Compassionate use of recombinant human IL-7-hyFc as a salvage treatment for restoring lymphopenia in patients with recurrent glioblastoma

Purpose Lymphopenia is frequently observed and is associated with poor prognosis in glioblastoma (GBM) patients. Restoring lymphopenia in cancer patients has been suggested as a novel immunotherapeutic strategy. As interleukin-7 (IL-7) is necessary for proliferation of lymphocytes and to amplify the total lymphocyte count (TLC), IL-7 therapy has been tried for various cancers, although the results are inconclusive. Here, we describe the clinical results of recurrent GBM treated with long-acting engineered version of recombinant human IL-7 (rhIL-7-hyFc). Methods This prospective case series based on compassionate use was approved by the Ministry of Food and Drug Safety in South Korea. Patients with recurrent GBM were enrolled to Seoul St. Mary's Hospital. Primary outcomes were the safety profile and elevated total lymphocyte count (TLC). Secondary outcomes were overall survival (OS) and progressionbfree survival (PFS). The duration of median follow up was 372.6 days (range 98-864 days). Results Among 18 patients enrolled, 10 received rhIL-7-hyFc with temozolomide, 5 received rhIL-7-hyFc with bevacizumab, 1 received rhIL-7-hyFc with PCV chemotherapy, and 2 received rhIL-7-hyFc alone. The mean TLC of enrolled patients after the first treatment with rhIL-7-hyFc was significantly increased from 1,131 cells/mm^3 (range 330-2,989) at baseline to 4,356 cells/mm^3 (range 661-22,661). Similar increase was observed in 16 of 18 patients (88.8%), only after the first treatment of rhIL-7-hyFc. TLCs of these patients were maintained higher while rhIL-7-hyFc was repeatedly administered. Most common adverse events were injection sites reactions (64.7%) including urticaria and itching sensation, however, there were no serious adverse events more than grade III. Median OS and PFS were 378 days (range 107-864 days) and 231 days (55-726 days), respectively. Conclusion Our study first reports that IL-7 immunotherapy can restore lymphopenia and maintain TLC with various salvageable chemotherapies in recurrent GBM patients without serious adverse toxicities. This outcome warrants further larger and randomized clinical trials to validate the clinical benefits of rhIL-7-hyFc for GBM patients.

Age-dependent normalisation functions for T-lymphocytes in healthy individuals

Lymphocyte numbers naturally change through age. Normalisation functions to account for this are sparse, and mostly disregard measurements from children in which these changes are most prominent. In this study, we analyse cross-sectional numbers of mainly T-lymphocytes (CD3+, CD3+CD4+ and CD3+CD8+) and their subpopulations (naive and memory) from 673 healthy Dutch individuals ranging from infancy to adulthood (0-62 years). We fitted the data by a delayed exponential function and received parameter estimates for each lymphocyte subset. Our modelling approach follows general laboratory measurement procedures in which absolute cell counts of T-lymphocyte subsets are calculated from observed percentages within a reference population that is truly counted (typically the total lymphocyte count). Consequently, we receive one set of parameter estimates per T-cell subset representing both the trajectories of their counts and percentages. We allow for an initial time delay of half a year before the total lymphocyte counts per µl of blood start to change exponentially, and we find that T-lymphocyte trajectories tend to increase during the first half a year of life. Thus, our study provides functions describing the general trajectories of T-lymphocyte counts and percentages of the Dutch population. These functions provide important references to study T-lymphocyte dynamics in disease, and allow one to quantify losses and gains in longitudinal data, such as the CD4+ T-cell decline in HIV-infected children, and/or the rate of T-cell recovery after the onset of treatment.

