Citations

Objective: To investigate fecal incontinence and defecatory, urinary, and sexual functional outcomes after transanal total mesorectal excision (taTME). Background: Proctectomy for rectal cancer may result in alterations in defecatory, urinary, and sexual function that persist beyond 12 months. The recent multicenter phase II taTME trial demonstrated the safety of taTME in patients with stage I to III tumors. Methods: Prospectively registered self-reported questionnaires were collected from 100 taTME patients. Fecal continence [Fecal Incontinence Quality of Life (FIQL), Wexner], defecatory function [Colorectal Functional Outcome (COREFO)], urinary function (International Prostate Symptom Score), and sexual function (Female Sexual Function Index-female, International Index of Erectile Function-male) were assessed preoperatively (PQ), 3 to 4 months postileostomy closure (FQ1), and 12 to 18 months post-taTME [postoperative questionnaire 2 (FQ2)]. Results: Among 83 patients who responded at all 3 time points, FIQL, Wexner, and COREFO significantly worsened postileostomy closure. Between FQ1 and FQ2, FIQL lifestyle and coping, Wexner, and COREFO incontinence, social impact, frequency, and need for medication significantly improved, while FIQL depression and embarrassment did not change. International Prostate Symptom Score did not change relative to preoperative scores. For females, Female Sexual Function Index declined for desire, orgasm, and satisfaction between PQ and FQ1, and did not improve between FQ1 and FQ2. In males, International Index of Erectile Function declined with no change between FQ1 and FQ2. Conclusions: Although taTME resulted in initial decline in defecatory function and fecal continence, most functional domains improved by 12 months after ileostomy closure, without returning to preoperative status. Urinary function was preserved while sexual function declined without improvement by 18 months post-taTME. Our results address patient expectations and inform shared decision-making regarding taTME.

AimsThe majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D‐negative CD34‐positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK‐rearrangements in DFSP and plaque‐like CD34‐positive dermal fibroma (P‐LDF).Methods and ResultsWe searched the archives of academic institutions for cases previously coded as DFSP and P‐LDF. NGS‐naïve or PDGFB‐negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK‐positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of “DFSP” and two “P‐LDF” with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0–2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP‐like cases and FLNA in P‐LDF‐like lesions. ALK FISH was positive in one (of two) cases previously labelled P‐LDF. Methylome profiling of two (of three) ALK‐rearranged DFSP‐like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months).ConclusionWe describe a cohort of novel ALK‐rearranged tumours with morphologic features similar to DFSP.

11118 Background: Lung cancer survivors experience more physical and mental challenges, heavier symptom burden, and poorer quality of life than survivors of other cancers. Many symptoms persist or worsen for survivors beyond 5 years of cancer diagnosis, referred as long-term lung cancer survivors (LTLCS). Social determinants of health (SDoH) factors negatively impact patient reported outcomes (PROs) among cancer survivors, but their role in outcomes is under reported in lung cancer survivors and unknown in LTLCS. We investigated the impact of SDoH on PROs in a 20-year prospective lung cancer cohort. Methods: Our cohort includes 19,251 lung cancer patients (cases) diagnosed from 1997 through 2016 and followed up to 27 years, of whom 4799 (25%) became LTLCS. SDoH information was obtained by a lung cancer study PRO questionnaire or an institution SDoH questionnaire. Analyzed in this report are 2982 cases and 480 controls who had a low-dose chest CT scan and were ruled out for cancer, all answered at least one PRO questionnaire (first response); and 1366 LTLCS answered 5 years after diagnosis (long-term response). Along with fatigue and dyspnea, 5 SDoH variables, i.e., financial concerns, legal concerns, family and friends support, spiritual well-being, and social activity were scored on a 0 (worst) - 10 (best) scale and dichotomized as 0-5 (deficit/worse/lower) or 6-10 (no deficit/better/higher). We also assessed employment and health-related work experience. A difference of 1.0 unit or more in score was considered clinically meaningful along with a 2-sided test P-value less than 0.05; Chi-square or Fisher’s Exact Test and Kruskal-Wallis test were used accordingly. Results: Compared to controls, cases were younger (mean age: 62 vs. 65 years, P<0.05); more women than men reported worse financial concerns (56% vs. 38%, P<0.01) and lower spiritual well-being (43% vs. 26%, P=0.04) at first response; this sex disparity reduced but remained significant at long-term. Worse dyspnea (4.4-4.8 vs. 5.6) and fatigue (4.7-4.8 vs. 5.8-5.9) were seen in cases with more financial and legal concerns compared to those with fewer concerns (Ps<0.01). Cases with higher family and friends support, spiritual well-being and social activity had less dyspnea (5.7-6.0 vs. 4.2-4.5) and fatigue (5.5-5.9 vs. 3.9-4.4) than those with lower scores (Ps<0.04). Employment and health-related work experience data were provided by 2213 responders: Comparing 1735 cases to 478 controls, a lower proportion of cases was employed (28% vs. 39%), more cases “often felt tired after work” (49% vs. 28%), and more cases had “quite a lot” of difficulty in daily work or could not work at all” (26% vs. 9%, Ps<0.01). Conclusions: We found that in lung cancer survivors, more women than men reported worse financial concerns, and lower SDoH status was correlated with worse dyspnea and fatigue, indicating SDoH-driven interventions are important to improve lung cancer survivors’ PROs.

