Prolonged Disease Research Articles

Deficiency in non-classical major histocompatibility class II-like molecule, H2-O confers protection against Staphylococcus aureus in mice.

Staphylococcus aureus is a human-adapted pathogen that replicates by asymptomatically colonizing its host. S. aureus is also the causative agent of purulent skin and soft tissue infections as well as bloodstream infections that result in the metastatic seeding of abscess lesions in all organ tissues. Prolonged colonization, infection, disease relapse, and recurrence point to the versatile capacity of S. aureus to bypass innate and adaptive immune defenses as well as the notion that some hosts fail to generate protective immune responses. Here, we find a genetic trait that provides protection against this pathogen. Mice lacking functional H2-O, the equivalent of human HLA-DO, inoculated with a mouse-adapted strain of S. aureus, efficiently decolonize the pathogen. Further, these decolonized animals resist subsequent bloodstream challenge with methicillin-resistant S. aureus. A genetic approach demonstrates that T-cell dependent B cell responses are required to control S. aureus colonization and infection in H2-O-deficient mice. Reduced bacterial burdens in these animals correlate with increased titers and enhanced phagocytic activity of S. aureus-specific antibodies. H2-O negatively regulates the loading of high affinity peptides on major histocompatibility class II (MHC-II) molecules. Thus, we hypothesize that immune responses against S. aureus are derepressed in mice lacking H2-O because more high affinity peptides are presented by MHC-II. We speculate that loss-of-function HLA-DO alleles may similarly control S. aureus replication in humans.

Remitting seronegative symmetrical synovitis with pitting edema syndrome: case report of an atypical presentation of a rare syndrome and literature review

BackgroundRemitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare syndrome. The following case shows an atypical course of the disease with successful treatment. In addition, the accompanied review highlights current findings in the pathogenesis and treatment. Clinicians should be aware of the differential diagnosis of RS3PE syndrome.Case presentationA 67-year-old female patient with recurrent, asymmetric, and painful swelling of both hands with pitting edema, predominantly affecting the dorsal right hand, presented at our in-patient clinic. Over the years of her disease, first diagnosed as rheumatoid arthritis and then psoriatic arthritis, prednisolone treatment had the most favorable effects over various disease-modifying antirheumatic drugs.Subsequent diagnostic evaluation confirmed RS3PE syndrome, a rare inflammatory disorder primarily affecting the elderly population. Manifesting as symmetrical joint inflammation of small joints with pitting edema, RS3PE syndrome typically onsets suddenly and may be accompanied by systemic symptoms like fever, fatigue, and weight loss. Although the precise etiology remains enigmatic, both the innate and the adaptive immune system seem to play a pathogenic role. Treatment is conventionally based on prednisolone, which effectively mitigates symptoms.Ultimately, RS3PE was diagnosed in the context of psoriatic arthritis without dermatological or nail involvement. Given the unusual presentation marked by female gender, asymmetry, and prolonged and extensive disease with various prior treatments and in the context of psoriatic arthritis, a tumor necrosis factor alpha inhibitor was initiated in addition to low-dose prednisolone resulting in clinical remission for the first time.ConclusionsIn conclusion, the aforementioned atypical manifestation highlights the significance of including RS3PE syndrome as a potential differential diagnosis, particularly in instances where specific diagnostic criteria for rheumatoid arthritis, polymyalgia rheumatica, or psoriatic arthritis are absent. RS3PE responds well to the administration of prednisolone. In refractory cases, a therapeutic trial with tumor necrosis factor alpha inhibitors can be conducted.

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.

3152 Background: Paclitaxel resistance in patients is a clinical challenge that limits the durability of clinical benefit in patients with taxane-responsive advanced solid tumors. One proposed mechanism for this resistance is overexpression of spleen tyrosine kinase (SYK); which can be inhibited with new molecules including TAK-659. In this phase I study, we have investigated the combination of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors; hypothesizing that use of TAK-659 would help to overcome resistance to prior taxane-based therapy. Methods: We included patients with advanced solid tumors who received and progressed on prior taxane-based therapy. Patients received treatment with intravenous paclitaxel on day 1,8, and 15 in addition of daily TAK-659 in 28-day cycles. Six cohorts were treated during dose escalation at different dose levels followed by a dose expansion phase in patients with advanced ovarian cancer. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for evaluation of toxicity and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for assessment of preliminary efficacy. Results: We included 49 patients with advanced solid tumors. The maximum tolerated dose was not reached in this study; and no patients experienced treatment-related deaths. Most adverse events were either grade 1 or 2. Grade 3 or more adverse events were reported in 47% of patients (n=23). The most common grade ≥3 adverse events were decreased neutrophil count (n=7; 14%), elevated lipase (n=6; 12%), anemia (n=5; 10%), increased amylase (n=4; 8%), and decreased white blood cell counts (n=4; 8%). In 44 patients with taxane-refractory tumors who were evaluable for efficacy, 9% (n=4) had RECIST partial response and 27% (n=12) had RECIST stable disease, including 3 patients with prolonged stable disease for at least 6 months. Conclusions: The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors. Clinical trial information: NCT03756818 .

