R-ketorolac ameliorates cancer-associated cachexia and prolongs survival of tumour-bearing mice.

BACKGROUND: Cancer-associated cachexia (CAC) is a debilitating syndrome associated with poor quality of life and reduced life expectancy of cancer patients. CAC is characterized by unintended body weight reduction due to muscle and adipose tissue loss. A major hallmark of CAC is systemic inflammation. Several non-steroidal anti-inflammatory drugs (NSAIDs) have been suggested for CAC treatment, yet no single medication has proven reliable. R-ketorolac (RK) is the R-enantiomer of a commonly used NSAID. The effect of RK on CAC has not yet been evaluated. METHODS: Ten- to 11-week-old mice were inoculated with C26 or CHX207 cancer cells or vehicle control (phosphate-buffered saline [PBS]). After cachexia onset, 2 mg/kg RK or PBS was administered daily by oral gavage. Body weight, food intake and tumour size were continuously measured. At study endpoints, blood was drawn, mice were sacrificed and tissues were excised. Immune cell abundance was analysed using a Cytek® Aurora spectral flow cytometer. Cyclooxygenase (COX) activity was determined in lung homogenates using a fluorometric kit. Muscle tissues were analysed for mRNA and protein expression by quantitative real-time PCR and western blotting analysis, respectively. Muscle fibre size was determined on histological slides after haematoxylin/eosin staining. RESULTS: Ten-day survival rate of C26-bearing animals was 10% while RK treatment resulted in a 100% survival rate (P = 0.0009). Chemotherapy resulted in a 10% survival rate 14 days after treatment initiation, but all mice survived upon co-medication with RK and cyclophosphamide (P = 0.0001). Increased survival was associated with a protection from body weight loss in C26 (-0.61 ± 1.82 vs. -4.48 ± 2.0 g, P = 0.0004) and CHX207 (-0.49 ± 0.33 vs. -2.49 ± 0.93 g, P = 0.0003) tumour-bearing mice treated with RK, compared with untreated mice. RK ameliorated musculus quadriceps (-1.7 ± 7.1% vs. -27.8 ± 8.3%, P = 0.0007) and gonadal white adipose tissue (-18.8 ± 49% vs. -69 ± 15.6%, P = 0.094) loss in tumour-bearing mice, compared with untreated mice. Mechanistically, RK reduced circulating interleukin-6 (IL-6) concentrations from 334 ± 151 to 164 ± 123 pg/mL (P = 0.047) in C26 and from 93 ± 39 to 35 ± 6 pg/mL (P = 0.0053) in CHX207 tumour-bearing mice. Moreover, RK protected mice from cancer-induced T-lymphopenia (+1.8 ± 42% vs. -49.2 ± 12.1% in treated vs. untreated mice, respectively). RK was ineffective in ameliorating CAC in thymus-deficient nude mice, indicating that the beneficial effect of RK depends on T-cells. CONCLUSIONS: RK improved T-lymphopenia and decreased systemic IL-6 concentrations, resulting in alleviation of cachexia and increased survival of cachexigenic tumour-bearing mice, even under chemotherapy and independent of COX inhibition. Considering its potential, we propose that the use of RK should be investigated in patients suffering from CAC.

Improvements in quality of life over 2 years with cladribine tablets in people with relapsing multiple sclerosis: The CLARIFY-MS study.

BACKGROUND: Multiple sclerosis (MS) negatively affects health-related quality of life (HRQoL). OBJECTIVE: To evaluate HRQoL in people with highly active relapsing MS treated with cladribine tablets (CladT; 3.5 mg/kg cumulative dose over 2 years) in CLARIFY-MS. METHODS: Changes in the MS quality of life (MSQoL)-54 scores were analysed using a repeated mixed-effects linear model. Subgroup analyses were performed for participants who were pretreatment-naïve and those pretreated with disease-modifying therapies (DMTs) before initiating CladT. Safety and tolerability of CladT were also assessed. RESULTS: MSQoL-54 physical (mean change = 4.86; 95% confidence interval (CI) = 3.18, 6.53) and mental health (4.80; 95% CI = 3.13, 6.46) composite scores (primary endpoints) showed significant improvement at Month 24 versus Baseline (p < 0.0001). Changes in the MSQoL-54 scores were consistent across the pretreatment-naïve and DMT-pretreated subgroups. No new severe or opportunistic infections occurred. Most post-baseline lymphopenia events were Grade 1-2 in severity. Transient Grade-3 lymphopenia was observed in 19.7% (95/482) of participants. Grade-4 lymphopenia was not observed. CONCLUSIONS: CladT treatment significantly improved the mean MSQoL-54 physical and mental health composite scores over 2 years. CladT efficacy in HRQoL, relapse rates and Expanded Disability Status Scale scores demonstrates its multidimensional effects in MS treatment.

