High Risk Of Relapse Research Articles

Identification of patients at high risk for relapse using the Merlin Assay (CP-GEP) in an independent cohort of 451 patients (pts) with stage I/II melanoma who did not undergo sentinel lymph node biopsy.

9574 Background: Sentinel lymph node biopsy (SLNB) is the gold standard for nodal assessment in staging cutaneous melanoma (CM) according to AJCC v8 guideline. 80-85% of pts are negative for nodal metastasis, but most pts who relapse or die from melanoma are initially diagnosed as ‘low risk’ early-stage. Previously we showed that the clinicopathological-gene expression profiling (CP-GEP) model is able to stratify SLNB negative pts for their risk of recurrence (1). Later we showed in a small cohort (n=80) that CP-GEP also has the potential to stratify pts who did not undergo SLNB in low and high-risk of recurrence (2). Here we investigate CP-GEP ability to stratify pts who did not undergo SLNB for their risk of recurrence in an expanded cohort. Methods: We analysedformalin-fixed paraffin-embedded primary tumor samples of 451 pts with stage I/II CM diagnosed between 2000-2017, included in the Central Malignant Melanoma Registry, who did not receive SLNB. Study hypothesis and protocol were prospectively formulated. Tumors were analyzed blinded to clinical outcome. The CP-GEP model used combines the expression of 8 genes ( SERPINE2, GDF15, ITGB3, CXCL8, LOXL4, TGFBR1, PLAT and MLANA) by quantitative reverse transcription polymerase chain reaction with age and Breslow thickness to obtain a binary output: CP-GEP Low- or High-Risk. Relapse-free survival (RFS), distant metastasis free survival (DMFS) and Melanoma Specific Survival (MSS) were evaluated using Kaplan-Meier curves. Results: We included 451 pts (stage IA-IIC). 40% were females, median age was 63-year-old, median Breslow thickness was 0.5 mm, and the majority were not ulcerated (96%). An interim analysis was performed on samples from 159 pts and showed the following survival: 5-year RFS 85.8%; DMFS 94.1; MSS 95.7%. The median follow-up time of 57 months (RFS). CP-GEP identified 149 pts as Low-Risk and 10 pts as High-Risk. The 5-year RFS rate was 90.5% and 0% (HR 23.85; p < 0.001), 5-year DMFS was 97.2% and 27% (HR 43.14; p < 0.001), respectively for CP-GEP Low-Risk and High-Risk pts. The 5-year MSS was 99.1% for Low-Risk pts and 25.7% for High-Risk patients (HR 112.96; p < 0.001), capturing 4 out of 5 melanoma specific deaths in the CP-GEP High-Risk group. The final survival analysis of the whole cohort will be presented at the congress. Conclusions: This study shows that CP-GEP has the potential to stratify pts with early-stage melanoma who did not undergo SLNB based on their risk of recurrence. Pts with CP-GEP Low-Risk have a good long-term survival. Contrary, pts with CP-GEP High-Risk have a high risk of recurrence. CP-GEP may have the potential to stratify pts beyond SLNB. 1. Amaral et al, ASCO 2022. 2. Amaral et al, EJC 2023.

The Prevalence of Pretransplant Frailty and Mental Distress in Hematopoietic Cell Transplantation and Association with Clinical Outcomes