Effect of N-Acetylcysteine on IL-10 and Total Lymphocyte Count in HIV Infected Patients Undergoing Antiretroviral Treatment

Objective: To determine NAC oral administration’s effect on changes in IL-10 levels and total lymphocyte count (TLC) in patients with HIV/AIDS in Dr Mohammad Hoesin Hospital, Palembang. Material and Methods: This study was a double-blind, randomized clinical trial. A total of 32 HIV/AIDS patients undergoing ARV treatment were randomly divided into two groups: the placebo and NAC groups. In the placebo group, patients were given capsules containing lactose at a dose of 3x1 capsules/ day, while the NAC group, were given NAC at a dose of 3x200 mg/day. Each group was treated for 12 weeks. Results: NAC administration significantly reduced IL-10 levels P= 0.038 but could not significantly increase TLC after treatment P= 0.376. However, TLC on the NAC group remained higher when compared with TLC on the placebo group. Conclusion: NAC administration significantly reduced levels of IL-10 and increased TLC; therefore, NAC has potential effects of increasing the effectiveness of antiretroviral therapy in HIV/AIDS patients, although it still needs to be studied further. J MEDICINE 2021; 22: 114-118

996. CD4+ T-Cell Lymphopenia Associated with Frequent Plateletpheresis in Healthy Donors

Background Frequent plateletpheresis using the Time Accel leukoreduction system chamber may result in lymphopenia in healthy donors, with increased donation in the previous year associated with CD4+ T-cell count of less than 200 cells/µL. However, this finding has not been replicated and the clinical significance of plateletpheresis-associated lymphopenia remains unclear. Methods A prospective observational study of healthy plateletpheresis donors aged 18 or older who donated at least once in the previous 365 days was conducted at the Kraft Blood Center at Brigham and Women’s Hospital/Dana Farber Cancer Institute, where the Time Accel system is used exclusively. Blood was drawn immediately before plateletpheresis or at least 2 weeks after the last donation to assess for total lymphocyte and CD4+ T-cell counts. Results A total of 86 participants were enrolled: 23 had 1-5 donations, 36 had 6-19 donations, and 27 had 20-24 donations within the previous 365 days (Figure 1). For the low-, medium-, and high-frequency donation groups, the median age was 53 years (IQR 43-64), 61 years (IQR 53-68), and 61 years (IQR 55-65), respectively. The median total lymphocyte count was 1.5 (IQR 1.3-1.9), 1.2 (IQR 0.9-1.5), 0.8 (IQR 0.6-0.9) 103 cells/µL, and the median CD4+ T-cell count was 648 (IQR 531-843), 525 (IQR 348-698), and 220 (IQR 184-347) cells/µL. CD4+ T-cell counts were < 200 cells/µL in 0/23 (0%), 3/36 (8%), and 9/27 (33%) participants across the three groups. Total lymphocyte and CD4+ T-cell counts were inversely correlated with the number of platelet donations in the prior 365 days, R2 = 0.384 (Fig 2) and 0.402 (Fig 3) respectively. Conclusion Frequent plateletpheresis using Time Accel leukoreduction system chamber is associated with CD4+ T-cell lymphopenia, with counts below 200 cells/µL seen in one third of those who donated 20-24 times in the previous year. Vaccine immunogenicity studies are ongoing to evaluate the clinical significance of this finding. Disclosures Stephen R. Walsh, MDCM, Janssen Vaccines (Scientific Research Study Investigator)Regeneron (Scientific Research Study Investigator)Sanofi Pasteur (Scientific Research Study Investigator)

Impact of total splenectomy on peripheral lymphocytes and their subsets in patients with hypersplenism associated with cirrhotic portal hypertension

