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Journal For Immunotherapy of Cancer Jun 2024Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble...
INTRODUCTION
Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.
MATERIALS AND METHODS
This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies.
RESULTS
169 irAEs were experienced by 86/143 patients (137 grades 1-2, 32 grades 3-4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597).
CONCLUSION
The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction.
Topics: Humans; Melanoma; Female; Male; Autoantibodies; Middle Aged; Retrospective Studies; Aged; Immune Checkpoint Inhibitors; Seroconversion; Adult; Aged, 80 and over; Programmed Cell Death 1 Receptor
PubMed: 38945553
DOI: 10.1136/jitc-2024-009215 -
Journal For Immunotherapy of Cancer Jun 2024How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
BACKGROUND
How distinct methods of host preconditioning impact the efficacy of adoptively transferred antitumor T helper cells is unknown.
METHODS
CD4 T cells with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to the T helper 17 (Th17) phenotype and then transferred into melanoma-bearing mice preconditioned with either total body irradiation or chemotherapy.
RESULTS
We found that preconditioning mice with a non-myeloablative dose of total body irradiation (TBI of 5 Gy) was more effective than using an equivalently dosed non-myeloablative chemotherapy (cyclophosphamide (CTX) of 200 mg/kg) at augmenting therapeutic activity of antitumor TRP-1 Th17 cells. Antitumor Th17 cells engrafted better following preconditioning with TBI and regressed large established melanoma in all animals. Conversely, only half of mice survived long-term when preconditioned with CTX and infused with anti-melanoma Th17 cells. Interleukin (IL)-17 and interferon-γ, produced by the infused Th17 cells, were detected in animals given either TBI or CTX preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, and keratinocyte chemoattractant) were significantly elevated in the serum of mice preconditioned with TBI versus CTX after Th17 therapy. The addition of fludarabine (FLU, 200 mg/kg) to CTX (200 mg/kg) improved the antitumor response to the same degree mediated by TBI, whereas FLU alone with Th17 therapy was ineffective.
CONCLUSIONS
Our results indicate, for the first time, that the antitumor response, persistence, and cytokine profiles resulting from Th17 therapy are impacted by the specific regimen of host preconditioning. This work is important for understanding mechanisms that promote long-lived responses by adoptive cellular therapy, particularly as CD4 based T-cell therapies are now emerging in the clinic.
Topics: Animals; Th17 Cells; Mice; Mice, Inbred C57BL; Immunotherapy, Adoptive; Whole-Body Irradiation; Melanoma, Experimental; Cyclophosphamide; Adoptive Transfer; Female; Melanoma
PubMed: 38945552
DOI: 10.1136/jitc-2023-008715 -
Journal of Gynecologic Oncology Jun 2024Cancer-field surgery by peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL) for the treatment of endometrial cancer (EC) aims at...
OBJECTIVE
Cancer-field surgery by peritoneal mesometrial resection and targeted compartmental lymphadenectomy (PMMR+TCL) for the treatment of endometrial cancer (EC) aims at optimal locoregional tumor control without the need for adjuvant radiotherapy. In a previous publication we could demonstrate the feasibility of the method and presented encouraging first oncologic data.
METHODS
Following up our 2021 publication, we present data on the treatment of EC by PMMR+TCL in much larger cohort and with longer follow-up.
RESULTS
One hundred and thirty-five patients with EC International Federation of Gynecology and Obstetrics (FIGO) I-IV (75.6% FIGO I) underwent cancer field surgery via PMMR+TCL for EC in the years 2016-2023. Mean follow-up in our cohort was 27.5 months (0, 83; 19.7). The procedure was feasible and safe with favorable intra-and postoperative complication rates. Even though 50.4% of patients had an indication for postoperative radiotherapy following national and international guidelines, the rate of postoperative irradiation administered was 10.4%. The overall recurrence rate was 8.1% and we observed 2 (1.5%) isolated locoregional recurrences.
CONCLUSION
Our results confirm the feasibility and safety of PMMR+TCL in EC patients. Oncologic data are very encouraging and hint at a superior locoregional control without adjuvant irradiation. Larger studies with longer follow-up will be needed to confirm these results.
PubMed: 38945527
DOI: 10.3802/jgo.2025.36.e13 -
Revista Portuguesa de Cardiologia :... Jun 2024
PubMed: 38945475
DOI: 10.1016/j.repc.2024.03.003 -
The Journal of Biological Chemistry Jun 2024DNA-PKcs is a DNA damage sensor kinase with established roles in DNA double-strand break repair via non-homologous end joining. Recent studies have revealed additional...