Frailty is a phenotype of decreased physiologic reserve associated with increased risk of toxicities and nonrelapse mortality (NRM) in hematopoietic cell transplant (HCT) recipients. The incidence, predictors, and adverse effects of pre-HCT frailty are not well known. We evaluated the association of pre-HCT frailty, defined using Fried's criteria, with age and baseline characteristics in patients ≥18 years undergoing autologous (auto) or allogeneic (allo) HCT for hematological malignancies. Assessments were performed as part of routine pre-HCT evaluations and then retrospectively analyzed. We additionally investigated the association of mental health distress indicators with frailty and the association between frailty and transplant outcomes including NRM and overall survival (OS) plus healthcare utilization. Patients undergoing HCT for hematological malignancies were analyzed (total n = 300; 162 auto, 138 allo). The overall prevalence of frailty was 18%, 21.7% among alloHCT, and 14.8% among autoHCT recipients, with similar distributions of frailty domains. Logistic regression analysis of the overall cohort revealed that older age was associated with an increased risk of frailty (odds ratio [OR] 1.37, 95% confidence interval [CI] [1.02-1.82]; P = 0.04). AlloHCT (OR 2.03, CI [1.07-3.84]; P = .03), and patient health questionnaire-9 (PHQ-9) (health depression) score ≥10 (OR 6.28, CI 1.93-20.43; P < .01) were each independently associated with pre-HCT frailty. In alloHCT patients, older age (OR 1.44, CI [1.00-2.06]; P = .05) was the only significant risk factor for pre-HCT frailty, while for autoHCT patients, only a higher PHQ-9 score was associated with frailty (OR 6.43, CI [1.34-30.82]; P = .02). For the whole cohort OS at 1 year was lower in frail recipients at 83% (95% CI, 70-91%) versus 92% (95% CI, 88-95%) in nonfrail (P = .04); with multivariate analysis showing higher risk of death in the frail group (hazard ratio [HR] 2.31, CI 0.97-5.46; P = .06). In the alloHCT cohort, multivariate analysis showed greater 1-year mortality in frail recipients (HR 2.55, CI [0.99-6.56]; P = .053). In the alloHCT recipients, we observed a 1-year NRM of 20% in frail patients versus 9% in nonfrail, and multivariate analysis showed a marginally higher risk of NRM in the frail group (HR 2.70, CI 0.90-8.10; P = .08). Frailty was not associated with higher risk of relapse in alloHCT or autoHCT recipients. Frail alloHCT patients experienced a longer initial hospital stay following HCT compared to nonfrail recipients (P < .01). We observed a high prevalence of pre-HCT frailty across all age groups, and identify older age is a risk factor for frailty, particularly in alloHCT recipients. Frailty is associated with a greater risk of NRM and lower survival which needs investigation in a larger cohort. Frailty associates with greater HCT complexity suggesting a need for early assessments and targeted interventions for this vulnerable population. Our findings suggest the utility of frailty and mental distress screening along with multidisciplinary interventions in pre-HCT to limit the morbidity of HCT.

1p and 1q: Partners in crime in multiple myeloma.

7571 Background: Cytogenetic abnormalities in multiple myeloma (MM) highly influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) among others are secondary CA. Gain (3 copies) and amplification (&gt;3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of novel therapies. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients with chromosome 1 abnormalities, mainly del 1p, treated with autologous stem cell transplant (ASCT) consolidation at our institution. Methods: We conducted a retrospective study of all NDMM patients who were treated with ASCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) were defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC CA. Results: Of 511 pts transplanted, 453 had cytogenetic data at the time of diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amplification 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of progression-free survival (PFS) (HR 1.35; 95% CI 1.06-1.73, p=0.016), time to next treatment (TTNT) (HR 1.84; 95% CI 1.40-2.42, p&lt;0.001) and overall survival (OS) (HR 1.47; 95% CI 1.06-2.02, p=0.02) compared to those without, consistent with published literature. The median PFS, TTNT and OS from ASCT in pts with gain/amp 1q were 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from the time of ASCT compared to those without del(1p). Conclusions: In our study of NDMM patients that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite induction therapy involving novel drugs and ASCT consolidation, patients with del(1p) at diagnosis continue to have inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.

Adjuvant tislelizumab combined with capecitabine for patients with biliary tract cancer with high risk of postoperative relapse (ACTIVE): Primary analysis from a prospective cohort study.

e16248 Background: Only 20% of biliary tract cancer (BTC) patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. This rate is even lower in patients with high-risk features. Capecitabine as an adjuvant therapy in biliary tract cancer has been verified to improve overall survival, however, the efficacy still remains limited. PD-1/L1 antibody combined with chemotherapy have been demonstrated to improve survival in advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of adjuvant tislelizumab and capecitabine following surgery for biliary tract cancer with high risk of recurrence. Methods: This was a single-center, prospective cohort phase II study. BTC patients (pts) underwent R0/R1 resection with high postoperative recurrence risk were eligible. The high-risk factors included positive resection margins, positive lymph nodes, positive perineural invasion, and tumor &gt; 5cm in diameter. The patients were divided into two groups, the tislelizumab (TIS 200 mg Q3W for 1 year )+capecitabine (CAP D1-14, 1500mg/m2 for eight 3-weekly cycles) group and the capecitabine group. The primary endpoint was DFS (disease free survival). The second endpoints was OS (overall survival) and adverse event (AE). Results: A total of 37 pts were enrolled into the study, while 22 pts in the TIS+CAP group and 15 in CAP group, 23 males and 14 females with a median age of 66 years. According to the location of the tumor, 37.8% pts were intrahepatic cholangiocarcinoma, 21.6% were gallbladder cancer, 5.4% were distal cholangiocarcinoma and 35.1% were hilar cholangiocarcinoma. The median DFS was 16.2 months (95% CI, 8.1-26.2) in the TIS+CAP group, which was longer than CAP group (11.4 months, 95% CI 4.2-27.1). 12-month RFS rates were 56.5% and 36.6% , respectively. The most common adverse events (AEs, any grade) were rash (18.2%), vomiting (13.6%), neutropenia (13.6%) and anorexia (13.6%) in the TIS+CAP group. Conclusions: Tislelizumab in combination with capecitabine were effective and safe as adjuvant therapy, which can prolong the DFS of BTC patients with high recurrence risk after resection. Clinical trial information: NCT04782804 .