Association of parental obesity with the profile of metabolic-bariatric surgery patients: a cohort study of the German StuDoQ|MBE registry

ObjectivesTo investigate the association of parental obesity (PO) with onset of obesity, pre-surgical disease duration and body mass index (BMI) at the time of surgery in patients undergoing metabolic-bariatric surgery...

Preliminary experience of ex-vivo expanded allogeneic universal donor TGFβi NK cell infusions in combination with irinotecan, temozolomide, and dinutuximab in patients with relapsed or refractory neuroblastoma: The Allo - STING trial.

10005 Background: Neuroblastoma (NBL) is the most common extra-cranial solid tumor in children and outcomes for children with relapsed/refractory (RR) NBL remain dismal. While the combination of chemoimmunotherapy (CIT) with the anti-GD2 antibody dinutuximab as per COG protocol ANBL1221 has improved responses, this regimen is still not curative. Dinutuximab can recruit NK cells for anticancer activity, however, NK cells are depleted in NBL patients undergoing chemotherapy. We devised a method to expand allogeneic NK cells ex vivo to improve effector function and render the NK cells resistant to TGFβ-induced suppression (TGFβi). These TGFβi NK cells are expanded from a universal donor (UD) pool, enabling multiple cycles of “off-the-shelf” high-dose therapy. We hypothesize that adoptive transfer of UD-TGFβi NK cells to patients with RR NBL sequentially following CIT is safe and improves outcomes compared to CIT alone. Methods: This Phase I/II study evaluates the safety and tolerability of UD-TGFβi NK cells in combination with CIT and compares anti-cancer efficacy to CIT alone. Eligibility includes age < 30 years, RR or progressive NBL, and prior treatment with at least 4 cycles of induction chemotherapy. The treatment protocol consists of 21-day cycles of CIT as per COG protocol ANBL1221 with UD-TGFβi NK cells (1x108 cells/kg) infused on day 8. Up to six cycles of treatment are permitted. Overall response rates are defined using the Revised International NBL Response Criteria, with 95% confidence intervals compared to the results from ANBL1221. Progression-free and overall survival will be estimated by the Kaplan Meier method. Results: Four subjects (7 – 11 years) have been enrolled. All patients presented with high risk NBL: three with relapsed disease and one with refractory disease. All received at least one prior salvage therapy. Three patients have completed all 6 cycles of protocol therapy, and one remains on treatment. 20 NK cell infusions have been administered to date. All NK cell infusions occurred within the protocol specified window. One subject experienced grade 1 fever with two NK cell infusions. There have been no other adverse events attributable to the NK cells. Adverse events attributable to CIT were similar to those described in COG ANBL 1221. Treatment delays for cytopenias due to CIT occurred in two patients. Three patients achieved a partial response. A fourth patient attained prolonged stable disease (9 months) but experienced a skeletal recurrence. Conclusions: UD allo-TGFβi NK cells can be safely and feasibly administered to children with RR NBL after treatment with CIT, with early objective responses observed in the preliminary cohort of patients. Ongoing studies will assess markers of response, NK cell persistence, pharmacokinetics and pharmacodynamics. Clinical trial information: NCT04211675 .

A phase I clinical trial investigating the safety, tolerability, and pharmacokinetics of HX301 (narazaciclib), a novel multi-kinase inhibitor targeting CSF1R, CDK 4/6, and ARK5, in patients with advanced solid tumors.

e15106 Background: HX301 (narazaciclib) is a promising novel multi-kinase inhibitor with potent activity against Colony Stimulating Factor 1 Receptor (CSF1R), Cyclin-Dependent Kinase 4/6 (CDK4/6), and Aurora Kinase 5 (ARK5), with a half-maximal inhibitory concentration (IC50) values in 0.29-4.95 nM range. It is an oral bioavailable agent and has the ability to cross blood-brain barrier. Preclinical data have showed significant antitumor activities, warranting further clinical trials to evaluate the safety, and potential efficacy in human subjects. Methods: Utilizing the standard 3+3 design, the study aimed to evaluate the safety, tolerability and pharmacokinetics of ascending doses of HX301. Patients with heavily pretreated advanced solid tumors received HX301single agent via oral administration, with doses ranging from 40mg to 200mg once daily for the first 21 days of each 28-day cycle. Results: As of December 27, 2023, a total of 20 patients (5 males, 15 females) were enrolled in the study, with varying doses of HX301 administered: 40 mg (n=3), 80 mg (n=3), 120 mg (n=4), 160 mg (n=3), and 200 mg (n=7). The median age of the patients was 55 years, ranging from 30 to 71. Notably, 15 patients (75%) had metastatic breast cancers. Dose-limiting toxicities (DLTs) were observed in 2 patients in the 200 mg group. These included a Grade 4 increase in alanine aminotransferase (ALT) and a Grade 3 decrease in platelet counts with associated epistaxis, both of which resolved after discontinuation of treatment. The most common treatment-related adverse events (AEs) observed were elevated aspartate aminotransferase (AST) (65.0%), decreased white blood cell count (50%), decreased neutrophil count (50%), elevated ALT (45%), elevated creatine kinase (45%), and elevated creatinine (35%). Additionally, 4 patients experienced Grade 3 or higher treatment-related AEs, including 1 patient in the 160 mg group with Grade 3 elevated γ-glutamyl transferase and alkaline phosphatase, and 3 patients in the 200 mg group with Grade 4 elevated ALT and Grade 3 elevated AST and Dyspepsia, Grade 3 decreased neutrophil and platelet counts, and Grade 3 hyperglycemia. Notably, no AEs led to death. Among the 20 patients evaluable for tumor assessment using RECIST 1.1 by Investigators, 4 obtained stable disease, including 2 patients in the 200 mg group, 1 in the 120 mg group, and 1 in the 80 mg group. Furthermore, 1 patient with HR+ breast cancer in the 200 mg group received study drug for over a year and achieved prolonged stable disease for more than 12 months, highlighting a notable clinical outcome. Conclusions: HX301 at dose levels ranging from 40mg to 160mg was tolerable with a manageable toxicity profile. Further clinical studies are needed to explore the drug's anti-tumor activity, particularly in combination settings. Clinical trial information: NCT05731934 .