DNA-PKcs is a DNA damage sensor kinase with established roles in DNA double-strand break repair via non-homologous end joining. Recent studies have revealed additional roles of DNA-PKcs in the regulation of transcription, translation, and DNA replication. However, the substrates through which DNA-PKcs regulates these processes remain largely undefined. Here we utilized quantitative phosphoproteomics to generate a high coverage map of DNA-PKcs signaling in response to ionizing radiation and mapped its interplay with the ATM kinase. Beyond the detection of the canonical S/T-Q phosphorylation motif, we uncovered a non-canonical mode of DNA-PKcs signaling targeting S/T-ψ-D/E motifs. Sequence and structural analyses of the DNA-PKcs substrate recognition pocket revealed unique features compared to closely related PIKK kinases that may explain its broader substrate preference. These findings expand the repertoire of DNA-PKcs and ATM substrates while establishing a novel preferential phosphorylation motif for DNA-PKcs.
PubMed: 38945450
DOI: 10.1016/j.jbc.2024.107513 -
The Journal of Hospital Infection Jun 2024Continuous fluid infusions delivered between therapies by piggy-back systems avoid disconnection and reconnection of central venous catheters (CVC), thereby reducing...
BACKGROUND
Continuous fluid infusions delivered between therapies by piggy-back systems avoid disconnection and reconnection of central venous catheters (CVC), thereby reducing opportunities for line contamination. However, the impact of continuous versus intermittent infusions on central line-associated bloodstream infections (CLABSI) is unknown.
AIM
To investigate the effect of temporary infusion interruption and line disconnection, with or without use of a 70% isopropyl alcohol cap (IPA-C) use on CLABSI rates in haematology patients.
METHODS
Quasi-experimental study in two haemato-oncology units. At baseline (P1, September 2020 - August 2021), continuous intravenous piggy-back infusions were mandatory. In a first intervention phase (P2, September 2021 - August 2022), infusion disconnections were implemented with use of a 70% isopropyl alcohol cap (IPA-C) for passive decontamination. In a second intervention phase (P3, September 2022 - August 2023), infusion disconnections continued without the use of IPA-C. Rates of CLABSI were compared across the three intervention periods using segmented Poisson regression.
FINDINGS
A total of 11,039 catheter-days across 764 CVC and 16,226 patient-days were included. 21 CLABSI were recorded across all intervention periods. Compared with P1, incidence rate ratios (IRRs) for CLABSI did not significantly change in P2 (IRR 0.76 [95% CI 0.27-2.15]) and P3 (IRR 0.79 [CI 95% 0.28-2.22]). No CVCs were removed due to occlusion during the study period. Five of 21 CLABSI were polymicrobial, and coagulase-negative staphylococci were isolated in 19/21 cases (90%).
CONCLUSION
Interruption of continuous infusions in haemato-oncology patients with a CVC was not associated with a substantial change in CLABSI rates, whether or not an IPA-C was used.
PubMed: 38945400
DOI: 10.1016/j.jhin.2024.05.021 -
Human Pathology Jun 2024MLH1 promoter hypermethylation (MPH) analysis is an essential step in the universal tumor testing algorithm for Lynch syndrome, the most common inherited predisposition...
MLH1 promoter hypermethylation (MPH) analysis is an essential step in the universal tumor testing algorithm for Lynch syndrome, the most common inherited predisposition to colorectal cancer (CRC). MPH usually indicates sporadic CRC. EPM2AIP1 gene shares the same promoter as MLH1, therefore MPH should also silence EPM2AIP1 transcription leading to loss of protein expression on immunohistochemistry (IHC). It has been previously reported that EPM2AIP1 IHC can be used as a surrogate for MPH in endometrial cancer. Our goal was to evaluate the feasibility of EPM2AIP1 IHC as a surrogate for MPH in CRC. 101 microsatellite instable CRC cases were selected, including 19 cases from whole tumor sections and 82 cases from tissue microarrays. 74 cases were with MPH and 27 without MPH. All 74 cases with MPH showed absent MLH1 by IHC, but only 47 (64%) exhibited loss of expression of EPM2AIP1. Of the 27 cases without MPH, 9 (33%) cases had unexpected loss of EPM2AIP1 expression. Of note, 10 cases were MLH1-mutated Lynch syndrome without MPH, 2 cases showed unexpected loss of EPM2AIP1 staining. Of the 6 cases with double somatic mutations of MLH1 gene (without MPH), only 4 cases demonstrated intact expression of EPM2AIP1 as expected. Taken together, EPM2AIP1 loss was 64% sensitive and 67% specific for MPH, with an accuracy of 64%. We conclude that, unless stain quality improves with different clones or platforms, EPM2AIP1 IHC will likely not be useful as a surrogate test for MPH in CRC.