Survival outcomes in patients with high-risk neuroblastoma (HRNB) in remission after relapsed or refractory treatment receiving eflornithine (DFMO) maintenance.

10060 Background: Five-year overall survival in newly diagnosed HRNB patients is around 50%, with relapse as the primary cause of mortality. While survival for newly diagnosed HRNB has improved with new treatment advances, relapsed or refractory (R/R) patients continue to have poor outcomes, with a high risk of subsequent relapse even among those who achieve remission, underscoring the need for treatments to improve EFS in this group. DFMO has been evaluated as a chemopreventative therapy in a single arm phase 2 study designed to compare Event Free Survival (EFS) and Overall Survival (OS) outcomes with published data for HRNB. The results of patients treated after standard therapy have been previously published. We now present an analysis of EFS/OS for patients with R/R disease, who historically have had a two-year EFS of approximately 10%. Methods: A total of 140 HRNB patients were enrolled, prospectively divided into two strata. S1 included patients in initial remission after upfront therapy, whereas S2 included patients who had either relapsed or had disease refractory to standard induction chemotherapy but achieved remission with additional therapy. Patients received 2 years of continuous treatment with oral DFMO 750 ±250 mg/m2 BID and were followed for up to 7 years. Results: A total of 35 patients withR/R disease who had achieved remission after additional therapy were enrolled onto S2, including 28 patients in remission after one or more prior relapses and 7 refractory patients in remission after subsequent therapies. Of the relapsed patients, 23 had one prior relapse, while 5 patients had two or more relapses prior to enrollment; only one previously relapsed patient had received chemoimmunotherapy prior to enrollment in the study. For the entireS2 cohort, two-year EFS was 46% (95% CI 29%, 61%) with the lower confidence interval above the 10% historical control estimate. Four-year EFS was 46% (95% CI 29%, 61%) and OS 62% (95% CI 44%, 76%), with no relapses occurring after 18 months. For patients enrolled with refractory disease only (n=7) the four-year EFS was 85.7%. In the 28 relapsed patients, the four-year EFS was 35.7%, with single relapse patients (n=23) having an EFS rate of 39.1% and multiple relapsed patients (n=5) 20.0%. Conclusions: Patients in remission after chemotherapy for relapsed or refractory HRNB and treated with DFMO had improved EFS compared to the best historical estimate available at the time of the study. Although the number of patients is too small to support clear conclusions, the subgroup of refractory patients had outcomes that trended better than the relapsed subgroup with an EFS rate that was unexpectedly similar to prior reports of DFMO-treated S1 patients in remission after standard upfront therapy. Clinical trial information: NCT02395666 , NCT00026312 .

Feasibility of induction chemoimmunotherapy (ID chemo-IO) followed by chemoradiation for locally advanced unresectable non-small cell lung cancer (NSCLC).