To study the impact of total splenectomy (TS) on peripheral lymphocytes and their subsets in patients with hypersplenism associated with cirrhotic portal hypertension (CPH). We studied 102 consecutive patients who received TS from January 2008 to January 2020 due to CPH-related hypersplenism. A similar number of healthy individuals are used as healthy controls (HC). The total lymphocyte counts and their percentages of B lymphocytes, total T lymphocytes (cluster of differentiation (CD)3+) and their subsets (CD4+, CD8+), and natural killer (NK) cells in preoperative peripheral blood samples in hypersplenism patients were significantly lower than that of the HCs (both P < 0.05). The total lymphocyte counts and percentages of B lymphocytes in peripheral blood were significantly increased 1 week and 1 month after TS when compared with the pre-TS values (P < 0.05). There was no significant difference in the percentages of NK cells before or after surgery (P > 0.05). However, the percentages of CD3+ cells was significantly higher 1 month after than before surgery (P < 0.001). The percentages of CD4+, and CD8+ T lymphocytes were significantly lower 1 week after surgery (P < 0.05), but they were significantly higher 1 month after surgery (P < 0.01). The CD4+:CD8+ ratio was not significantly different from those before surgery, and 1 week or 1 month after surgery (P > 0.05). Patients with hypersplenism associated with CPH were significantly immunosuppressed preoperatively. After TS, the total lymphocyte count and percentages of B lymphocytes, and total T lymphocytes and their subsets increased significantly, resulting in improved immune functions.

Correlation between Ascites and Total Lymphocyte Count with Occurrence of Hepatic Encephalopathy in Liver Cirrhosis Patients

Hepatic encephalopathy (HE) is brain dysfunction manifested as a broad spectrum of neuropsychiatric abnormalities caused by hepatic insufficiency or portosystemic shunting due to portal hypertension. Portal hypertension in liver cirrhosis also causes ascites, as the most common clinical manifestation. Further, immune dysfunction, one of which is decreased total lymphocyte count (TLC), happens at liver cirrhosis, which triggers the systemic inflammatory response. This systemic inflammatory response plays a role in HE. Objective of this study is to know the correlation between ascites and TLC with occurence of HE in liver cirrhosis patient. This study was conducted by retrospective cohort design in Saiful Anwar Hospital. Determination of sample amount at this study used total sampling method. Hepatic encephalopathy diagnosis was based on West Haven Criteria. Ascites was determined by physical examination and/or abdominal ultasonography. Total lymphocyte count data was taken from medical record, with complete blood count examination used XS-800i hematology analyzer machine. Data were analyzed using a logistic regression test, with p&lt;0.05 was considered significant and Confidence Interval (CI) 95%. Seventy-eight liver cirrhosis patients were observed using a retrospective cohort method regarding the HE occurrence, and physical examination for ascites and laboratory examination were performed. The statistical analysis result of the correlation between ascites and HE is significant with an odds ratio of 5.108 and CI of 1.36-19.25. On the other hand, TLC has no significant correlation with the occurrence of HE. Based on this analysis result, it is concluded that ascites has a correlation with HE, but TLC does not.<p> </p>

Low Total Lymphocyte Count as the Risk of Hospital Acquired Malnutrition in Children

Background: Hospital Acquired Malnutrition (HAM) is characterized by inadequate nutritional therapy and the risk of developing malnutrition during the hospital stay. In clinical practice, there are many measurements to determine nutritional status. Total lymphocyte count (TLC) is associated with impaired function of immune system in malnutrition. The purpose of this study was to evaluate the prognostic value of TLC to the occurrence of HAM in pediatric patients.Materials and Methods: This an observational study with a prospective cohort design. Subjects were assessed for weight at the first day of hospitalization, then the subjects were followed until they were discharged. Body weight was re-measured on discharge to determine the presence or absence of HAM. This research was conducted at Sanglah Hospital from May-December 2019. Subjects who met the inclusion and exclusion criteria were enrolled in the study.Results: Among 120 subjects, 55 subjects or 45.8% were malnourished on admission. Subjects with a low TLC compared to a normal TLC had a 3.9-fold risk of experiencing hospital acquired malnutrition (95% Confidence Interval: 1.59 to 7.19, p=0.001). Subjects who had a low TLC had HAM of 61.8%, while subjects who had a normal TLC had HAM of 32.3%. In multivariate analysis, low TLC was the only risk factor for HAM in this research.Conclusion: This study proved that low TLC is the risk of HAM. Total lymphocyte count could be used as predictor of the risk of HAM in hospitalization children.Keywords: hospital malnutrition, total lymphocyte, children

