UNASSIGNED: Platinum-free interval (PFI) is the period from the end of platinum-based chemotherapy to the date of recurrence. If the PFI is > 6 months, a platinum-based chemotherapy rechallenge is considered; however, its efficacy after poly adenosine 5\'-diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy is unknown. This study aimed to examine the efficacy of a platinum-based chemotherapy rechallenge after PARP inhibitor therapy.
UNASSIGNED: We retrospectively evaluated patients with ovarian cancer with a PFI≥6 months with PARP inhibitor maintenance therapy, receiving platinum-based chemotherapy. Duration of PARP inhibitor therapy, best response to subsequent platinum chemotherapy rechallenge, and clinical characteristics were collected from medical records. Tumor response was assessed according to RECIST 1.1. Correlations were calculated using Spearman\'s correlation coefficients.
UNASSIGNED: Among the 10 included patients, seven (70 %) received PARP inhibitors after primary chemotherapy, and three (30 %) received chemotherapy for platinum-sensitive relapse. One and five patients harbored a germline BRCA1 and BRCA wild-type mutations, respectively, and two had homologous recombination proficiency. The median PFI was 303.5 (182-602) days, and PARP inhibitor therapy duration was 249 (147-570) days. Platinum chemotherapy rechallenge efficacy was complete and partial response and stable disease in one (10 %), six (60 %), and three (30 %) patients, respectively. The longer the duration of PARP inhibitor treatment, better the response to platinum agents (Spearman correlation coefficient 0.284, p = 0.0288).
UNASSIGNED: Platinum-based chemotherapy rechallenge is reasonable for patients with platinum-sensitive disease, using the traditional PFI cutoff of 6 months, even when the PFI is obtained with a maintenance PARP inhibitor.

BACKGROUND: Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy.
METHODS: We focused on patients who received 12 cycles of FOLFIRINOX (arm A, N = 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, N = 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated.
RESULTS: Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant.
CONCLUSIONS: Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337).

BACKGROUND: Chemotherapy remains the standard first-line treatment for pancreatic adenocarcinoma, but with limited efficacy. We aimed to explore the feasibility of adding the PARP inhibitor fuzuloparib to mFOLFIRINOX in the locally advanced/metastatic (LA/M) setting.
METHODS: This was the dose-escalation and -expansion, phase 1b portion of a phase 1b/2 study. Patients were given oral fuzuloparib at escalating doses starting at 30 mg twice daily (BID) plus intravenous mFOLFIRINOX q2w for 8-12 cycles, followed by maintenance fuzuloparib at 150 mg BID. Cohorts at the maximal tolerated dose (MTD) and lower dose of fuzuloparib were expanded. Primary endpoints were dose-limiting toxicity (DLT), MTD, and recommended phase 2 dose (RP2D).
RESULTS: As of data cutoff on Jan 15, 2023, 39 patients were recruited. 12 patients were enrolled during dose escalation (30 mg [n = 4]; 60 mg [n = 6]; 100 mg [n = 2]). DLT occurred in 1 patient in 60 mg cohort and 1 patient in 100 mg cohort. 60 mg BID was determined to be the MTD, and then 60 and 30 mg cohorts were expanded to 22 and 15 patients, respectively. The most common grade ≥ 3 treatment-related adverse events were hematologic toxicities. Efficacy in 60 mg cohort seemed to be most favorable, with an objective response rate of 50.0% (95% CI, 26.0-74.0) and disease control rate of 94.4% (95% CI, 72.7-99.9).
CONCLUSIONS: First-line fuzuloparib plus mFOLFIRINOX followed by maintenance fuzuloparib was generally safe and showed encouraging anti-tumor activity in patients with LA/M pancreatic adenocarcinoma. The RP2D of fuzuloparib combination was 60 mg BID.
BACKGROUND: ClinicalTrials.gov, NCT04228601.

During tumorigenesis, the recently identified tumor-specific memory T cells in draining lymph nodes (TdLN-TTSM cells) play a pivotal role in tumor repression that gives rise to progenitor exhausted T (TPEX) cells and further replenishes tumor-specific CD8+ T cells residing in the tumor microenvironment (TME). However, how TTSM cells are maintained in TdLN is largely unknown. Here, we show that the transcription regulator ID3 (inhibitor of DNA binding 3) is highly expressed by TTSM cells compared with other CD8+ T cell subsets. The deficiency of ID3 significantly interrupts the maintenance of TTSM and TPEX cells, resulting in decreased tumor-infiltrating CD8+ T cells and impaired tumor control. Consistent with this, overexpression of ID3 in CD8+ T cells increases the TTSM cell population and enhances the anti-tumor immune response.

