapy and/or radiotherapy for cancer. The changes in patients' fertility can be temporary or permanent damage. Fertility preservation can help people diagnosed with cancer or other non-malignant diseases. More and more fertility preservation methods are being used to preserve the fertility of cancer patients and protect their reproductive organs from gonadotoxicity. Fertility preservation may be appropriate for young patients with early-stage cancers and good prognosis before they undergo treatments (chemotherapy and/or radiotherapy) that can negatively affect their fertility. It is also appropriate for patients with chronic conditions or those who have encountered environmental exposures that affect their gonadal function. Fertility preservation methods include oocyte cryopreservation, embryo cryopreservation, and ovarian tissue cryopreservation (OTC) for women and sperm freezing and testicular tissue freezing for men. The survival rates of children and adolescents diagnosed with malignant tumors have been steadily increasing as a result of advances in cancer treatments. Cryopreservation of oocytes and sperm is recognized as a well-established and successful strategy for fertility preservation in pubertal patients. OTC is the sole option for prepubertal girls. On the other hand, cryopreservation of immature testicular tissue remains the only alternative for prepubertal boys, but the technology is still in the experimental stage. A review showed that the utilization rate of cryopreserved semen ranged from 2.6% to 21.5%. In the case of cryopreserved female reproductive materials, the utilization rate ranged from 3.1% to 8.7% for oocytes, approximately from 9% to 22.4% for embryos, and from 6.9% to 30.3% for ovarian tissue. When patients have needs for fertility treatment, cryopreserved vitrified oocytes are resuscitated and in vitro fertilization-embryo transfer (IVF-ET) was performed to help patients accomplish their reproductive objectives, with the live birth rate (LBR) being 32%. On the other hand, when cryopreserved embryos are resuscitated and transferred, the LBR was 41%. OTC has the advantage of restoring natural fertility and presents a LBR of 33%, compared with the LBR of 19% among 266 IVF patients. In addition, OTC has the benefit of restoring the endocrine function. It has been observed that the shortest recovery time of the first menstruation after transplantation was 3.9 months, and the recovery rate of ovarian function reached 100%. To date, a growing number of cancer survivors and patients with other diseases are benefiting from fertility preservation measures. In the face of declining human fertility, fertility preservation provides a new approach to human reproduction. Fertility preservation should be applied in line with the ethical principles so as to fully protect the rights and interests of patients and their offsprings.

Model-Based Antithymocyte Globulin in αβhaplo-Hematopoietic Stem Cell Transplantation Facilitates Engraftment, Expedites T Cell Recovery, and Mitigates the Risk of Acute Graft-versus-Host Disease

In αβ T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αβhaplo-HSCT) recipients, antithymocyte globulin (ATG; Thymoglobulin) is used for preventing graft rejection and graft-versus-host disease (GVHD). The optimal dosing remains to be established, however. Here we present the first comparative analysis of 3 different ATG dosing strategies and their impact on immune reconstitution and GVHD. Our study aimed to evaluate the effects of 3 distinct dosing strategies of ATG on engraftment success, αβ+ and γδ+ T cell immune reconstitution, and the incidence and severity of acute GVHD in recipients of αβhaplo-HSCT. This comparative analysis included 3 cohorts of pediatric patients with malignant (n = 36) or nonmalignant (n = 8) disease. Cohorts 1 and 2 were given fixed ATG doses, whereas cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW). Cohort 3 showed a 0% incidence of day 100 grade II-IV acute GVHD, compared to 48% in cohort 1 and 27% in cohort 2. Furthermore, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4+ and CD8+ naïve T cells by day 90 (P = .04 and .03, respectively). Additionally, we found that the reconstitution and maturation of γδ+ T cells post-HSCT was not impacted across all 3 cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T cell-replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (P = .007). Conversely, a post-HSCT ATG exposure of 10 to 15 AU*day/mL was optimal for improving day 100 CD4+ (P = .058) and CD8+ (P = .03) immune reconstitution without increasing the risk of relapse or nonrelapse mortality. This study represents the first comparative analysis of ATG exposure in αβhaplo-HSCT recipients. Our findings indicate that (1) a 1- to 2-fold ATG to ATLG bioequivalence is more effective than previously established standards, and (2) ATG exposure post-HSCT does not adversely affect γδ+ T cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and day 100 acute GVHD while also promoting early CD4+/CD8+ immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes.