8071 Background: Data from the PACIFIC study demonstrated a 5-yr median progression free survival (PFS) and overall survival (OS) of 16.9 and 47.5 months respectively for patients with stage 3A and stage 3B NSCLC demonstrating a high risk of relapse. The 8th ed. of the IASLC staging project reports that the 60-month OS for stage 3A, B and C disease is 41%, 24% and 12% respectively, indicating that improved treatment options are needed for this patient population. Induction chemo-IO (ID chemo-IO) followed by concurrent chemo-radiation (CRT) has not been fully investigated due to concerns regarding the toxicity profile, but this may representant an important unexplored avenue for research. We aim to describe the outcomes of patients who received ID chemo-IO followed by CRT with or without maintenance IO. Methods: We conducted a retrospective study across all Mayo Clinic sites. Patients were included if they were diagnosed with Stage 3 NSCLC deemed ineligible for resection and/or requiring raditation over a large-field ] by a multidisciplinary team with plans for ID chemo-IO prior to CRT and maintenance IO. A total of 927 cases of stage 3 NSCLC patients were screened and those receiving ID chemo-IO followed by CRT were extracted (n = 36). Clinical endpoints are PFS, OS, overall response rate (ORR) and treatment related adverse events (TrAE) defined using CTCAE 5.0. Results: The median age was 67 years, 52.8% were female, all patients were past smokers and 97.2% identified as white. The tumor histologies were adenocarcinoma (66.67%), squamous (27.8%), mucinous adenocarcinoma (2.8%) and sarcomatoid (2.8%). Majority were Stage 3B (47.2%) followed by 3C (38.9%) and 3A (13.9%). N2 and N3 disease was noted in 36.1% and 55.6% of patients respectively. PD-L1 by IHC was &gt; 1-49% (47.2%), &gt; 50% (22.2%) and &lt; 1% (19.4%). Patients received ID chemo-IO with pembrolizumab (83.3%), nivolumab (11.1%) and atezolizumab (2.78%). Average number of ID chemo-IO cycles were 3.67 cycles. The ORR to ID chemo-IO was 86.11%. The median PFS was 23.67 mths and the median OS was 32.07 months. About 94% of patients received CRT afterwards and 66.67% received maintenance IO with pembrolizumab (53.17%) or durvalumab (45.83%). Any grade TrAE occured in 58.33% of patients. Pneumonitis was the most common event (38.9%). Grade 3 -4 pneumonitis was noted in 28.5% (4/11) patients. Other toxicities included hepatitis (8.3%), colitis (11.1%) and myasthenia gravis (2.8%) and 22% of these TrAE’s were grade 3 or 4. Conclusions: Our results indicate that ID chemo-IO shows promise as a therapeutic approach for patients with unresectable stage III NSCLC, especially for patients deemed ineligible or high risk for upfront radiation. Further investigation is needed through a randomized clinical trial to systematically explore and validate the safety and efficacy of ID chemo-IO.

Is location more determining than WHO grade for long-term clinical outcome in patients with meningioma in the first two decades of life?

To identify factors for tumor relapse and poor outcome in patients with meningiomas in the first two decades of life. All patients ≤ 21years of age who underwent resection of ameningioma at the department of neurosurgery, Medical University of Vienna between 1989 and 2022 were included in this retrospective study. Clinical and radiological data were extracted from the medical records. Outcome and tumor relapse were analyzed for tumor location, histological findings and extent of resection. In this study 18 patients were included, 6 meningiomas were located in the skull base, 5 in the convexity and 7 in other locations including intraventricular and spine (2 patients each), falx, intraparenchymal and optic nerve sheath. Most frequent symptoms were seizures and cranial nerve palsy. In total 56% of the meningiomas were World Health organization (WHO) grade1, 39% grade2 and 5% grade3. Gross total resection was achieved in 67%. The overall relapse rate was 61% and 50% underwent repeat surgery. All patients with convexity meningiomas became seizure free and had afavorable outcome. Relapse and clinical outcome were independent of WHO grade among the whole cohort but the outcome significantly depended on the WHO grade when patients with skull base meningiomas were analyzed as asubgroup. The relapse rate was significantly higher in cases of skull base location (100% vs. 42%, p = 0.038) and after subtotal resection (100% vs. 42%, p = 0.038). Clinical outcome was also significantly worse and the rate of complications was higher in patients with skull base meningiomas. Patients with convexity meningiomas in the first two decades of life have agood outcome due to high chance of gross total resection. Patients with skull base meningioma are at high risk of relapse and poor outcome, particularly those with WHO grades2 and 3. Subtotal resection in patients with skull base location is probably the main reason for this difference.

Identifying Giant Cell Arteritis patients with higher risk of relapse and vascular events: a cluster analysis.

Giant cell arteritis (GCA) is one of the most common large vessel (LVV) vasculitis and is associated with a high risk of relapse and cardiovascular complications. Improving risk stratification remains a significant issue in this patient population. We aimed to perform a cluster analysis among GCA to identify clusters and evaluate their prognostic value. In a multicenter cohort study, we performed hierarchical cluster analysis on the factor analysis of mixed data coordinates results with 283 GCA patients' characteristics to generate clusters and assess incidence of relapse, cardiovascular events and death. Three clusters were identified: "Vascular relapsing profile" (23.0%), "Typical GCA profile" (47.7%), and "Ophthalmologic elderly profile" (29.3%). The "Vascular relapsing profile" cluster included younger patients with more frequent relapses and cardiovascular events, particularly thoracic aortic aneurysms. The "Typical GCA profile" was the largest, with classic cranial manifestations and frequently associated polymyalgia rheumatica. The "Ophthalmologic elderly profile" had the oldest patients with more visual loss and the highest mortality rate. Our findings underline the varied prognostic landscape within GCA, emphasizing the poor cardiovascular prognosis of younger patients with LV involvement and the higher mortality among elderly patients. This reinforces the need for further research regarding the screening of aortic abnormalities and whether those patients might benefit from intensive treatment with biotherapy and cardiovascular risk factors management.