Isometric resistance training (IRT) has emerged as an efficacious therapeutic intervention to reduce ambulatory blood pressure (BP), and BP diurnal variability. However, once the required decreases in BP have been achieved the efficacy of implementing a reduced maintenance dose is not understood. Therefore, the purpose of this study was to determine the effects of an 8-week maintenance period (8-week) following the cessation of the prescribed 8-week IRT in young normotensives. Twenty-two recreationally active, not resistance trained, normotensive (24-h ambulatory SBP, ≥130 mmHg) young adults were randomly assigned to a training-maintenance [TG-MT; n = 13 (female = 5); age 21 ± 2 years] or a non-training control [CON; n = 9 (female = 4); age 23 ± 3 years] group. Ambulatory BP, morning BP surge (MBPS) and average real variability (ARV) were measured prior to, after 8 weeks of bilateral leg IRT (4x2-minute contractions at 20% MVC with 2-min rest periods, 3 days/week) and following an 8-week (once per week) maintenance period. On completion of the maintenance period the significant reductions seen following the IRT were maintained within the TG-MT group in 24-h ambulatory SBP (6 ± 4 mmHg, p < 0.001), daytime (5 ± 5 mmHg, p = 0.002), MBPS (7 ± 10 mmHg, p = 0.019) and 24-h SBP ARV (2.03 ± 1.44 mmHg, p = 0.001), daytime SBP ARV (2.04 ± 1.78 mmHg, p = 0.003). These results show that reductions in ambulatory BP (24-h SBP and daytime SBP), in addition to BP diurnal variations (MBPS, 24-h SBP ARV and daytime SBP AVR) are maintained following an 8-week maintenance dose in young adults and add further weight to the growing body of evidence promoting IRT as an efficacious therapeutic exercise intervention to prevent or reduce BP.

OBJECTIVE: Acid secretion inhibitors are associated with hypergastrinemia, which can lead to gastric mucosal changes. Potassium-competitive acid blockers, such as vonoprazan, are more potent than proton pump inhibitors, but long-term safety data are lacking.
METHODS: In this phase 4, randomized trial, patients with erosive esophagitis (EE) received induction therapy (once-daily vonoprazan 20 mg or lansoprazole 30 mg; ≤8 weeks). Those with healed EE received maintenance therapy (once-daily vonoprazan 10 mg or lansoprazole 15 mg) for 260 weeks (2:1). The primary endpoint was the proportion of patients with malignant epithelial cell alterations, parietal cell hyperplasia, foveolar hyperplasia, enterochromaffin-like (ECL) cell hyperplasia, and G-cell hyperplasia.
RESULTS: Overall, 202/208 patients (vonoprazan n=139; lansoprazole n=69) achieved healed EE and received maintenance therapy. No malignant alterations or gastric neuroendocrine tumors (NETs) were observed; there was one adenoma in each group. At week 260, more patients taking vonoprazan versus lansoprazole had parietal cell hyperplasia (97.1% vs 86.5%) and foveolar hyperplasia (14.7% vs 1.9%); proportions of patients with ECL cell hyperplasia (4.9% vs 7.7%) and G-cell hyperplasia (85.3% vs 76.9%) were similar. Median serum gastrin levels were higher with vonoprazan treatment versus lansoprazole (625 pg/mL vs 200 pg/mL). Incidences of adverse events were comparable for both treatments.
CONCLUSIONS: The exploratory VISION study assessed the safety profile of vonoprazan and lansoprazole over 5 years in Japanese patients with healed EE. While gastrin concentration, parietal cell hyperplasia and foveolar hyperplasia were higher in the vonoprazan group, there was no increased risk of malignant epithelial cell alterations and gastric NETs. (ClinicalTrials.gov, NCT02679508.).

OBJECTIVE: Our aim was to investigate the impact of smoking on pocket closure at six months after treatment of severe periodontitis, in relation to residual clinical inflammation.
METHODS: The clinical records of deep pockets (probing depth≥6 mm, n=984) in 46 individuals with periodontitis were analyzed. Following baseline clinical assessments (plaque index, probing depth, clinical attachment level, and bleeding on probing), non-surgical periodontal treatment was performed. Clinical assessments were repeated at 2 and 24 weeks after periodontal therapy. A logistic regression model using generalised estimation equations (GEE) adapting the cluster robust standard errors was performed to investigate potential associations between bleeding on probing and pocket closure at post-treatment 24 weeks.
RESULTS: Absence of bleeding at two weeks after non-surgical treatment related to pocket closure after six-months. Pockets that do not bleed neither at baseline nor two weeks (OR=2.7; P <.005) and pockets of non-smokers (OR=6.32; P <.001) and females (OR=1.79; P =.022) associated with pocket closure at six months.
CONCLUSIONS: Pocket closure is associated with being a non-smoker and the absence of inflammation after non-surgical periodontal treatment, which indicates the importance of smoking cessation and inflammation control in achieving optimal clinical outcomes.