Impact of Total Splenectomy on Peripheral Lymphocytes and Their Subsets in Patients with Hypersplenism Associated with Cirrhotic Portal Hypertension

Objective To study the impact of total splenectomy (TS) on peripheral lymphocytes and their subsets in patients with hypersplenism associated with cirrhotic portal hypertension (CPH). Methods Consecutive patients who underwent TS for hypersplenism associated with CPH from January 2008 to January 2020 were studied. A group of a similar number of healthy individuals was used as healthy controls (HCs). Results The total lymphocyte counts and their percentages of B lymphocytes, total T lymphocytes (cluster of differentiation (CD)3+) and their subsets (CD4+, CD8+), and natural killer (NK) cells in preoperative peripheral blood samples in hypersplenism patients were significantly lower than that of the HCs (both P < 0.05). The total lymphocyte counts and percentages of B lymphocytes in peripheral blood were significantly increased 1 week and 1 month after TS when compared with the pre-TS values (P < 0.05). There was no significant difference in the percentages of NK cells before or after surgery (P > 0.05). However, the percentages of CD3+ cells was significantly higher 1 month after than before surgery (P < 0.001). The percentages of CD4+, and CD8+ T lymphocytes were significantly lower 1 week after surgery (P < 0.05), but they were significantly higher 1 month after surgery (P < 0.01). The CD4+:CD8+ ratio was not significantly different from those before surgery, and 1 week or 1 month after surgery (P > 0.05). Conclusions Patients with hypersplenism associated with CPH were significantly immunosuppressed preoperatively. After TS, the total lymphocyte count and percentages of B lymphocytes, and total T lymphocytes and their subsets increased significantly, resulting in improved immune functions.

Medical Nutrition Therapy in Ascendens Colon Perforation Due to Intestinal Tuberculosis With Severe Malnutrition: A Case Report

Objectives Intestinal tuberculosis (TB) cases increased with the increase in TB cases in general. Intestinal TB was found in 11% of extrapulmonary TB patients. Severe malnutrition was associated with poor outcome in TB patients. Due to inflammation process, TB patients were in hypermetabolic conditions which caused increase in nutritional requirements. Intestinal TB with severe malnutrition need spesific nutritional therapy, tailored to each patient based on their nutritional status and clinical condition. Methods A 41-year old male patient with severe malnutrition (body mass index 17,9 kg/m2) diagnosed with post laparotomy due to perforation of ascending colon due to Intestinal TB. Oral intake decreased due to loss of appetite and abdominal pain. Patient showed pale in conjunctival, loss of subcutaneous fat, wasting and edema in extremities. Laboratory findings were anemia (7.5 g/dL), hypoalbuminemia (2.4 g/dL), hyponatremia (130 mmol/L), hypokalemia (3.0 mmol/L) and severe depletion of total lymphocyte count (477/mL). Patient suffered from post-operative complications in the form of post-operative ileus, low output enterocutaneous fistula and suspected an anastomoses leakage. Results Medical nutrition therapy was given with a total calorie of 1175 kcal and increased gradually to 2000 kcal, protein 0.8–2 g/Ideal Body Weight/day using high protein formula and amino acids parenteral nutrition, including glutamine infussion. We administered suplementations which were zinc, multivitamins, curcuma and snakehead fish extract. Patient was discharged after 37 days with clinical and functional capacity improvement assessed with handgrip dynamometer from 11.2 to 23.4 kg. Laboratory improvement were Hemoglobin 10.1 g/dL, Albumin 2.8 mg/dL, Sodium 143 mmol/L, Potassium 4.2 mmol/L and Total lymphocyte count 904/mL. Post-operative complications were improved. Conclusions Malnourished patient with intestinal TB who undergoing surgery had an increased risk of nutritional deficiencies and postoperative complications. Specific nutritional therapy to reduce inflammation or hypermetabolic, and to treat post surgical complications, proper monitoring and nutritional education results in a good outcome for patient. Funding Sources The author(s) received no financial support for the research, autorship and/or publication of this article.