Extracellular volume measured by whole body CT scans predicts chronic cardiotoxicity in breast cancer patients treated with neoadjuvant therapies based on anthracyclines: A retrospective study

IntroductionNeoadjuvant chemotherapies for breast cancer (BC) are effective but potentially cardiotoxic, and expose long survivors at risk of chemotherapy-related cardiac dysfunction (CTRCD). Unfortunately, early screening for CTRCD has actual diagnostic limits. Myocardial extracellular volume (mECV) is a radiological marker used in cardiac CT scans and cardiac magnetic resonance for diagnosis and follow-up of CTRCD. It can be measured in whole-body CT (WB-CT) scan, routinely performed in patients at high risk of relapse, to evaluate CTRCD occurrence during oncological follow-up. Methods82 WB-CT scans were examined at baseline (T0) and during oncological follow-up at first year (T1) and fifth year (T5) after the end of neoadjuvant treatment. mECV was measured at 1 min (PP) and 5 min (DP) after contrast injection. 31 echocardiograms were retrieved in T1 to perform a linear correlation between mECV and left ventricular ejection fraction (LVEF). ResultsmECV values in T0 were similar between the two groups both in PP and in DP. Significant results were found for PP values in T1 (37.0 % vs 32 %, p = 0.0005) and in T5 (27.2 % vs 31.2 %, p = 0.025). A cut-off value of 35 % in PP proved significant in T1 (OR = 12.4, p = 0.004), while mECV was inversely correlated with LVEF both in PP (adj-S = −3.54, adj-p = 0.002) and in DP (adj-S = −2.51, adj-p = 0.0002), suggesting a synergistic action with the age at diagnosis (p < 0.0001, respectively). ConclusionsWB-CT scans performed during oncological reassessment in patients at high-risk of recurrence could be used for CTRCD screening in cardiovascular low-risk patients, especially in aging patients with mECV values above 35 %.

Real-world case series of maintenance theta burst stimulation therapy following response to acute theta burst stimulation therapy for difficult-to-treat depression.

Treatment and management for difficult-to-treat depression are challenging, especially in a subset of patients who are at high risk for relapse and recurrence. The conditions that represent this subset are recurrent depressive disorder (RDD) and bipolar disorder (BD). In this context, we aimed to examine the effectiveness of maintenance transcranial magnetic stimulation (TMS) on a real-world clinical basis by retrospectively extracting data from the TMS registry data in Tokyo, Japan. Data on patients diagnosed with treatment-resistant RDD and BD who received maintenance intermittent theta burst stimulation (iTBS) weekly after successful treatment with acute iTBS between March 2020 and October 2023 were extracted from the registry. All patients (21 cases: 10 cases with RDD and 11 cases with BD) could sustain response, and 19 of them further maintained remission. In this study, maintenance iTBS did not exacerbate depressive symptoms in any of the cases, but may rather have the effect of stabilizing the mental condition and preventing recurrence. This case series is of great clinical significance because it is the first study to report on the effectiveness of maintenance iTBS for RDD and BD, with a follow-up of more than 2years. Further validation with a randomized controlled trial design with a larger sample size is warranted.

Refining Parent SMART: User feedback to optimize a multi-modal intervention

IntroductionThe continuing care period following residential substance use treatment is a time when adolescents are at especially high risk for relapse, yet few families engage in traditional office-based care. Parent SMART (Substance Misuse among Adolescents in Residential Treatment) is a multi-component continuing care intervention for parents that combines three digital health technologies – an “off the shelf” online parenting program, daily phone notifications, and an online parent networking forum – with support from a parent coach. The current study solicited both qualitative and quantitative user feedback about Parent SMART to ensure responsivity to user preferences, refinement, and continuous improvement of the intervention. MethodsExit interviews were conducted with 30 parents who received Parent SMART, which includes (1) a parent networking forum; (2) daily text messages reminders of skills, (3) an “off-the-shelf” online parenting program; and (4) in-person or telehealth parent coaching sessions. The study collected qualitative feedback using semi-structured interviews and obtained quantitative feedback via a series of ratings of each Parent SMART component on a 5-point Likert scale administered at each follow-up assessment. ResultsQuantitative feedback suggest that parents rated all four elements of Parent SMART as easy to use. Qualitative feedback revealed that parents valued several aspects of Parent SMART including the brevity and structure of the intervention elements, the reminders to use parenting skills, and the sense of social connectedness fostered by different components. Recommended refinements included a number of strategies to enhance personalization and ease of navigation. ConclusionsParent feedback informed enhancements to the Parent SMART intervention prior to implementation in a larger, ongoing pragmatic effectiveness trial. The current study serves as a model for applying a staged person-centered approach and eliciting both quantitative and qualitative feedback to refine digital health technologies.

Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia.

Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.

Antipsychotic Medication Continuation vs Taper and Discontinuation in Patients With Schizophrenia and Other Nonaffective Psychotic Disorders.

Schizophrenia is a major mental illness that is managed with long-term antipsychotic medication as a standard of care. Antipsychotic medications, however, are associated with many subjective and objective adverse effects. These adverse effects have driven the study of risk-mitigation strategies such as targeted intermittent therapy and dose reduction and drug discontinuation. Randomized controlled trials (RCTs) of these strategies have been synthesized in meta-analysis; both strategies have been associated with no functional benefits and with an increased risk of relapse. The RCTs, however, have been criticized because, in many, patients were abruptly switched to the target dose or too rapidly tapered, thereby predisposing the RCT to failure of the intervention. Two important RCTs examined gradual individualized dose reduction and discontinuation. One, conducted in first-episode psychosis patients who were free from positive symptoms for 6 months, found that, at 18-month follow-up, dose reduction was associated with a higher risk of relapse (number needed to harm [NNH] = 5) and with no functional benefits. However, after return to routine clinical care, at a 7-year follow-up, the dose reduction group had better functional outcomes and similar clinical outcomes relative to the maintenance treatment group. The other RCT, conducted in patients with relapsing psychosis, found that, at a 2-year follow-up, dose reduction was associated with a higher risk of relapse (NNH = 5) and with no improvements in social, cognitive, quality of life, satisfaction, and other domains. Many large nationwide observational studies have found that antipsychotic discontinuation by patients with first-episode psychosis and schizophrenia is associated with increased relapse, rehospitalization, suicide mortality, cardiovascular mortality, and all-cause mortality. There is also the ethical matter that attempts to identify the few who may benefit from antipsychotic dose reduction and discontinuation may compromise the health and stability of the many who require long-term maintenance treatment.

Clinical characteristics and courses of Korean patients with giant cell arteritis: a multi-center retrospective study.

Giant cell arteritis (GCA) is a large-vessel vasculitis that primarily affects elderly individuals. However, data regarding Korean patients with GCA are scarce owing to its extremely low prevalence in East Asia. This study aimed to investigate the clinical characteristics of Korean patients with GCA and their outcomes, focusing on relapse. The medical records of 27 patients with GCA treated at three tertiary hospitals between 2007 and 2022 were retrospectively reviewed. Seventeen (63.0%) patients were females, and the median age at diagnosis was 75 years. Large vessel involvement (LVI) was detected in 12 (44.4%) patients, and polymyalgia rheumatica (PMR) was present in 14 (51.9%) patients. Twelve (44.4%) patients had fever at onset. The presence of LVI or concurrent PMR at diagnosis was associated with a longer time to normalization of the C-reactive protein level (p=0.039) or erythrocyte sedimentation rate (p=0.034). During follow-up (median 33.8 months), four (14.8%) patients experienced relapse. Kaplan-Meier analyses showed that relapse was associated with visual loss (p=0.008) and the absence of fever (p=0.004) at onset, but not with LVI or concurrent PMR. Concurrent PMR and LVI were observed in approximately half of Korean patients with GCA, and the elapsed time to normalization of inflammatory markers in these patients was longer. The relapse rate in Korean GCA is lower than that in Western countries, and afebrile patients or patients with vision loss at onset have a higher risk of relapse, suggesting that physicians should carefully monitor patients with these characteristics.

Proteogenomic characterization of difficult-to-treat breast cancer with tumor cells enriched through laser microdissection