10608 Background: Cancer is one of the most feared diseases. Multi-cancer early detection (MCED) tests have the potential to expand the number of cancers that are detected at earlier stages, which could result in better clinical outcomes. However, behavioral impacts based on MCED test results could affect the utility and value of these tests. Methods: Two independent data sources evaluated the impact of MCED test results on behavioral intentions and perceptions: a survey of the general population and PRO in an MCED clinical trial. A web-based, 30-minute survey of the US general population was used to ascertain attitudes toward a hypothetical MCED test. Eligible respondents were adults aged 40-80 years without a cancer diagnosis in the previous 5 years. The survey assessed the perceived value of negative results (ie, no cancer signal detected [NCSD]) and the projected impact on post-test behaviors. The prospective PATHFINDER study (NCT04241796) of adults aged ≥50 years who underwent MCED cancer screening included PRO assessments. Post-test assessments included: "I am feeling relieved about my test result" from the adapted MICRA and “How likely are you to follow your healthcare provider’s cancer screening recommendations.” The consistency of sentiment after an NCSD MCED result from the online survey and clinical study was assessed. Results: Of the 1073 online survey respondents, 53% were female, 77% White, 14% Black/African American, and 13% Hispanic. Mean age was 58 years. The most common anticipated emotional impacts were relief (84%), happiness (72%), and confidence (69%). Respondents (66-70%) reported they would expect less worry, fear, stress, and anxiety after an NCSD MCED result. The majority (73%) reported they would maintain or improve health behaviors after an NCSD result. NCSD results were projected to lead to an increase in health-related behaviors, including adherence to recommended cancer screening (98%; 68% increase, 30% maintain current level) and regular doctor visits (46%). Of the 6529 PATHFINDER study participants who received NCSD results, 64% were female, 92% White. Mean age was 63 years. 80% of participants (n = 4685/5865) with NCSD felt relief "sometimes" or "often" after their MCED test result. Over 95% of participants (n = 5637/5863) with NCSD indicated they were "likely" or "very likely" to adhere to cancer screening recommendations in the future. Conclusions: Results from a general population survey and a prospective clinical study indicate that an NCSD result may be associated with positive cancer screening intentions and other preventive healthcare behaviors. An NCSD result may also positively impact psychological and emotional health. While these findings suggest that an NCSD result may provide additional value beyond traditional clinical benefits associated with cancer screening, future research is needed to delineate the behavioral impact following MCED screening. Clinical trial information: NCT04241796 .

7561 Background: Pts with TCE RRMM have poor outcomes and a high unmet need, with no established SOC tx. LINKER-MM1 (NCT03761108) is a single-arm, Phase 1/2 study investigating linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody, in pts with RRMM who were previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody, or were triple-class refractory (TCR) to these tx. The aim of this study was to contextualize LINKER-MM1 by comparing outcomes with linvoseltamab vs a real-world (RW) external control arm (ECA). Methods: A RW ECA was derived from 2 US electronic health record databases (COTA, Guardian Research Network) of pts who started a new line of therapy (LOT) after classification as TCE or TCR and met key eligibility criteria for LINKER-MM1. Eligibility was assessed at the initiation of each new LOT, and all eligible LOTs were included in the ECA. Data in Phase 2 pts who received linvoseltamab 200 mg in LINKER-MM1 were included (data cutoff: Sep 8, 2023). Inverse probability of tx weighting (IPTW) was used to reduce imbalances between the RW and LINKER-MM1 cohorts. Key prognostic factors were identified using a systematic review and rank ordered by an international committee of MM experts (Kumar et al., 2023). Outcomes included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). An independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments prior to conducting comparative analyses. Results: Comparative analyses were performed in 105 pts in the linvoseltamab cohort and 101 RW pts (137 LOTs). Following IPTW, the distribution of cytogenetic risk, age, TCR status, Eastern Cooperative Oncology Group Performance Status, and platelet count were balanced between the 2 cohorts (absolute standardized mean difference <0.10). After adjustment, pts receiving linvoseltamab had significantly improved ORR, PFS, TTNT, and OS vs the RW ECA (see table). Conclusions: Linvoseltamab significantly improved outcomes vs RW SOC in the US, highlighting its potential as a highly effective tx in pts with TCE RRMM. [Table: see text]