The effect of radioiodine therapy on blood cell count in patients with differentiated thyroid cancer.

PURPOSE: This study aimed to investigate the long-term effects of radioiodine treatment (RAI) on blood cell counts in patients with differentiated thyroid cancer (DTC) and to describe the characteristics of patients at high risk for blood cell count abnormalities. METHODS: The study included patients with DTC who underwent RAI treatment between 2007 and 2017. Patients with regular complete blood counts for at least 5 years were included, while those with diseases or treatments that could influence blood count parameters were excluded. Blood cell count abnormalities were defined according to the Common Terminology Criteria for Adverse Events version 5.0, and factors influencing these abnormalities were examined. RESULTS: A total of 225 patients were analyzed. The mean age at diagnosis was 45.8 ± 13.9 years, and 76.5% of patients were female. In the first year after RAI, leukocyte, neutrophil, and lymphocyte counts were significantly reduced compared with baseline values. The leukocyte and neutrophil counts returned to baseline values by the third year, while the decrease in lymphocytes continued until the fifth year. Blood cell count abnormalities developed in 16 patients (7.1%) within the first year after RAI. Risk factors for blood cell count abnormalities within the first year after RAI included male sex, older age, T4, N1, and M1 disease, as well as higher RAI doses. In logistic regression analysis, only RAI dose remained independently associated with blood cell count abnormalities. CONCLUSION: These results suggest an association between RAI dose and blood cell count abnormalities, characterized by mild lymphopenia, and indicate that the risk of mild lymphopenia persists over time. Careful consideration should be given when planning high-dose RAI for patients at a high risk of blood cell count abnormalities, such as males with metastatic disease and of advanced age.

Cladribine tablets for highly active relapsing-remitting multiple sclerosis in Poland: a real-world, multi-centre, retrospective, cohort study during the COVID-19 pandemic.

INTRODUCTION: Treatment with cladribine tablets is indicated in highly active relapsing-remitting multiple sclerosis (RRMS). Cladribine tablets proved safe and effective in the pivotal CLARITY trial, but that trial included primarily treatment-naïve patients. In clinical practice however, cladribine tablets are often given to patients who have failed other treatments. Therefore, this study investigated the real-world safety and efficacy of cladribine tablets. MATERIAL AND METHODS: We gathered data from nine MS clinical centres across Poland for patients with RRMS who started treatment with cladribine tablets from December 2019 to June 2022. RESULTS: We enrolled 140 patients, with follow-up data available for 136 in year 1 and for 66 in year 2. At baseline, the mean age was 35.6 years, mean disease duration was 7.3 years, median EDSS score was 2.5, and 94% of patients were treatment- -experienced. Thirty-nine patients (27.9%) had undergone COVID-19, and 94 (67.1%) were vaccinated against COVID-19. The annualised relapse rate (ARR) decreased from 1.49 at baseline to 0.33 in year 1 (p < 0.001) and to 0.25 in year 2 (p < 0.001). The percentage of relapse-free patients increased from 11.5% at baseline to 70.2% in year 1 and 82.1% in year 2. The percentage of patients with active lesions decreased from 91.4% at baseline to 36.2% in year 1 and 18.2% in year 2. EDSS score remained stable or improved in 83.7% of patients in year 1 and 89.6% in year 2. No evidence of disease activity (NEDA-3) was achieved in 42.7% of patients in year 1 and 66.7% in year 2. Only one patient (0.72%) had grade 4 lymphopenia and 21 (15.1%) had grade 3 lymphopenia. Varicella zoster virus infections occurred in three patients. Eight patients discontinued treatment with cladribine: five due to inefficacy, one due to lymphopenia, and two due to a personal decision. CONCLUSIONS: Cladribine tablets proved safe and effective in a real-world cohort of treatment-experienced patients. However, the efficacy measures improved to a lesser extent in our cohort than in the pivotal clinical trial, which is probably due to a higher proportion of treatment-experienced patients in our cohort.

Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial.

BACKGROUND: Lymphomatoid granulomatosis is a rare Epstein-Barr virus-associated B-cell lymphoproliferative disorder with a median overall survival of less than 2 years. In this study, we hypothesised that low-grade lymphomatoid granulomatosis is immune-dependent and high-grade lymphomatoid granulomatosis is immune-independent. On the basis of this hypothesis, we investigated the activity and safety of new treatment with immunotherapy in patients with low-grade disease and standard chemotherapy in patients with high-grade disease. METHODS: In this open-label, single-centre, phase 2 trial, we enrolled patients aged 12 years or older with untreated, or relapsed or refractory lymphomatoid granulomatosis at the National Cancer Institute (National Institutes of Health, Bethesda, MD, USA). Patients with low-grade disease received dose-escalated interferon alfa-2b, starting at 7·5 million international units subcutaneously three times per week for up to 1 year past best response, and patients with high-grade disease received six cycles every 3 weeks of intravenous, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). Starting doses were 50 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for etoposide; 60 mg/m2 twice daily by mouth from day 1 to day 5 for prednisone; 0·4 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for vincristine; 750 mg/m2 intravenous on day 5 for cyclophosphamide; 10 mg/m2 per day as a continuous intravenous infusion from day 1 to day 4 (96 h) for doxorubicin; and 375 mg/m2 intravenous on day 1 for rituximab. The doses of doxorubicin, etoposide, and cyclophosphamide were adjusted up or down on the basis of neutrophil and platelet nadirs. Patients with residual or progressive disease after initial therapy crossed over to alternative therapy. The primary endpoint was the proportion of patients who had an overall response and the 5-year progression-free survival after initial or cross-over treatment. Analysis of response included all participants who underwent restaging imaging; safety analysis included all patients who received any dose of study drugs. The trial is open for enrolment and is registered at ClinicalTrials.gov, NCT00001379. FINDINGS: 67 patients were enrolled between Jan 10, 1991, and Sept 5, 2019 (42 [63%] were male). 45 patients received initial treatment with interferon alfa-2b (16 of whom crossed over to DA-EPOCH-R) and 18 received initial treatment with DA-EPOCH-R (eight of whom crossed over to interferon alfa-2b); four underwent surveillance only. After initial treatment with interferon alfa-2b, the overall response was 64% (28 of 44 evaluable patients) with 61% (27 of 44) having a complete response, whereas, after cross-over treatment with interferon alfa-2b, the overall response was 63% (five of eight evaluable patients) with 50% (four of eight) having a complete response. After initial treatment with DA-EPOCH-R, the overall response was 76% (13 of 17 evaluable patients) with 47% (eight of 17) having a complete response, whereas, after cross-over treatment with DA-EPOCH-R, the overall response was 67% (ten of 15 evaluable patients) with 47% (seven of 15) having a complete response. 5-year progression-free survival was 48·5% (95% CI 33·2-62·1) after initial treatment with interferon alfa-2b, 50·0% (15·2-77·5) after cross-over treatment with interferon alfa-2b, 25·4% (8·2-47·2) after initial treatment with DA-EPOCH-R, and 62·5% (34·9-81·1) after cross-over treatment with DA-EPOCH-R. The most common grade 3 or worse adverse events in patients treated with interferon alfa-2b included neutropenia (27 [53%] of 51 patients), lymphopenia (24 [47%]), and leukopenia (24 [47%]). The four most common grade 3 or worse adverse events in patients treated with DA-EPOCH-R included neutropenia (29 [88%] of 33 patients), leukopenia (28 [85%]), infection (18 [55%]), and lymphopenia (17 [52%]). Serious adverse events occurred in 13 (25%) of 51 patients receiving treatment with interferon alfa-2b and 21 (64%) of 33 patients receiving DA-EPOCH-R, with five treatment-related deaths: one thromboembolic, one infection, and one haemophagocytic syndrome with interferon alfa-2b, and one infection and one haemophagocytic syndrome with DA-EPOCH-R. INTERPRETATION: Interferon alfa-2b is efficacious for treating low-grade lymphomatoid granulomatosis and hence reducing progression to high-grade disease, whereas patients with high-grade lymphomatoid granulomatosis showed expected responses to chemotherapy. Uncontrolled immune regulation of Epstein-Barr virus is hypothesised to result in the emergence of low-grade disease after chemotherapy, for which treatment with interferon alfa-2b is efficacious. FUNDING: Intramural Research Programs of the National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial.