A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors

Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors. Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n= 31; 63%), increased alanine aminotransferase (n= 26; 53%), decreased neutrophil count (n= 26; 53%), and decreased white blood cell count (n= 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4patients (9%) achieved a partial response. The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.

Dendrimer-enhanced (DEP) SN38 (DEP irinotecan) in patients (pts) with advanced solid tumors: A phase 1/2 trial.

3014 Background: Dendrimer nanoparticles enable prolonged cytotoxic drug targeting to tumors. DEP SN38 is a water-soluble version of SN38, the active metabolite of irinotecan, attached to a dendrimer, so avoiding usual metabolic pathways of conventional irinotecan (c-IRI). This phase 1/2 (P1/2) trial evaluated safety, tolerability and efficacy of DEP SN38 in pts with advanced solid tumors, including colorectal (CRC), platinum-resistant high-grade serous ovarian (HGSOC) and breast (BC). Methods: Pts who had exhausted standard therapy were enrolled in dose assessment (P1)/dose expansion (P2) cohorts of DEP SN38 given IV 3-weekly (Q3W) or Q2W alone or in combination with 5-fluorouracil & leucovorin (5FU/LV combo). Efficacy was evaluated by RECIST 1.1 and serum tumor markers. (EudraCT 2019-001318-40). Results: 114 pts were enrolled. The Q3W Recommended Dose (RD) was 12.5 mg/m2 SN38 with dose limiting toxicity (DLT) in 1/7 pts (grade (G) 4 neutropenia > 7d). The Q2W RD was 12.5 mg/m2 for SN38 alone or with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens with mostly mild/moderate (G1/2) treatment-related adverse events (TRAEs) & no new events compared with c-IRI. TRAEs in ≥ 10% pts included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, diarrhea, constipation and alopecia. Of734 DEP SN38 cycles only 1 event of G3 diarrhea (0.9% pts) and no cholinergic symptoms have been observed, contrasting with c-IRI (~20% & 47% pts respectively). G3 nausea (1.8% pts) and vomiting (0.9% pts) occurred less frequently than with c-IRI (both ~10% pts). Febrile neutropenia was the DLT at 15 mg/m2 Q2W monotherapy (2/6 pts), with neutropenia otherwise essentially uneventful and managed with G-CSF. 38 CRC pts received DEP SN38 monotherapy (31 evaluable) and 17 received the 5FU/LV combo (14 evaluable). CRC pts had a mean 4 prior lines with 97% receiving ≥ 1 c-IRI containing line. The disease control rate (DCR) in monotherapy was 48% (stable disease (SD) up to 72 wks). The 5FU/LV combo cohort DCR was 85.7%, the objective response rate (ORR) was 14.3%, with disease control observed for at least 35 wks. Several CRC pts continue combo treatment. 23 HGSOC pts with a mean of 6 prior lines received DEP SN38 monotherapy (18 evaluable). The DCR for Q2W was 100% with 33.3% ORR, and 72% DCR for all HGSOC pts. 3 pts have PRs for at least 36 wks; with 1 pt achieving complete tumor & ascites resolution. Reduced CA-125 of up to 98% was observed in 75% pts. Several HGSOC pts continue DEP SN38 treatment. 8 BC pts with a mean of 7 prior lines received DEP SN38 monotherapy Q3W (5 evaluable). The DCR was 100% with SD up to 72 wks. Conclusions: DEP SN38 shows promising clinical utility with encouraging antitumor activity including prolonged disease control & durable PRs in heavily pre-treated CRC, HGSOC & BC pts. DEP SN38 is well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to c-IRI, & warrants further clinical assessment. Clinical trial information: 2019-001318-40 .