BackgroundBreast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer death among women globally. Despite advances, there is considerable variation in clinical outcomes for patients with non-luminal A tumors, classified as difficult-to-treat breast cancers (DTBC). This study aims to delineate the proteogenomic landscape of DTBC tumors compared to luminal A (LumA) tumors.MethodsWe retrospectively collected a total of 117 untreated primary breast tumor specimens, focusing on DTBC subtypes. Breast tumors were processed by laser microdissection (LMD) to enrich tumor cells. DNA, RNA, and protein were simultaneously extracted from each tumor preparation, followed by whole genome sequencing, paired-end RNA sequencing, global proteomics and phosphoproteomics. Differential feature analysis, pathway analysis and survival analysis were performed to better understand DTBC and investigate biomarkers.ResultsWe observed distinct variations in gene mutations, structural variations, and chromosomal alterations between DTBC and LumA breast tumors. DTBC tumors predominantly had more mutations in TP53, PLXNB3, Zinc finger genes, and fewer mutations in SDC2, CDH1, PIK3CA, SVIL, and PTEN. Notably, Cytoband 1q21, which contains numerous cell proliferation-related genes, was significantly amplified in the DTBC tumors. LMD successfully minimized stromal components and increased RNA–protein concordance, as evidenced by stromal score comparisons and proteomic analysis. Distinct DTBC and LumA-enriched clusters were observed by proteomic and phosphoproteomic clustering analysis, some with survival differences. Phosphoproteomics identified two distinct phosphoproteomic profiles for high relapse-risk and low relapse-risk basal-like tumors, involving several genes known to be associated with breast cancer oncogenesis and progression, including KIAA1522, DCK, FOXO3, MYO9B, ARID1A, EPRS, ZC3HAV1, and RBM14. Lastly, an integrated pathway analysis of multi-omics data highlighted a robust enrichment of proliferation pathways in DTBC tumors.ConclusionsThis study provides an integrated proteogenomic characterization of DTBC vs LumA with tumor cells enriched through laser microdissection. We identified many common features of DTBC tumors and the phosphopeptides that could serve as potential biomarkers for high/low relapse-risk basal-like BC and possibly guide treatment selections.

Histologic Disease Persists beyond Mucosal Healing and Could Predict Reactivation in Ulcerative Colitis.

Mucosal healing (MH) is the main target in ulcerative colitis (UC) treatment. Even if MH lowers the risk of disease reactivation, some patients still relapse. Histologic activity (HA) beyond MH could explain these cases. This study aims to assess how many patients with MH have HA and which lesions are associated with relapse. We retrospectively enrolled UC patients showing MH, expressed as a Mayo Endoscopic Subscore (MES) of 0 and 1 upon colonoscopy. We reviewed the histological reports of biopsies evaluating the presence of typical lesions of UC and assessed the number of clinical relapses after 12 months. Among 100 enrolled patients, 2 showed no histological lesions. According to univariate analysis, patients with a higher number of histological lesions at the baseline had a higher risk of relapse (OR 1.25, p = 0.012), as well as patients with basal plasmacytosis (OR 4.33, p = 0.005), lamina propria eosinophils (OR 2.99, p = 0.047), and surface irregularity (OR 4.70, p = 0.010). However, in the multivariate analysis, only basal plasmacytosis (OR 2.98, p = 0.050) and surface irregularity (OR 4.50, p = 0.024) were confirmed as risk factors for disease reactivation. HA persists in a significant percentage of patients with MH. Despite the presence of MH, patients with basal plasmacytosis and surface irregularity have a higher risk of relapse.

VP3-2024: A randomized study of 6 vs 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse

VP3-2024: A randomized study of 6 vs 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse

Evaluating the effectiveness of a mobile app-based self-guided psychological interventions to reduce relapse in substance use disorder: protocol for a randomized controlled trial.

Substance Use Disorder (SUD) persists as a significant public health challenge worldwide, with an estimated prevalence of approximately 10-15% across the global populace. This condition is characterized by a notably high risk of lapses and relapses, even subsequent to treatment interventions. Mobile health interventions, owing to their widespread accessibility, emerge as a promising approach to diminish the risk of relapse post-treatment and to broaden the scope of care, especially in regions with a scarcity of trained medical professionals. This study is designed to assess the effectiveness of mobile interventions in mitigating cravings and preventing lapses among individuals diagnosed with SUD. Employing a two-armed, randomized controlled trial framework, the study will evaluate a self-administered psychological intervention delivered through a mobile application, Nałogometr 2.0. Over a period of three months, participants will engage with intervention modules that primarily incorporate mindfulness techniques and Cognitive Behavioral Therapy (CBT) principles. Ecological Momentary Assessment (EMA) will be utilized to gather longitudinal data on a range of variables that are indicative of craving intensity and the risk of lapse. In addition to this, a monthly-administered battery of questionnaires will be employed to gauge the severity of substance dependence, as well as to measure levels of anxiety, depression, and overall life satisfaction. Results will be submitted for publication in peer-reviewed journals. https://clinicaltrials.gov/, identifier [NCT05730504].