BACKGROUND: Survival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial. METHODS: The Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing. FINDINGS: From Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106 vs 53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53-5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75 vs 36 [64%] of 56, OR 13·33 [3·71-47·84], p<0·0001), and hypogammaglobulinemia (67 [71%] of 95 vs 37 [47%] of 79, OR 2·72 [1·45-5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94 vs 16 [25%] of 63, OR 3·64 [1·81-7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164 vs nine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23-5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 for Streptococcus pneumoniae (pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration. INTERPRETATION: Children with high-risk mature B-cell non-Hodgkin lymphoma receiving chemotherapy with rituximab were at risk of prolonged hypogammaglobulinemia, although severe infections were rare. Strategies for immunoglobulin replacement and revaccination are needed. FUNDING: Clinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network in England, Children's Cancer Foundation Hong Kong, US National Cancer Institute, F Hoffmann-La Roche.

Neural network based ensemble model to predict radiation induced lymphopenia after concurrent chemo-radiotherapy for non-small cell lung cancer from two institutions.

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT. In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end of treatment. Multi-institutional data of 139 LA-NSCLC patients from two hospitals were collected for training and validation of our suggested model. Ensemble learning was combined with a bootstrap strategy to stabilize the model, which was evaluated internally using repeated cross validation. The performance of our proposed model was compared to conventional models using the same input features, such as Logistic Regression (LR) and Random Forests (RF), using the Area Under the Curve (AUC) of Receiver Operating Characteristics (ROC) curves. Our suggested model (AUC=0.77) outperformed the comparison models (AUC=0.72, 0.74) in terms of absolute performance, indicating that the convolutional structure of the network successfully abstracts additional information from the differential DVHs, which we studied using Gradient-weighted Class Activation Map. This study shows that clinical factors combined with dDVHs can be used to predict the risk of RIL for an individual patient and shows a path toward preventing lymphopenia using patient-specific modifications of the radiotherapy plan.

Therapeutic Drug Monitoring of Ganciclovir in Cytomegalovirus-Infected Patients With Solid Organ Transplants and Its Correlation to Efficacy and Toxicity.

BACKGROUND: Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance. METHODS: A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log 10 increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis. RESULTS: A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively ( P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint ( P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia ( P = 0.02). CONCLUSIONS: Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation.

Impact of lymphopenia on efficacy of nivolumab in head and neck cancer patients.

INTRODUCTION: Lymphopenia has been correlated with poorer survival in patients with metastatic cancers treated with anti-PD-1 immunotherapy. Treatments such as chemotherapy, surgery or radiotherapy can induce lymphopenia. Radiation-induced lymphopenia is common and prolonged in head and neck cancer (HNSCC) patients. We evaluated the impact of lymphopenia, on efficacy of anti PD-1 nivolumab immunotherapy in HNSCC patients. METHODS: a multicenter retrospective study included consecutive patients treated with nivolumab for recurrent/metastatic (R/M) HNSCC between January 2017 and June 2019. Lymphopenia was defined as lymphocyte counts below 1000 cells/mm3 upon initiation of nivolumab. Logistical regression was performed on factors associated with lymphopenia and ROC analyses assessed association between lymphopenia and survival. RESULTS: median age was 65. Of the 100 included patients, 60% had been treated by surgery, 67% had had first-line chemotherapy, and 89% loco-regional radiotherapy, 65% had concurrent chemotherapy with radiotherapy. Lymphopenia occurred in 56 (56%) patients upon initiation of nivolumab, with 29 (29%) patients having radiation-related lymphopenia. Prior locoregional radiotherapy was the only factor associated with lymphopenia upon initiation of nivolumab by logistical regression (OR 0.144 [0.029-0.706], p - 0.017). Lymphopenia upon initiation of nivolumab did not affect progression-free survival (PFS) (p - 0.815), overall survival (OS) (p - 0.783) or disease control rate (DCR) (p - 0.125). Locoregional symptomatology (HR - 2.37 [1.24-4.54], p - 0.009), metastatic symptomatology (HR - 4.74 [2.21-10.15], and persistent lymphopenia under nivolumab (HR 3.96 [1.19-13.17] p - 0.034) were associated with poorer OS in multivariate analysis. CONCLUSIONS: Lymphopenia upon initiation of nivolumab was not associated with poorer survival in R/M HNSCC patients, but persistence of lymphopenia during immunotherapy might be a prognostic marker of patient survival.