Prognostic factors for patients with sarcoma with brain metastases.

e23542 Background: Sarcomas arise in mesenchymal tissue occurring anywhere in the body with a propensity to metastasize often to the lung, liver, and bones. The brain is a rare site of metastasis with increasing incidences found in those relapsing after prolonged disease control with treatment. Brain metastases development has been associated with dismal prognoses, and more data is necessary to assess factors for improved outcomes of patients. Methods: The retrospective cohort includes 81 patients diagnosed with sarcomas metastasizing to the brain treated at five sarcoma centers between 1/1998 and 12/2021. Demographic data, characteristics and presentation of brain metastases, and treatment modalities for malignancy were identified and analyzed. Results: In total, there were 45 men and 36 women with the mean age of diagnosis being 43 years. Upon presentation, 89% of patients were symptomatic with the most common presenting symptom being focal neurological deficits (37.9%) and headaches (22.1%). At the time of analysis, 58 patients (71.6%) had died of metastatic sarcoma, 16 patients (19.8%) were alive with disease, and 3 patients (3.7%) were alive without evidence of disease. The most frequent histologies were leiomyosarcoma (12.3%) and undifferentiated pleomorphic sarcoma (12.3%). In 70.4% of patients, the tumor also had metastasized to the lung. Median time from sarcoma diagnosis to brain metastases was 1.9 years (range: 0-34.6 yrs). Median time from diagnosis of brain metastases until death was 6 months (range: 0.5-330 mo). Treatment modalities of brain metastasis varied widely with 18 patients (22.2%) undergoing whole brain radiation therapy (WBRT), 11 (13.6%) undergoing systemic chemotherapy and WBRT, and 10 (12.3%) undergoing combined surgery, systemic chemotherapy, and stereotactic radiosurgery. In multivariate analysis, the variables identified as statistically significant for predicting improved survival outcomes included surgery (HR 0.30) and chemotherapy (HR 0.24), but not radiation therapy. In patients undergoing surgery or chemotherapy, the median survival time after brain metastasis diagnosis was markedly improved, with 13.9 months and 12 months respectively versus the overall patient median of 6 months. In patients undergoing radiation therapy, there was significantly improved survival with stereotactic radiosurgery (SRS, mOS 11.6mo) as opposed to whole brain radiation therapy (WBRT, mOS 8.3mo) probably due to decreased mean number of brain metastases found in those necessitating SRS (3.2) compared to WBRT (5.7). Conclusions: Together, our findings identify that patients with metastatic sarcoma to the brain have poor prognoses, often have concurrent metastasis, and have median survival of only 6 months. However, there were significantly improved outcomes with interventions such as surgery, chemotherapy, or SRS, suggesting that aggressive treatments are warranted despite the overall poor prognosis.

Phase I trial of chidamide, an oral HDAC inhibitor, in combination with oral etoposide in patients with refractory/recurrent neuroblastoma.

10034 Background: Chidamide, an oral subtype-selective histone deacetylase (HDAC) inhibitor, has been shown to be effective in adult patients with hematological tumors. However, there is no data on its safety and efficacy in pediatric cancer patients. Combination of HDAC inhibitors and etoposide have shown synergistic anti-tumor effects in preclinical studies of neuroblastoma. We conducted a phase I trial in pediatric patients with recurrent or refractory neuroblastoma to determine the maximum tolerable dose (MTD) of chidamide combined with oral etoposide treatment. Methods: Daily oral etoposide 35 mg/m2/dose was administered on days 1–21 in combination with escalating doses of chidamide (14 and 17 mg/m2/d) twice weekly in each 28-day cycle using the standard 3 + 3 design. Patients with response or stable disease after two cycles would maintain treatment until disease progression or unacceptable toxicity occurred. Chidamide pharmacokinetic testing was performed. Results: 31 patients were enrolled in this study. The median age was 7 years (range 3 – 18). 14 patients were included in the dose escalation phase (Ia), 17 patients in the expansion cohort (Ib). The MTD of chidamide was 14 mg/m2/d, with dose limiting neutropenia and thrombocytopenia observed at 17 mg/m2/d. Median number of cycles completed was 2.5 (range 1–11). A total of 19 patients (61.3%) experienced treatment-related grade 3/4 hematologic toxicity, and no grade 3/4 non-hematological toxicity was observed. No objective responses were seen. Conclusions: In children with refractory/recurrent neuroblastoma, chidamide is well-tolerated at 14 mg/m2/d twice weekly when combining with oral etoposide 35 mg/m2/d daily. Prolonged disease stability achieved in patients with minimal residual diseases deserves further investigation. Clinical trial information: NCT05338541 .

Results of a retrospective study on the efficacy and safety of alpelisib in patients with HR+/HER2- metastatic breast cancer in real-world clinical practice.