Abstract PO1-20-02: MiRaDor: A proof-of-concept study of treatment efficacy by monitoring Minimal Residual Disease (MRD) using circulating tumor DNA (ctDNA) in hormone receptor-positive/HER2-negative (HR+/HER2-) early breast cancer (EBC)

Abstract Background: Detection of MRD through ctDNA has been consistently associated with high risk of relapse. Longitudinal evaluation of ctDNA to monitor MRD is a minimally invasive tool that may predict disease recurrence and treatment response. MiRaDor aims to improve the clinical utility of ctDNA and understand its applicability in high-risk, HR+/HER2- EBC patients (pts). Trial Design: MiRaDor (NCT05708235) is a multicenter, open-label, non-comparative, phase II trial. Selection criteria include pts: a) with HR+/HER2- EBC at high risk of relapse, b) on adjuvant treatment with endocrine therapy (ET) for at least 2 years with 3 additional years of planned ET, c) no prior treatment with cyclin-dependent kinases 4/6 inhibitors or fulvestrant, and d) had surgery for their primary BC in the last 5 years. The trial has two phases, ctDNA surveillance (n=1260) and treatment (n=40-60). The surveillance phase will analyze ctDNA, with the FoundationOne® Tracker, every 3 months for the 1st year and every 6 months thereafter until ctDNA detection, end of the adjuvant ET, or completion of treatment phase accrual. Pts with positive ctDNA without radiological disease progression (PD) will be allocated to 1 of the treatment arms (n=10): A) standard ET; B) giredestrant; C) giredestrant + abemaciclib; or D) giredestrant + inavolisib (if PIK3CA mutation). Treatment will continue until evidence of PD, physician’s and/or patient’s decision, or until the end of study treatment (abemaciclib/inavolisib for up to 2 years, 5 years for ET). Tumor assessments will be periodically performed to rule out radiological PD. The primary objective is to evaluate the rate of pts with at least 90% decrease or clearance in ctDNA after 3 months of treatment. Key secondary objectives include the proportion of pts with 90% decrease in baseline ctDNA at 6, 9, and 12 months, 70%, and 50% decrease in ctDNA at 3, 6, 9, and 12 months, and treatment safety and tolerability. A cohort expansion up to 20 pts in 1 or 2 arms will occur if at 3 months a 90% ctDNA decrease is observed in at least 30% of pts and if, after 3 additional months, a 90% ctDNA decrease is maintained in at least 20% of pts. Citation Format: Antonio Llombart-Cussac, José Manuel Pérez-García, María Gion, Daniel Alcalá-López, Janet Fazal-Salom, Alexandros Lazaris, Mario Mancino, Eileen Shimizu, Susana Victorino, Rui Rui Zhang, Zuzana Machackova, Frauke Schimmoller, Matthew Wongchenko, Joseph Gligorov, Peter Schmid, Javier Cortés. MiRaDor: A proof-of-concept study of treatment efficacy by monitoring Minimal Residual Disease (MRD) using circulating tumor DNA (ctDNA) in hormone receptor-positive/HER2-negative (HR+/HER2-) early breast cancer (EBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-02.

Abstract PO5-19-07: A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer

Abstract Background: Triple negative breast cancer (TNBC) is a biologically distinct subtype with a high risk of early relapse. Patients not achieving a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) have a 3-year event free survival (EFS) of &amp;lt; 60%. Approximately 1/3 of patients receiving NAC with pembrolizumab-mediated immune therapy will not achieve a pCR and of those, approximately 1/3 will experience a recurrence within 3 years. Physical disruption of tumors with local strategies such as cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. The combination of cryo with immune checkpoint inhibition (ICI) has been shown to induce tumor regression and prevented tumor re-challenge in pre-clinical models. Clinical studies have also demonstrated that the combination of pre-operative cryo with ICI is safe in women with operable, early-stage breast cancer and generates intra-tumoral and systemic immune responses (NCT01502592, NCT02833233). This multi-center, single arm, phase 2 study is currently evaluating the impact of cryo with standard-of-care pembrolizumab (pembro) in women with residual TNBC after taxane-based NAC, a group at high risk of early relapse (NCT03546686). Methods: Eligible women are ≥18y, with ER &amp;lt; 10%, PR &amp;lt; 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and receive peri-operative pembro per standard-of-care. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients are stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Funding sources: Conquer Cancer Foundation, Breast Cancer Research Foundation, Boston Scientific Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen Solomon, Sangeetha Reddy, Isaac Chan, Baṣak Dogan, Dawn Klemow, Nisha Unni, Jorge Henrique Santos Leal, Cristal Martinez, Reva Basho, Dorothy Park, Philomena McAndrew, Brigid Larkin, David Page, William Mills, Staci Mellinger, Nicole Fredrich, Nicole Moxon, Lynette Currie, Meredith Carter, Melissa Ramos, Stephanie Rice, Sujata Patil, Margaret Gatti-Mays, Larry Norton. A Single Arm Phase 2 Study of Peri-Operative Immune Checkpoint Inhibition and Cryoablation in Women With Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-07.