BACKGROUND: FLT3-ITD AML is associated with an increased risk of relapse, leading many patients to receive an allogeneic hematopoietic stem cell transplantation (alloHCT) after induction. Unfortunately, relapse rate after alloHCT remains high and strategies are needed to improve outcomes.
METHODS: We performed a retrospective analysis of adult patients with FLT3-ITD AML who received alloHCT from 6/1/2016 to 12/31/2020 and received gilteritinib (GILT) or sorafenib (SORA)as post-transplant maintenance, outside of a clinical trial.
RESULTS: A total of 55 patients were treated with either GILT (n = 27) or SORA (n = 29) for post-HCT maintenance. One patient was treated with SORA after first alloHCT and GILT after second alloHCT. Patient characteristics were comparable between groups. FLT3 inhibitors were utilized in pre-alloHCT therapy in all but 1 patient. The median duration of time that patients remained on GILT was 385 days (range, 10-804) and on SORA 315 days (range, 3-1777). 1-year PFS and relapse incidence were similar between GILT and SORA; PFS was 66% versus 76% (P = .4) and relapse incidence was 19% versus 24% (P = .6), respectively.Both groups had high incidence of Grade 3-4 hematological toxicity, including neutropenia (45% GILT and 34% SORA) and thrombocytopenia (30% GILT and 52% SORA). Only 44% and 14% patients who received GILT and SORA did not discontinue maintenance, respectively.
CONCLUSIONS: Our results revealed comparable PFS and a similar toxicity profile when SORA and GILT are used as post- HCT maintenance therapy.

Verbal working memory (vWM) is an essential limited-capacity cognitive system that spans the fronto-parietal network and utilizes the subprocesses of encoding, maintenance, and retrieval. With the recent widespread use of noninvasive brain stimulation techniques, multiple recent studies have examined whether such stimulation may enhance cognitive abilities such as vWM, but the findings to date remain unclear in terms of both behavior and critical brain regions. In the current study, we applied high-definition direct current stimulation to the left and right parietal cortices of 39 healthy adults in three separate sessions (left anodal, right anodal, and sham). Following stimulation, participants completed a vWM task during high-density magnetoencephalography (MEG). Significant neural responses at the sensor-level were imaged using a beamformer and whole-brain ANOVAs were used to identify the specific neuromodulatory effects of the stimulation conditions on neural responses serving distinct phases of vWM. We found that right stimulation had a faciliatory effect relative to left stimulation and sham on theta oscillations during encoding in the right inferior frontal, while the opposite pattern was observed for left supramarginal regions. Stimulation also had a faciliatory effect on theta in occipital regions and alpha in temporal regions regardless of the laterality of stimulation. In summary, our data suggest that parietal HD-tDCS both facilitates and interferes with neural responses underlying both the encoding and maintenance phases of vWM. Future studies are warranted to determine whether specific tDCS parameters can be tuned to accentuate the facilitation responses and attenuate the interfering aspects.

UNASSIGNED: The incidence of brain metastases in ovarian cancer is quite rare, being approximately 1%-2%. According to retrospective studies, patients with BRCA 1/2 mutations present a higher risk. The trimodal approach based on surgery, radiotherapy, and chemotherapy presents better outcomes, but the prognosis remains poor with overall survival since the brain progression is around 1 year. Poly-ADP-ribose polymerase inhibitors (PARPi) have provided a new alternative for the management of advanced ovarian cancer. The SOLO2, NOVA, and ARIEL3 clinical trials do not refer data on patients with brain metastases, and the published evidence for PARPi in this setting comes only from case reports and retrospective studies.
UNASSIGNED: We present the case of a 54-year-old woman with stage IV ovarian high-grade serous papillary carcinoma who, after 37 months of treatment with olaparib, presented a single brain lesion. After radical treatment with surgery and adjuvant whole-brain radiotherapy, she resumed olaparib with no evidence of disease during 15 months. After a second single brain relapse treated with stereotactic radiosurgery, the patient continued olaparib beyond the brain progression with no evidence of extracranial disease. Despite that there were no changes in size or number of brain lesions, the neurological situation progressively worsened and the patient died 8 months after the second progression.
UNASSIGNED: The higher incidence of brain metastases of ovarian cancer points out a possible tropism for the CNS in BRCA-mutated patients. In preclinical studies, PARPi has shown to cross the blood-brain barrier, with possible antitumor activity in the central nervous system (CNS) while maintaining control of extracranial disease. The best survival data are obtained with a trimodal approach, and adding a PARPi could improve the survival outcomes in the context of platinum-sensitivity disease. Targeted therapies combined with local treatments are also used in other malignancies, suggesting potential effectiveness due to tumor heterogeneity. PARPi before brain metastasis may delay its diagnosis, and using iPARP after brain metastases could improve the outcome of this population.
UNASSIGNED: The role that PARPi may have in the treatment of brain metastases of ovarian cancer requires more studies. In the context of radical treatment of brain metastasis (surgery and/or RT), with no evidence of extracranial disease, maintaining treatment with PARPi beyond the brain progression should be considered.