e13058 Background: The combination of alpelisib and fulvestrant is an optimal therapy option for patients with hormone receptor-positive (HR+), HER2-negative (HER2–) metastatic breast cancer with PIK3CA gene mutations. The aim of this work to retrospectively analyze the efficacy and safety of alpelisib in real-world clinical practice in patients with pre-treated luminal HER2– negative metastatic breast cancer. Methods: The study included an analysis of 33 patients with widespread luminal HER2- negative breast cancer with detected PIK3CA gene mutation. The median age was 57 ± 13 months (95% CI 52-62). In 12 (36.4%) patients, the PIK3CA gene mutation was detected in exon 9, and in 21 (63.6%) – in exon 20. Alpelisib was prescribed to pre-treated patients in different lines. Most women (32/33; 97%) had received ET combined regimens with CDK4/6 inhibitors before starting alpelisib therapy: 14 (42.4%) patients underwent palbociclib therapy in combination with fulvestrant; 4 (12.1%) – palbociclib with aromatase inhibitors; 13 (39.5%) – ribociclib in combination with fulvestrant; 1 (3.0%) – ribociclib with aromatase inhibitors. It is important to note that 63.6% of patients had previous progression on fulvestrant monotherapy and 72.7% on aromatase inhibitor therapy. Patients with luminal B-subtype of breast cancer dominated - 72.7% (24/33). Results: The median overall survival (OS) in this study was 14 ± 2.5 months (95% CI: 9-18.9), and the median progression-free survival (PFS) was 6 ± 2.7 months (95% CI: 0.7-11.3). The rate of objective response was 30.3%, and prolonged disease stabilization was observed in 24.2% of cases. Prognostic factors were brain metastases (increasing the risk of death by 18 times) and discontinuation of the drug for any reason (increasing the risk of death by 8 times). It should be noted that the main reason for discontinuation or disruption of the drug's timing was unmanageable toxicity. All patients registered adverse events of varying degrees, with 21 (63.6%) patients experiencing hyperglycemia (grade 3-4 – 30.3%) and 14 (42.4%) patients experiencing skin toxicity (grade 3-4 – 15.2%). In the SOLAR-1 study, the frequency of hyperglycemia was comparable (64.8%), and rash was noted in a third of all patients, which is comparable to our data. Conclusions: The results of using alpelisib with fulvestrant confirm its effectiveness in real-world clinical practice in patients with pre-treated HR+HER2- negative widespread breast cancer with the presence of somatic PIK3CA gene mutation. Brain involvement is an unfavorable prognostic factor in patients with PIK3CA mutation and increases the risk of death by 18 times, requiring the need to optimize the therapeutic algorithm, including through radiation methods. Discontinuation of the drug, which increases the risk of death by 8 times.

The toxicity swimmer plot: A novel approach for evaluating patient-level toxicity following immune checkpoint inhibitor (ICI) therapy on the Checkmate 214 trial.

11014 Background: Treatment with ICIs creates the possibility of prolonged disease control or remission but also creates the possibility of prolonged toxicity even after treatment is discontinued. Treatment-free survival (TFS) with and without toxicity has previously been described as an integral piece of a partitioned survival analysis in advanced renal cell carcinoma (aRCC). Prior analyses have reported further partition of TFS as mean duration of TFS with and without treatment-related adverse events (TRAEs), but this metric fails to provide more granular information regarding individual patients experiencing toxicity during TFS. We present a novel extended swimmer plot that characterizes patient-level toxicity data within TFS using the example of the Checkmate 214 trial to complement analyses of the population average experience. Methods: Data were analyzed from the Checkmate 214 trial which randomized 1096 patients with aRCC to receive either first-line (1L) nivolumab plus ipilimumab (n = 550) or sunitinib (n = 546). The minimum follow-up from protocol therapy initiation was 42 months. Patients’ overall survival was partitioned into 3 survival states: time on 1L protocol therapy, TFS, and survival after subsequent therapy initiation. With a re-defined time origin relative to cessation of 1L protocol therapy, we generated swimmer plots highlighting the TFS period and documenting each patient’s experience with and without grade 2+ and grade 3+ TRAEs during TFS. The swimmer plot was sorted by duration of TFS and duration of TFS with grade 2+ TRAEs in order to illustrate patterns of individuals’ experiences. Results: The 42-month mean TFS was 7.8 months (with grade 2+ TRAEs: 3.2 months) for patients treated with nivolumab plus ipilimumab and 3.3 months (1.6 months) for patients treated with sunitinib. In the respective treatment groups, TFS with grade 2+ TRAEs was experienced by 32% and 25% of patients and comprised of 13% and 9% of patients for whom it was the entire TFS period. These percentages were consistent regardless of TFS duration. TFS with grade 3+ TRAEs was experienced by 15% and 3% of patients, respectively. For most patients having TFS with TRAEs, the TRAEs persisted from the protocol therapy period, but 7% and 1% of patients in the respective treatment groups had new-onset grade 3+ TRAE during TFS. A swimmer plot will be presented as a visual presentation of this study’s results. Conclusions: We describe a novel extension of swimmer plots for presenting patient-level information and illustrating patterns in toxicity duration relative to TFS by incorporating individual toxicity data into a swimmer plot of partitioned survival. This approach allows for a more comprehensive understanding of toxicity trends and risk of prolonged toxicity after treatment is discontinued.

Partitioned overall survival: Comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma (aRCC).