Summary Informed by the almost unimaginable unmet need for cardiac surgery in the developing regions of the world, leading surgeons, cardiologists, editors in chief of the major cardiothoracic journals as well as representatives of medical industry and government convened in December 2017 to address this unacceptable disparity in access to care. The ensuing “Cape Town Declaration” constituted a clarion call to cardiac surgical societies to jointly advocate the strengthening of sustainable, local cardiac surgical capacity in the developing world. The Cardiac Surgery Intersociety Alliance (CSIA) was thus created, comprising The Society of Thoracic Surgeons (STS), the American Association for Thoracic Surgery (AATS), the Asian Society for Cardiovascular and Thoracic Surgery (ASCVTS), the European Association for Cardio-Thoracic Surgery (EACTS) and the World Heart Federation (WHF). The guiding principle was advocacy for sustainable cardiac surgical capacity in low-income countries. As a first step, a global needs assessment confirmed rheumatic heart disease as the overwhelming pathology requiring cardiac surgery in these regions. Subsequently, CSIA published a request for proposals to support fledgling programmes that could demonstrate the backing by their governments and health care institution. Out of 11 applicants, and following an evaluation of the sites, including site visits to the 3 finalists, Mozambique and Rwanda were selected as the first Pilot Sites. Subsequently, a mentorship and training agreement was completed between Mozambique and the University of Cape Town, a middle-income country with a comparable burden of rheumatic heart disease. The agreement entails regular video calls between the heart teams, targeted training across all aspects of cardiac surgery, as well as on-site presence of mentoring teams for complex cases with the strict observance of ‘assisting only’. In Rwanda, Team Heart, a US and Rwanda-based non-governmental organization (NGO) that has been performing cardiac surgery in Rwanda and helping to train the cardiac surgery workforce since 2008, has agreed to continue providing mentorship for the local team and to assist in the establishment of independent cardiac surgery with all that entails. This involves intermittent virtual conferences between Rwandan and US cardiologists for surgical case selection. Five years after CSIA was founded, its ‘Seal of Approval’ for the sustainability of endorsed programmes in Mozambique and Rwanda has resulted in higher case numbers, a stronger government commitment, significant upgrades of infrastructure, the nurturing of generous consumable donations by industry and the commencement of negotiations with global donors for major grants. Extending the CSIA Seal to additional deserving programmes could further align the international cardiac surgical community with the principle of local cardiac surgery capacity-building in developing countries.

Importance Neurological manifestations during acute SARS-CoV-2–related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. Objective To assess the association of severe neurological manifestations during a SARS-CoV-2–related hospital admission with new neurocognitive or functional morbidities at discharge. Design, Setting, and Participants This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. Exposure Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. Main Outcomes and Measures The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2–related condition. Results Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P &amp;lt; .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations ( P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. Conclusions and Relevance The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

5546 Background: Advanced ovarian cancer (OC) is managed with cytoreductive surgery and platinum-based chemotherapy. Prehabilitation is a multimodal intervention to improve physical and mental health prior to oncologic surgery. This study evaluates baseline differences in clinical characteristics, functional status, and patient-reported outcomes (PROs) between patients undergoing primary cytoreductive surgery (PCS) versus neoadjuvant chemotherapy (NACT) who enrolled in a prospective prehabilitation trial. Methods: This was a single-institution, non-randomized prospective behavioral intervention trial of patients with suspected advanced stage (IIIC/IV) OC. Baseline functional testing included the Short Physical Performance Battery (SPPB), Fried Frailty Index (FFI), gait speed, and grip strength. Patient-Reported Outcomes Measurement Information System (PROMIS) metrics, the Mindfulness Attention Awareness Scale (MAAS), and the Perceived Stress Scale (PSS-10) were used to evaluate PROs. Comparisons between cohorts utilized two-sample t-test or Kruskal Wallis test for continuous variables and chi-square or Fisher’s exact test for categorical variables. T-scores were obtained for PROMIS data using the HealthMeasures Scoring Service; validated cut points for PROMIS, MAAS, and PSS-10 were used for categorization. Results: Amongst the 53 enrolled patients, physical and emotional distress was higher amongst OC patients compared to population means. When compared to PCS patients, NACT patients were more likely to report “severe” in at least one PROMIS domain (emotional distress and anxiety, pain interference, physical function, and fatigue, p<0.01). NACT patients reported significantly higher levels of perceived stress (p<0.01). NACT patients were more likely to have stage IV disease, albumin <3.5 g/dL, and lower gait speed and grip strength (all p<0.01). Despite differences in clinical variables and PROs including physical function, there were no measurable differences in physical function based on SPPB and FFI. Conclusions: Advanced OC patients have high psychosocial needs, with NACT patients reporting severe perceived symptoms on PRO measures. The PSS-10 may be a valuable screening tool for patients undergoing NACT to prioritize supportive care services. Clinical trial information: NCT05047926 . [Table: see text]