Impact of Radiation Dose to Circulating Immune Cells on Tumor Control and Survival in Esophageal Cancer.

Background: The immune system is well known to exert tumor immunosurveillance effects, and that immune cells circulating in the peripheral blood affect tumor prognosis. The study investigated the effect of estimated dose of radiation on circulating immune cells (EDRIC) and tumor control for esophageal cancer patients treated with concurrent chemo-radiotherapy. Materials and Methods: A total of 146 esophageal cancer patients treated with radiotherapy between January 2016 and June 2020 were retrospectively identified. We determined EDRIC, known prognostic factors, and the association of these factors with progression-free survival (PFS) and overall survival (OS). Results: The median follow-up was 17.9 months (2.7-60.4 months). The 3-year OS was 39.2%. Severe post-treatment lymphopenia was observed in 84.2% of patients. A negative correlation between EDRIC and absolute lymphocyte count was found (r = -0.679; p < 0.001). Patients with EDRIC ≥10.3 Gy were more likely to demonstrate grade 4 lymphopenia (55.2% vs. 4.5%; p < 0.001). Patients with grade 4 lymphopenia had a worse OS and PFS. On multivariate analysis, EDRIC was independently associated with OS (hazard ratio [HR], 1.142; p = 0.016) and PFS (HR, 1.121; p = 0.019). Conclusions: EDRIC can predict lymphocyte reduction and poor prognosis for esophageal cancer patients treated with radiotherapy.

Death from human cytomegalovirus infection in a girl with congenital thymic dysplasia.

We report the case of a girl with congenital thymic dysplasia and refractory disseminated Human Cytomegalovirus (CMV) infection diagnosed by autopsy. Additionally, she was diagnosed with T-cell lymphopenia immunodeficiency and received antiviral therapy with ganciclovir (GCV) /valganciclovir (V-GCV) and enhanced foscarnet. The CMV viral load (VL) monitoring was elevated with retinitis, interstitial pneumonia, and hepatitis. The phenotype of T-cell lymphopenia was uncertain, which limited any alternative therapy by whole-exome sequencing (WES) and lymphocyte subset panel until autopsy. The girl died of progressive respiratory failure and septic shock at ten months of age. Severe disseminated CMV infection typically develops in infants with primary maternal infections and occurs earlier during gestation and in people with a weakened host immune system. Individuals with CMV infection with initial immunodeficiency are associated with a poor prognosis, which is similar to patients with secondary immunodeficiency. This case describes the difficult treatment and prognosis of CMV infection in patients with congenital immunodeficiency, highlighting the importance of early aggressive anti-CMV antiviral therapy in immunodeficiencies, VL monitoring, drug resistance and the role of T-cells in CMV infection.

Neutropenia and Lymphocytopenia Among Arab Females with Iron Deficiency Anemia (IDA) and their Response to Iron therapy.

. INTRODUCTION: The link between iron deficiency anemia (IDA) and neutropenia/ lymphocytopenia is not well established in the literature. This study aims at assessing the prevalence and clinical characteristics of neutropenia and lymphocytopenia in IDA patients considering the impact of iron replacement on the total and differential WBCs' count. SUBJECTS AND METHODS: The records of all female patients with IDA who attended our hematology clinic (Jan 2018 to Jan 2020) were retrospectively reviewed. Patients with systemic or chronic diseases were excluded. Age, BMI, CBC, and iron parameters were collected before and after IV iron therapy. Results: Out of 1,567 adult females with IDA, 80 patients had leukopenia (5.1%), 64 had neutropenia (4.0%), and 20 had lymphocytopenia (1.2%). After iron therapy, their mean leukocytes, neutrophils, and lymphocytes increased significantly to 4.38 ± 1.82 ×103/L, 2.3 ±1.56 ×109/L and 1.76 ± 0.48 ×103/L, respectively. About 67% of women with IDA and neutropenia had increased ANC in response to iron therapy. However, no significant correlation was found between leukocytes, ANC, or lymphocytes with TIBC or serum iron concentration. CONCLUSIONS: Neutropenia and/or lymphocytopenia may occur in patients with IDA and are reversible with iron therapy. Iron therapy led to the correction of anemia in 100% and increased ANC in 67%. Therefore, neutropenic women with IDA should be treated, initially only with iron, and observed for their Hb and ANC responses before starting any other treatment.