4507 Background: Immunotherapy regimens can be associated with prolonged disease control after treatment discontinuation without the need for further anticancer therapy. An integrated, comprehensive partitioned survival analysis describes how patients spend overall survival (OS) time, on/off treatment, with/without toxicity. Previous analysis of first-line (1L) nivolumab (NIVO) + ipilimumab (IPI) for aRCC in CheckMate 214 showed treatment-free survival (TFS) twice as long vs sunitinib (SUN). TFS and survival states for immune checkpoint inhibitor plus tyrosine kinase inhibitor (TKI) combination are of interest. Methods: Overall, 651 patients (pts) with aRCC were randomized to receive 1L NIVO + cabozantinib (CABO) or SUN in the CheckMate 9ER trial; treatment continued until progression or intolerance, NIVO for at most 24 months. Minimum follow-up was 4 years. We partitioned area under the Kaplan–Meier (KM) OS curve into 3 survival states, defined from randomization: time on 1L protocol therapy, TFS, and survival after subsequent systemic therapy (second line [2L]) initiation. TFS and protocol therapy were subdivided as mean times with/without reported grade 2+ treatment-related adverse events (TRAEs). Areas under and between KM curves were estimated by 48-month restricted mean times to event. Bootstrapped 95% CIs for between-group differences are reported. Results: At 4 years post randomization, KM estimates of OS were 49.2% vs 40.2% of pts assigned to NIVO+CABO vs SUN, respectively; 17.6% vs 4.7% of pts were surviving treatment-free, and 15.8% vs 8.2% were continuing on 1L protocol therapy. Over the 48-month period since randomization (Table), the mean TFS (95% CI) was 2.4 (0.8–3.9) months longer after treatment with NIVO+CABO than SUN. At least half of TFS was spent with toxicity in both treatment groups, resulting in difference in mean TFS (95% CI) without toxicity of 0.7 (−0.4 to 1.8) month. The NIVO+CABO group spent a mean (95% CI) of 8.5 (6.2–10.8) months more survival time on 1L protocol therapy, whereas the SUN group spent a mean (95% CI) of 6.5 (4.4–8.6) months more survival time after 2L therapy initiation. Conclusions: Over the 4-year period since initiation of 1L therapy for aRCC, the longer OS achieved with NIVO+CABO was accompanied by 1.5 times longer mean time surviving treatment-free before 2L therapy compared with SUN, a smaller difference than seen for NIVO + IPI vs SUN. [Table: see text]

Assessing mortality risk in Type 2 Diabetes patients with prolonged ASCVD risk factors: the inclusive Poh-Ai predictive scoring system with CAC Score integration

PurposeTo enhance the predictive risk model for all-cause mortality in individuals with Type 2 Diabetes (T2DM) and prolonged Atherosclerotic Cardiovascular Disease (ASCVD) risk factors. Despite the utility of the Coronary Artery Calcium (CAC) score in assessing cardiovascular risk, its capacity to predict all-cause mortality remains limited.MethodsA retrospective cohort study included 1929 asymptomatic T2DM patients with ASCVD risk factors, aged 40–80. Variables encompassed demographic attributes, clinical parameters, CAC scores, comorbidities, and medication usage. Factors predicting all-cause mortality were selected to create a predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups.ResultsIn our analysis of all-cause mortality in T2DM patients with extended ASCVD risk factors over 5 years, we identified significant risk factors, their adjusted hazard ratios (aHR), and scores: e.g., CAC score > 1000 (aHR: 1.57, score: 2), CAC score 401–1000 (aHR: 2.05, score: 2), and more. These factors strongly predict all-cause mortality, with varying risk groups (e.g., very low-risk: 2.0%, very high-risk: 24.0%). Significant differences in 5-year overall survival rates were observed among these groups (log-rank test < 0.001).ConclusionThe Poh-Ai Predictive Scoring System excels in forecasting mortality and cardiovascular events in individuals with Type 2 Diabetes Mellitus and extended ASCVD risk factors.

Clinical and immunophenotype correlating with response to immunotherapy in paediatric patients with primary liver carcinoma. A case series

Paediatric hepatocellular carcinomas (HCC) traditionally arise in the context of a normal structural and functional liver and carry a dismal prognosis. While chemotherapy is the frontline standard, there is emerging interest in the study of immunotherapies for paediatric patients with relapsed/refractory disease. There is limited data to support whether immunotherapies will be of utility in this patient population. Six paediatric patients (median age:16 years, range: 12-17at the time of treatment) with advanced hepatocellular neosplams, either conventional hepatocellular or fibrolamellar carcinoma, were treated with immunotherapy. Patients were consented to institutional genomic profiling and biobanking protocols. Baseline samples and serial tissue samples, when available, were evaluated for somatic mutation rate, actionable gene mutations, and pan-immune bulk RNA expression profiling. Results were correlated with clinical course. Three patients responded to checkpoint inhibition: one achieved a complete, durable response and the other two, prolonged stable disease. Three additional patients progressed. Diagnostic tissue from the complete responder demonstrated a higher relative mutational burden and robust immune infiltrate. Pre-treatment samples from the three responders demonstrated decreased expression of genes associated with T-cell dysfunction. A subset of patients with primary paediatric hepatocellular tumours will respond to immunotherapy. Immunotherapies are currently under prospective study for relapsed/refractory liver tumours in paediatric patients. Results from this report support the prospective collection of serial serum and tissue samples which may further identify genomic and immunophenotypic patterns predictive of response. This work was supported by Philanthropic funds (Pan Mass Challenge, Team Angus and Team Perspective).