PubMed: 38945374
DOI: 10.1016/j.humpath.2024.06.017 -
Clinics (Sao Paulo, Brazil) Jun 2024
PubMed: 38945114
DOI: 10.1016/j.clinsp.2024.100426 -
Clinics (Sao Paulo, Brazil) Jun 2024[Cr]CrEDTA is used to measure the Glomerular Filtration Rate (GFR) in different clinical conditions. However, there is no consensus on the ideal number of blood samples...
Comparison of plasma clearance of [Cr]CrEDTA based on three, two and single samples to measure the glomerular filtration rate in patients with solid tumors: a prospective cross-sectional analysis.
OBJECTIVES
[Cr]CrEDTA is used to measure the Glomerular Filtration Rate (GFR) in different clinical conditions. However, there is no consensus on the ideal number of blood samples to be taken and at what time points to measure its clearance. This study aimed to compare Slope Intercept (SI) and Single-Sample (SS) methods for measuring GFR in patients with solid tumors, stratified by age, GFR, and Body Mass Index (BMI).
METHODS
1,174 patients with cancer were enrolled in this prospective study. GFR was calculated by the SI method using blood samples drawn 2-, 4-, and 6-hours after [Cr]CrEDTA injection (246-GFR). GFR was also measured using the SI method with samples at 2 and 4 hours (24-GFR) and at 4 and 6 hours (46-GFR), and SS methods according to Groth (4Gr-GFR) and Fleming (4Fl-GFR). Statistical analysis was performed to assess the accuracy, precision, and bias of the methods.
RESULTS
Mean 246-GFR was 79.2 ± 21.9 mL/min/1.73 m. ANOVA indicated a significant difference between 4Gr-GFR and the reference 246-GFR. Bias was lower than 5 mL/min/1.73 m for all methods, except for SS methods in subgroups BMI > 40 kg/m; GFR > 105 or < 45. Precision was adequate and accuracy of 30 % was above 98% for all methods, except for SS methods in subgroup GFR < 45.
CONCLUSION
46-GFR and 246-GFR have high agreement and may be used to evaluate kidney function in patients with solid tumors. Single-sample methods can be adopted in specific situations, for non-obese patients with expected normal GFR.
PubMed: 38945113
DOI: 10.1016/j.clinsp.2024.100427 -
Translational Oncology Jun 2024Adjuvant radiotherapy after mastectomy or breast conserving surgery (BCS) is the standard of care for majority of patients with breast cancer. This is however associated...
BACKGROUND
Adjuvant radiotherapy after mastectomy or breast conserving surgery (BCS) is the standard of care for majority of patients with breast cancer. This is however associated with mucosal and epidermal toxicity of organs at risk (OARs). Breast cancer patients are exposed to a plethora of wrong perceptions, misinformation and myths concerning the usefulness and adverse effects of radiotherapy. There is paucity of literature on the incidence and severity of radiation-induced acute toxicities experienced by patients with breast cancer in Ghana.
AIM
To assess the occurrence and severity of four main acute radiation-induced toxicities among female breast cancer patients treated with external beam radiotherapy at a major cancer treatment centre in Ghana.
METHODS
Data on the occurrence of acute toxicities among patients was collected from patients' medical records, through a semi-structured questionnaire and via weekly clinical assessments. The Common Terminology Criteria for Adverse Events (CTCAE) grading scale (version 4.0) was used to grade the severity of these toxicities. Descriptive and inferential statistics using an independent two-sampled t-test (two-tailed), one-way analysis of variance (ANOVA), Pearson's Chi-square and Fisher's exact tests were performed.
RESULTS
Dermatitis, fatigue, pharyngitis, and breast (chest) pain were the radiation toxicities found among the breast cancer patients undergoing treatment on the two machines. The mean predominant radiation doses associated with the onset of dermatitis, fatigue, pharyngitis, and chest pain in the breast cancer patients were 22.32 Gy, 22.48 Gy, 13.59 Gy, and 19.27 Gy respectively for treatment with a statistically significant (p = 0.0173). Radiation dermatitis was the most dominant acute radiation toxicity recorded, and its incidence and severity. The range of Fisher's p-values (0.689-0.999) between the acute radiation toxicities with both machines revealed no statistical significance.
CONCLUSION
Radiation dermatitis was the dominant acute toxicity, both in incidence and severity for patients treated. There was no statistical significance in the incidence and severity of acute radiation side effects.
PubMed: 38945020
DOI: 10.1016/j.tranon.2024.102032