Fatal nocardiosis infection in a pediatric patient with an immunodeficiency after heart re-transplantation.

BACKGROUND: Nocardia infections are rare opportunistic infections in SOT recipients, with few reported pediatric cases. Pediatric patients with single ventricle congenital heart defects requiring HT may be more susceptible to opportunistic infections due to a decreased T-cell repertoire from early thymectomy and potential immunodeficiencies related to their congenital heart disease. Other risk factors in SOT recipients include the use of immunosuppressive medications and the development of persistent lymphopenia, delayed count recovery and/or lymphocyte dysfunction. METHODS: We report the case of a patient with hypoplastic left heart syndrome who underwent neonatal congenital heart surgery (with thymectomy) prior to palliative surgery and 2 HTs. RESULTS: After developing respiratory and neurological symptoms, the patient was found to be positive for Nocardia farcinica by BAL culture and cerebrospinal fluid PCR. Immune cell phenotyping demonstrated an attenuated T and B-cell repertoire. Despite antibiotic and immunoglobulin therapy, his symptoms worsened and he was subsequently discharged with hospice care. CONCLUSION: Pediatric patients with a history of congenital heart defects who undergo neonatal thymectomy prior to heart transplantation and a long-term history of immunosuppression should undergo routine immune system profiling to evaluate for T- and B-cell deficiency as risk factors for opportunistic infection. Such patients could benefit from long-term therapy with TMP/SMX for optimal antimicrobial prophylaxis, with desensitization as needed for allergies. Disseminated nocardiosis should be considered when evaluating acutely ill SOT recipients, especially those with persistent lymphopenia and known or suspected secondary immunodeficiencies.

Early onset drug-induced hypersensitivity syndrome with lymphopenia, hepatitis, and normal eosinophils induced by BRAF/MEK inhibitor after immune checkpoint inhibitor therapy.

Targeted therapy (BRAF/MEK inhibitors) is frequently employed in the treatment of metastatic melanoma following immune checkpoint inhibitor therapy inefficacy or intolerance. Although BRAF inhibitors are commonly associated with cutaneous eruptions, they rarely cause severe cutaneous adverse drug reactions such as drug-induced hypersensitivity syndrome (DIHS). Drug-induced hypersensitivity syndrome is a severe drug reaction characterized by extensive eruption often seen in conjunction with fever, facial edema, lymphadenopathy, eosinophilia, atypical lymphocytosis, and variable visceral organ injury characteristically beginning 2-8 weeks after initiating the causative drug. We report a case of atypical DIHS with reduced latency, mucosal involvement, lymphopenia, normal eosinophils, and no lymphadenopathy that occurred secondary to vemurafenib and cobimetinib therapy following melanoma progression while on pembrolizumab. Previous immune checkpoint inhibitor therapy has been associated with atypical DIHS in patients on BRAF/MEK inhibitors. Early recognition of the atypical clinical features of this hypersensitivity reaction is important so that drug discontinuation and corticosteroids can be initiated early.

Crotalid Polyvalent F(ab)2 Antivenom Treatment in a Red-Tailed Hawk (Buteo jamaicensis).