5010 Background: hK2 (encoded by the KLK2gene) is a novel target expressed on the cell surface of prostate cancer cells with restricted expression elsewhere. JNJ-6420 is a first-in-class anti-hK2 antibody–based targeted radiotherapy delivering 225Ac, a high-energy short-range alpha-particle emitter, to prostate cancer cells. Here we report the first-in-human study evaluating JNJ-6420 in heavily pretreated biomarker-unselected participants (pts) with mCRPC who received ≥1 prior androgen receptor pathway inhibitor. Methods: Intravenous JNJ-6420 was escalated from 50 μCi to 400 μCi every 8-12 weeks in the outpatient setting with no residential radioprotective restrictions. Prior radioisotopic therapy was an exclusion criterion. Primary objectives were safety and defining a recommended phase 2 dose (RP2D). Secondary objectives included preliminary assessment of clinical activity. Results: As of January 5, 2024, 67 pts received ≥1 JNJ-6420 dose. Exposure and clinical activity for the 57 pts in the ≥150 μCi JNJ-6420 cohorts are summarized (see Table); 35/57 (61.4%) experienced grade ≥3 TEAEs, and 21 (36.8%) had a serious TEAE. TEAEs of note included thrombocytopenia (63.2%) and interstitial lung disease (ILD, 9%). All instances of ILD occurred at cumulative doses ≥500 μCi and prior to implementation of pulmonary function surveillance. Grade ≥3 TEAEs (≥10%) included anemia (26.3%), thrombocytopenia (17.5%), lymphopenia (10.5%), and leukopenia (10.5%). 9/57 (15.8%) pts discontinued treatment due to TRAEs; 4 TRAEs resulted in death. At doses ≥150 μCi, the PSA50 rate was 45.6%. To date, across all dose cohorts, 31 pts (46%) remained on treatment for ≥24 weeks. Prolonged clinical, biochemical, and radiographic responses were noted in pts receiving doses of 150 μCi and higher. Durable responses included pts on treatment for 112 weeks (96 weeks since last dose), 88 weeks (13 weeks since last dose), and 46 weeks (after a single dose). Conclusions: In this first-in-human study, key TEAEs of JNJ-6420 were thrombocytopenia and ILD, both associated with repeated dosing. At ≥150 μCi, 1-2 doses of JNJ-6420 elicited profound and durable biochemical and radiographic responses. Evaluation of the RP2D is ongoing. These data highlight hK2 as a novel target for targeted alpha-particle therapy. Clinical trial information: NCT04644770 . [Table: see text]

Context.— The joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee works to ensure competency and proficiency of clinical cytogenetics testing laboratories through proficiency testing programs for various clinical tests offered by such laboratories, including the evaluation of constitutional abnormalities. Objective.— To review and analyze 20 years of constitutional chromosome analysis proficiency testing results (2003–2022), primarily utilizing G-banded karyograms. Design.— A retrospective review of results from 2003 through 2022 was performed, identifying challenges addressing constitutional disorders. The chromosomal abnormalities and overall performance were evaluated. Results.— A total of 184 cases from 161 proficiency testing challenges were administered from 2003 through 2022. Challenges consisted of metaphase images and accompanying clinical history for evaluation of numerical and/or structural abnormalities. Of the 184 cases, only 2 (1%) failed to reach an 80% grading consensus for recognition of the abnormality. Both cases illustrated the limitations of correctly characterizing some chromosomal abnormalities, including recombinant chromosomal abnormalities and isochromosome identification. In addition, 2 cases failed to reach a consensus for nomenclature reporting: 1 with an isochromosome and another with a duplication. Conclusions.— This 20-year review illustrates the high rate of competency and proficiency of cytogenetic laboratories in the correct identification of constitutional chromosome abnormalities.