Narirutin mitigates dextrose sodium sulfate-induced colitis in mice by modulating intestinal flora

BackgroundUlcerative colitis (UC) is a prolonged inflammatory disease of the gastrointestinal tract. Current therapeutic options remain limited, underscoring the imperative to explore novel therapeutic strategies. Narirutin (NR), a flavonoid naturally present in citrus fruits, exhibits excellent anti-inflammatory effects in vitro, yet its in vivo efficacy, especially in UC, remains underexplored. ObjectiveThis work examined the effect of NR on dextrose sodium sulfate (DSS)-induced UC in mice in vivo, with a specific focus on the role of gut flora in it. MethodsThe effects of NR (10, 20, and 40 mg/kg) on DSS-induced UC in mice were investigated by monitoring changes in body weight, disease activity index (DAI) scores, colon length, and histological damage. Colonic levels of pro-inflammatory mediators, tight junction (TJ) proteins, and inflammation-related signaling pathway proteins were analyzed via enzyme-linked immunosorbent assay, western blot, and immunofluorescence. The role of gut microbiota in NR against colitis was analyzed through 16S rRNA sequencing, flora clearance assays, and fecal microbiota transplantation (FMT) assays. ResultsNR administration suppressed DSS-induced colitis as reflected in a decrease in body weight loss, DAI score, colon length shortening, and histological score. Furthermore, NR administration preserved the integrity of the DSS-induced intestinal barrier by inhibiting the reduction of TJ proteins (claudin3, occludin, and zonula occludens-1). Moreover, NR administration markedly repressed the activation of the toll-like receptor 4-mitogen-activated protein kinase/nuclear factor-κB pathway and reduced the amount of pro-inflammatory mediators in the colon. Importantly, the results of 16S rRNA sequencing showed that the intestinal flora of mice with colitis exhibited richer microbial diversity following NR administration, with elevated abundance of Lactobacillaceae (Lactobacillus) and decreased abundance of Bacteroidaceae (Bacteroides) and Shigella. In addition, the anti-colitis effect of NR almost disappeared after gut flora clearance. Further FMT assay also validated this gut flora-dependent protective mechanism of NR. ConclusionOur findings suggest that NR is a prospective natural compound for the management of UC by modulating intestinal flora.

Chronic Kidney Disease Study in Diabetic Patients: Insights From Primary Care Units in Northern Portugal.

Introduction Diabetes mellitus (DM) remains a primary cause of morbidity and mortality, leading to complications such as blindness, kidney failure, and lower limb amputations. Early detection of kidney damage, indicated by microalbuminuria (MA), is crucial for managing DM. Given the impact of these conditions, evaluating the prevalence of chronic kidney disease (CKD) in diabetic populations within primary healthcare is essential. Methodology This was a cross-sectional and observational study. Adults diagnosed with DM type 1 or 2, from five primary care units (PCUs) located in the North of Portugal, were included in this study.Descriptive and correlational statistics were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, NY).Statistical significance was set to P< 0,05. Logistic regression models were created to identify the factors associated with CKD and DM. Results A sample of 357 diabetic patients was obtained, with 166 (46.5%) females. Of the sample, 250 (70.1%) were aged 65 or older, and the median known duration of DM was 9.36 years. Excess weight or obesity accounted for 79.8%, with a median body mass index of 28.73 kg/m2and hypertension in 284 (79.6%). An estimated glomerular filtration rate (eGFR) less than 60 mL/min was present in 89 (24.9%) and an MA of 30 mg/dL or higher was present in 68 (19.0%). In total, 130 (36.4%) individuals exhibited eGFR and MA consistent with CKD. Among these, 25 (78.1%) had other identifiable causes of CKD besides DM, hypertension, overweight, or obesity. Binary logistic regression models were constructed to find a relationship between CKDwith eGFR < 60 mL/min and MA. A statistically significant association was found between CKD with eGFR < 60 mL/minute and age (odds ratio [OR] = 1.150; P< 0.001), kidney stones (OR = 5.112; P= 0.003), absence of excess weight or obesity (OR = 0.267; P< 0.001). The use of GLP1 agonists showed statistical significance as a predictor (OR = 4.653; P= 0.042) of the presence of MA. Discussion The study investigates the impact of DM and its complications in the surveyed population. While most patients had controlled DM (284, 76.2%), prolonged disease duration correlated with poorer glycemic control, underscoring the need for more effective management strategies in advanced disease stages. Notably, a third of individuals with DM had CKD, with significant implications for therapeutic interventions and heightened risks of renal failure and cardiovascular morbidity. MA was a crucial marker for endothelial injury, with prevalence influenced by DM duration and medication type. However, in many cases, correct identification of CKD was lacking, suggesting under-recognition of renal deterioration in DM. While the study offers valuable insights, its limited sample size and geographic scope warrant cautious interpretation, emphasizing the need for broader, context-specific research to inform comprehensive healthcare strategies. Conclusions In conclusion, this study highlights the significant burden of CKD among diabetic patients, emphasizing the need for proactive screening, personalized management, and accurate diagnosis. Despite limitations, it underscores the importance of early detection and tailored interventions, advocating for improved diabetes care to mitigate renal complications on a broader scale.

Defining the Subtypes of Long COVID and Risk Factors for Prolonged Disease: Population-Based Case-Crossover Study.