MODELS OF HLA-DPB1 PERMISSIVENESS AND UNRELATED DONOR HEMATOPOIETIC CELL TRANSPLANTATION

In current allo-HCT practice, a fully HLA-matched sibling donor is the best donor associated with improved transplant outcomes. When a matched sibling donor is unavailable, the second best available donor option is a matched unrelated donor (MUD), either HLA 8/8 or HLA 10/10. One notable characteristic in the MUD setting is that HLA-DPB1 mismatches are present in around 80/85% of unrelated donor/recipient pairs. This unique feature has an additional layer of complexity as these HLA-DPB1 incompatibilities may be further divided into permissive and non-permissive mismatches by two biological-driven permissiveness models, namely T-cell epitope (TCE) and DP expression. In the current review article, we described the basics of T-cell allorecognition, the unique HLA-DPB1 immunogenetics, the early conflicting results regarding HLA-DPB1 mismatching in allo-HCT, the development and the clinical impact of T-cell epitope and Expression models, the new indirect allorecognition algorithm of HLA-DPB1 permissiveness (PIRCHE model), the role of HLA-DPB1 in nonmalignant disease setting, and future perspectives on HLA-DPB1 permissiveness. Keywords: HLA-DPB1, Permissive mismatch, Unrelated donor

Time to therapy and safety of testicular tissue cryopreservation in children undergoing gonadotoxic treatment or hematopoietic stem cell transplant

BackgroundWith the use of multimodal treatments and hematopoietic stem cell transplant, the majority of children diagnosed with malignancies and hematologic diseases are now surviving into adulthood. Due to the gonadotoxic effects and potential for future infertility associated with many of these treatments, fertility counseling with sperm cryopreservation prior to starting therapy is the standard of care for post-pubertal males. Unfortunately, the options are limited for pre-pubertal patients or those unable to provide a specimen. Testicular tissue cryopreservation (TTC) is an investigational method to surgically obtain germ cells from testicular tissue and potentially restore future spermatogenesis. While TTC has been shown to be safe, little is reported on the time to treatment following the procedure to ensure adequate wound healing and avoid delays in definitive therapy. ObjectivesThe primary outcome was the time to initiation of treatment following TTC. Secondary outcomes were complication rates, delays in treatment due to TTC, and presence of germ cells. MethodsWe conducted a single-institution retrospective cohort study of patients undergoing TTC between 2017-2023. Patients at significant risk for treatment related infertility based on established criteria were eligible for TTC. Patients were excluded if they received their oncology or hematology care elsewhere. All patients were enrolled in an IRB approved research protocol with 75% of the tissue submitted for cryopreservation and 25% for research purposes. Time to therapy was defined as the first receipt of gonadotoxic treatment following TTC. ResultsA total of 122 patients (53=malignant, 69=non-malignant) underwent TTC with a median age of 5.9 years (IQR 2.3-9.35). Germ cells were identified in 115 (94%) specimens. A total of 109 (89%) patients underwent concomitant procedures. The median time to initiation of therapy was 5 (IQR 1.0-7.0) and 7 days (IQR 6.0-13.0) for malignant and non-malignant disease, respectively. The 30-day surgical complication rate was 2.5% and was similar between malignant vs non-malignant diagnoses (p=0.58). All surgical complications were managed non-operatively. No patients had a delay in definitive treatment due to concern for wound healing or complications. DiscussionOur surgical complication rates are similar to previous studies and are not affected by the time to treatment following TTC. Limitations of the study are its retrospective design, single institution, and short-term follow up. ConclusionTTC can be performed safely, efficiently, and in conjunction with other necessary procedures without resulting in delays of definitive treatment . TTC affords the opportunity for fertility preservation in children who have no other options.

Supportive and palliative care needs in advanced non-malignant liver disease: systematic review

Advanced cirrhosis confers a significant symptom burden and has a 50% 2-year mortality rate in those with decompensated disease. There is increasing demand for supportive and palliative care (SAPC) for...