Envenomation in avian species can result in death, with few cases of successful treatment described. A juvenile, wild-caught, intact female red-tailed hawk (Buteo jamaicensis) used in falconry was presented for emergency evaluation after being bitten by a Northern Pacific rattlesnake (Crotalus oreganus) approximately 2 hours before presentation. On presentation, the bird was quiet, alert, and responsive, with moderate swelling and discomfort of the digits on the right foot. Complete blood count (CBC) and plasma biochemistry abnormalities included a regenerative left shift, severe lymphopenia, and a moderate hypoproteinemia characterized by moderate hypoalbuminemia. Analgesic and antibiotic medications were administered during hospitalization. In addition, 5 mL of VenomVet was administered intravenously with crystalloid fluids over 60 minutes; no adverse effects were noted secondary to infusion. Improvement in the swelling was observed immediately after antivenom administration and nearly resolved within 12 hours. Complete resolution of digital swelling with no discomfort on palpation of that foot was observed 1 week after initial presentation. Blood collected at the 1 week reexamination was submitted for a CBC and plasma biochemistry panel. The results of the CBC revealed a reduced regenerative left shift, increased heterophil count, and a moderate monocytosis; the lymphopenia was resolved. A mild hypoalbuminemia still persisted. Ten months after presentation, the bird was reported to be doing well with no changes in function of the right foot and subsequently released from captivity.

A phase 1 and pharmacodynamic study of chronically-dosed, single-agent veliparib (ABT-888) in patients with BRCA1- or BRCA2-mutated cancer or platinum-refractory ovarian or triple-negative breast cancer.

PURPOSE: BRCA1 or BRCA2 mutated cancers (BRCAmut) have intrinsic sensitivity to PARP inhibitors due to deficiency in homologous recombination-mediated DNA repair. There are similarities between BRCAmut and BRCAwt ovarian and basal-like breast cancers. This phase I study determined the recommended phase II dose (RP2D) and preliminary efficacy of the PARP inhibitor, veliparib (ABT-888), in these patients. PATIENTS AND METHODS: Patients (n = 98) were dosed with veliparib 50-500 mg twice daily (BID). The BRCAmut cohort (n = 70) contained predominantly ovarian (53%) and breast (23%) cancers; the BRCAwt cohort (n = 28) consisted primarily of breast cancer (86%). The MTD, DLT, adverse events, PK, PD, and clinical response were assessed. RESULTS: DLTs were grade 3 nausea/vomiting at 400 mg BID in a BRCAmut carrier, grade 2 seizure at 400 mg BID in a patient with BRCAwt cancer, and grade 2 seizure at 500 mg BID in a BRCAmut carrier. Common toxicities included nausea (65%), fatigue (45%), and lymphopenia (38%). Grade 3/4 toxicities were rare (highest lymphopenia at 15%). Overall response rate (ORR) was 23% (95% CI 13-35%) in BRCAmut overall, and 37% (95% CI 21-55%) at 400 mg BID and above. In BRCAwt, ORR was 8% (95% CI 1-26%), and clinical benefit rate was 16% (95% CI 4-36%), reflecting prolonged stable disease in some patients. PK was linear with dose and was correlated with response and nausea. CONCLUSIONS: Continuous veliparib is safe and tolerable. The RP2D was 400 mg BID. There is evidence of clinical activity of veliparib in patients with BRCAmut and BRCAwt cancers.