There have been over 772 million confirmed cases of COVID-19 worldwide. A significant portion of these infections will lead to long COVID (post-COVID-19 condition) and its attendant morbidities and costs. Numerous life-altering complications have already been associated with the development of long COVID, including chronic fatigue, brain fog, and dangerous heart rhythms. We aim to derive an actionable long COVID case definition consisting of significantly increased signs, symptoms, and diagnoses to support pandemic-related clinical, public health, research, and policy initiatives. This research employs a case-crossover population-based study using International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) data generated at Veterans Affairs medical centers nationwide between January 1, 2020, and August 18, 2022. In total, 367,148 individuals with ICD-10-CM data both before and after a positive COVID-19 test were selected for analysis. We compared ICD-10-CM codes assigned 1 to 7 months following each patient's positive test with those assigned up to 6 months prior. Further, 350,315 patients had novel codes assigned during this window of time. We defined signs, symptoms, and diagnoses as being associated with long COVID if they had a novel case frequency of ≥1:1000, and they significantly increased in our entire cohort after a positive test. We present odds ratios with CIs for long COVID signs, symptoms, and diagnoses, organized by ICD-10-CM functional groups and medical specialty. We used our definition to assess long COVID risk based on a patient's demographics, Elixhauser score, vaccination status, and COVID-19 disease severity. We developed a long COVID definition consisting of 323 ICD-10-CM diagnosis codes grouped into 143 ICD-10-CM functional groups that were significantly increased in our 367,148 patient post-COVID-19 population. We defined 17 medical-specialty long COVID subtypes such as cardiology long COVID. Patients who were COVID-19-positive developed signs, symptoms, or diagnoses included in our long COVID definition at a proportion of at least 59.7% (268,320/449,450, based on a denominator of all patients who were COVID-19-positive). The long COVID cohort was 8 years older with more comorbidities (2-year Elixhauser score 7.97 in the patients with long COVID vs 4.21 in the patients with non-long COVID). Patients who had a more severe bout of COVID-19, as judged by their minimum oxygen saturation level, were also more likely to develop long COVID. An actionable, data-driven definition of long COVID can help clinicians screen for and diagnose long COVID, allowing identified patients to be admitted into appropriate monitoring and treatment programs. This long COVID definition can also support public health, research, and policy initiatives. Patients with COVID-19 who are older or have low oxygen saturation levels during their bout of COVID-19, or those who have multiple comorbidities should be preferentially watched for the development of long COVID.

Modelling African swine fever introduction in diverse Australian feral pig populations

African swine fever (ASF) is a viral disease that affects domestic and feral pigs. While not currently present in Australia, ASF outbreaks have been reported nearby in Indonesia, Timor-Leste, and Papua New Guinea. Feral pigs are found in all Australian states and territories and are distributed in a variety of habitats. To investigate the impacts of an ASF introduction event in Australia, we used a stochastic network-based metapopulation feral pig model to simulate ASF outbreaks in different regions of Australia. Outbreak intensity and persistence in feral pig populations was governed by local pig recruitment rates, population size, carcass decay period, and, if applicable, metapopulation topology. In Northern Australia, the carcass decay period was too short for prolonged persistence, while endemic transmission could possibly occur in cooler southern areas. Populations in Macquarie Marshes in New South Wales and in Namadgi National Park in the Australian Capital Territory had the highest rates of persistence. The regions had different modes of transmission that led to long-term persistence. Endemic Macquarie Marshes simulations were characterised by rapid transmission caused by high population density that required a fragmented metapopulation to act as a bottleneck to slow transmission. Endemic simulations in Namadgi, with low density and relatively slow transmission, relied on large, well-connected populations coupled with long carcass decay times. Despite the potential for endemic transmission, both settings required potentially unlikely population sizes and dynamics for prolonged disease survival.

Korean Hospital Nurses’ Experiences with COVID-19: A Meta-Synthesis of Qualitative Findings

During the COVID-19 pandemic, hospital nurses in South Korea cared for patients amid their own anxiety and fear of infection, armed with a sense of professional duty and overcoming all odds to end the country’s infectious disease pandemic. This study aims to provide a meta-synthesis of qualitative studies examining the perceptions and experiences of nurses who cared for patients in dedicated COVID-19 hospitals in South Korea. Electronic databases, including RISS, KISS, KMbase, NDSL, KoreaMed, DBpia, PubMed, CINAHL, and Cochrane, were searched for research published until 2023. The study included research using qualitative approaches. These were reviewed and analyzed using a thematic synthesis approach. The quality of the studies was ascertained using the Critical Appraisal Skills Program checklist for qualitative research. Ultimately, 13 studies involving 219 nurses were included in the final review. Six major themes and thirteen subthemes emerged. The six topics are: “The crisis of a pandemic that suddenly appeared”, “Challenges in nursing patients with infectious diseases”, “A struggle in an unknown time due to a prolonged infectious disease”, “Ethical dilemmas in the face of infectious diseases”, “Duality of the social support system”, and “Professional growth for nurses regarding infectious diseases”. During the unexpected COVID-19 pandemic, nurses were able to overcome difficult situations through their interactions with patients, sense of professional mission, and commitment to nursing. Most importantly, they persevered through their collaboration and closeness with fellow nurses, despite confusion about their professional identity, the ethical dilemmas they faced in patient care, and dual attitudes regarding their social support system. To prepare for future infectious disease outbreaks, a multifaceted support system should be established to enable nurses to have positive interactions with their families, colleagues, and patients, which are central to their resilience.