[Salmonella Bacteremia Accompanying COVID-19: The First Salmonella Co-Infection in the World Unrelated to Pakistan]. / COVID-19'a Eslik Eden Salmonella Bakteremisi: Pakistan ile Iliskisiz Dünyadaki Ilk Salmonella Ko-Enfeksiyonu.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection emerged in China at the end of 2019 and caused coronavirus disease 2019 (COVID-19). The lymphopenia seen in COVID-19 increases the incidence of susceptibility to other microorganisms and may cause co-infections. As the signs and symptoms of the diseases overlap with other infectious diseases and due to the intensity in health services, the diagnosis of co-infections becomes difficult and the treatment may be delayed. Therefore, infections accompanying COVID-19 cause an increase in morbidity and mortality.The isolation and quarantine measures taken during the COVID-19 process have reduced the number of infections transmitted from person to person. However, there was no significant decrease in diseases transmitted by food, such as salmonellosis. During the pandemic, salmonellosis continued to be a problem, especially in endemic areas such as Pakistan, and an increase in Salmonella infections associated with backyard poultry has been reported in countries such as the United States. A co-infection of COVID-19 and enteric fever associated with travel to Pakistan was reported for the first time in the literature in February 2021. In this case report, the first co-infection of COVID-19 and Salmonella in our country was presented. A 56-yearold male patient with no known systemic disease was admitted to the hospital with fever, shortness of breath, weakness and myalgia lasting for three days. SARS-CoV-2 polymerase chain reaction test was positive. The patient has been hospitalized and favipiravir, moxifloxacin, and methylprednisolone were started. Blood cultures were taken from the patient whose clinical picture worsened and fever continued despite of the medical treatment. Salmonella enterica spp. enterica was isolated and ceftriaxone treatment was started. The patient's anamnesis was deepened, but no diarrhea, abdominal pain, suspicious food consumption, travel history were determined. From the second day of the ceftriaxone treatment, the patient's fever decreased and no growth was detected in the control blood cultures. Ceftriaxone treatment was completed in 14 days and the patient was discharged on the 28th day. Approximately 87-95% of Salmonella strains isolated in our country are S.enterica spp. enterica, and S.enterica spp. enterica was also isolated in our case. Salmonella infections most commonly present as gastroenteritis, but the risk of bacteremia increases in case of immunosuppression. Although there was no additional disease in our case, it was considered that the infection in the form of bacteremia occurred due to an immunosuppression caused by COVID-19. In this context; drawing blood cultures of patients hospitalized with the diagnosis of COVID-19 is very important in terms of detecting co-infections and superinfections, and administering appropriate antibiotic therapy at appropriate treatment times. Presentation of first case of Salmonella bacteremia and simultaneous COVID-19 infection in our country was the strong side of our report. In addition, our case is also important as being the first SARS-CoV-2 and Salmonella co-infection unrelated to Pakistan in the literature. The limitation of our case was that S.enterica spp. enterica detected in the blood culture could not be subtyped and the stool culture could not be examined. However, this does not constitute a diagnostic requirement. In addition, the patient's pre-COVID-19 Salmonella carrier status was also unknown. As a result, patients become vulnerable to other infections due to the lymphopenia seen in COVID-19. Therefore, Salmonella bacteremia can be seen with SARS-CoV-2 infection without a comorbid condition. Drawing blood cultures in hospitalized patients with the diagnosis of COVID-19 is very important in terms of detecting concomitant infections in a short time. In patients whose clinical condition does not improve and fever continues despite of treatment, blood cultures should be taken, especially in the case of an advanced immunosuppresive treatment plan, and it should always be kept in mind that secondary infections and co-infections may occur.

Prognostic significance of therapy-induced myelosuppression in newly diagnosed glioblastoma.

BACKGROUND: Myelosuppression is the major toxicity encountered during temozolomide chemoradiotherapy for newly diagnosed glioblastoma. METHODS: We assessed the association of myelosuppression (neutropenia, thrombocytopenia, anemia, and lymphopenia) during temozolomide chemoradiotherapy alone or in combination with experimental agents with progression-free survival (PFS) or overall survival (OS) in 2073 patients with newly diagnosed glioblastoma enrolled into five clinical trials: CENTRIC, CORE, EORTC 26082, AVAglio, and EORTC 26981. A landmark Cox model was used. For each primary association analysis, a significance level of 1.7% was used. RESULTS: Lower neutrophil counts at baseline were associated with better PFS (P = .011) and OS (P < .001), independently of steroid intake. Females experienced uniformly more myelotoxicity than males. Lymphopenia during concomitant chemoradiotherapy was associated with OS (P = .009): low-grade (1-2) lymphopenia might be associated with superior OS (HR 0.78, 98.3% CI 0.58-1.06), whereas high-grade (3-4) lymphopenia might be associated with inferior OS (HR 1.08, 98.3% CI 0.75-1.54). There were no associations of altered hematological parameters during concomitant chemoradiotherapy with PFS. During maintenance chemoradiotherapy, no significant association was found between any parameter of myelosuppression and PFS or OS, although exploratory analysis at 5% significance level indicated that either mild-to-moderate (HR 0.76, 95% CI 0.62-0.93) or high-grade lymphopenia (HR 0.65, 95% CI 0.46-0.92) was associated with superior OS (P = .013), but not PFS. CONCLUSIONS: The association of higher neutrophil counts at baseline with inferior PFS and OS requires further prospective evaluation. The link of therapy-induced lymphopenia to better outcome may guide the design for immunotherapy trials in newly diagnosed glioblastoma.

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.