Citations

The NCCN Guidelines for Survivorship include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from adult-onset cancer and its treatment and provide a framework for coordination of survivorship care. They also include recommendations to help cancer survivors enhance their wellness and maintain a healthy lifestyle. These NCCN Guidelines Insights summarize the panel’s current recommendations and recent updates regarding physical activity, nutrition, and weight management for cancer survivors.

ABSTRACT Human alanine:glyoxylate aminotransferase (AGT) is a liver peroxisomal enzyme that metabolizes glyoxylate, the oxalate precursor, to glycine. AGT deficiency, due to recessive pathogenic changes in the AGXT gene, results in calcium oxalate accumulation and kidney stones, a condition known as primary hyperoxaluria type 1 (PH1). Most missense variants lead to PH1 by causing AGT misfolding, but their effects manifest differently based on the presence of two polymorphic variants, p.Pro11Leu (p.P11L) and p.Ile340Met (p.I340M), which are usually present in linkage disequilibrium and generate the minor haplotype. While the p.P11L substitution reduces AGT global stability and worsens the effects of pathogenic changes, the p.I340M exerts a stabilizing effect whose role on PH1 pathogenesis has never been elucidated. The p.Ile279Thr (p.I279T) variant is frequent in healthy populations (0.29%), mainly on the major allele, but we present data from six PH1 families (eight patients) suggesting p.I279T as a PH1 pathogenic allele. Interestingly, in these families, p.Thr279 is always associated with p.Leu11 and p.Ile340, thus with a split AGXT haplotype. Analysis of the effects of the p.I279T mutation by in silico predictions, biochemical analyses on purified proteins, and expression in two cellular models of disease ( AGXT1 ‐KO HepG2 and CHO cells) shows that it causes a folding defect that is exacerbated by p.P11L but mitigated by p.I340M, thus explaining why p.Thr279 is pathogenic just on the p.Leu11–p.Ile340 haplotype. These data indicate that genetic screenings for PH1 should document the AGXT haplotype, including its components, to obtain an accurate diagnosis and possible prognostic information.

A 10-year-old girl with a past medical history significant for prematurity at 29 weeks, short bowel syndrome secondary to necrotizing enterocolitis, prior episodes of small intestinal bacterial overgrowth complicated by D-lactic acidosis, and gastric tube dependence presented to an emergency department with emesis, slurred speech, somnolence, and unsteady gait. Workup was initiated, and she was started on broad-spectrum antibiotics and transferred to our pediatric intensive care unit for further evaluation and treatment. Differential diagnosis on admission was broad, and, through thorough laboratory evaluation, imaging, and multiple subspecialty inputs, an unusual diagnosis was confirmed.

Abstract Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.

Abstract Aim Growing evidence suggests that immune/inflammatory pathways play a crucial role in the persistence of symptoms in diverticular disease (DD). We hypothesize that chronic diverticulitis triggers a self‐sustained inflammatory status which can be detected by measuring the levels of tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6). The aim of this study was to investigate the systemic levels of TNF‐α and IL‐6 before and after elective surgery in patients with DD, and their relationship with the gastrointestinal quality of life index (GIQLI) score. Method This prospective multicentric study enrolled patients from the Diverticular Disease Registry (DDR‐Trial, NCT04907383). All adult patients diagnosed with symptomatic uncomplicated diverticular disease (SUDD), uncomplicated recurrent diverticulitis (URD) and smouldering diverticulitis (SmD) between 1st December 2022 and 31st December 2023 were included in this study. Exclusion criteria were as follows: no surgery, a concurrent chronic immunomodulated systemic disease, a SARS‐CoV‐2‐positive test in the previous 12 months, a history of cancer in the previous 5 years, patients treated with immunomodulators, an American Society of Anesthesiologists category of class IV, and complicated acute diverticulitis. Results Seventy‐two patients were included: 52 (72%) with URD, 11 (15%) with SUDD, and nine (13%) with SmD. The median postsurgery – presurgery (Δ)IL‐6 and ΔTNF‐α levels were −16.8 and −17.3 pg/mL, respectively ( p < 0.001 for both; Wilcoxon test). Spearman correlation revealed a significant, negative association between the ΔGIQLI and the ΔIL‐6, as well as the ΔTNF‐α ( p < 0.001 for both). Greater reduction in the levels of IL‐6 and TNF‐α following surgery are associated with higher GIQLI scores postoperatively. Conclusion Patients with chronic diverticulitis may experience persistent systemic inflammation driven by a colonic trigger. Surgical removal of this trigger appears to enhance GIQLI outcomes reducing IL‐6 and TNF‐α across surgery.

Background Given the low haemorrhagic risk of intracranial low-grade dural arteriovenous fistulas (dAVFs), the benefits of routine intervention remain controversial. This study compares patient outcomes treated with stereotactic radiosurgery (SRS) versus conservative management. Method Multicentre retrospective analysis of the Consortium for Dural Arteriovenous Fistula Outcomes Research and the International Radiosurgery Research Foundation data. Inclusion criteria were (1) intracranial low-grade dAVF diagnosed by catheter-based angiography, (2) no prior dAVF-related haemorrhage and (3) management with upfront SRS (intervention group) or conservative management (observation group). The primary outcome was symptomatic improvement. Secondary outcomes included dAVF obliteration, up-conversion, haemorrhage, improvement and favourable modified Rankin Scale (mRS) at follow-up. Results 304 patients with a mean age of 56 years (SD 13.5) and a follow-up of 46.7 months (SD 45.5) were included. 135 (44.4%) were managed conservatively and 169 (55.6%) had upfront SRS. Compared with the observation group, symptomatic and mRS Score improvement (≥1-point decrease in baseline score) was more likely in the intervention group (95.1% vs 58.5%; OR=13.75 (5.61–33.69) and 37.0% vs 24.0%; OR=1.85 (1.09–3.15), respectively). These findings remained significant after multiple imputation and propensity score matching. Remaining outcomes were similar between groups. The all-cause mortality rate was 5.4% (n=16), unrelated to the dAVF or treatment. Five (3.0%) SRS-related complications were reported and resolved during the follow-up period. Conclusions SRS was associated with increased symptomatic and mRS Score improvement for low-grade dAVFs compared with conservative management. SRS had a low complication risk and did not appear to alter dAVF obliteration or haemorrhage. Future prospective trials on SRS as a first-line intervention for symptomatic low-grade dAVFs should be considered.

Abstract Photon-counting detector CT (PCD-CT) represents a significant advancement in medical imaging, particularly for musculoskeletal (MSK) applications. Its primary innovation lies in enhanced spatial resolution, which facilitates improved detection of small anatomical structures such as trabecular bone, osteophytes, and subchondral cysts. PCD-CT enables high-quality imaging with reduced radiation doses, making it especially beneficial for populations requiring frequent imaging, such as paediatric patients and individuals with multiple myeloma. Additionally, PCD-CT supports advanced applications like bone quality assessment, which correlates well with gold-standard tests, and can aid in diagnosing osteoporosis and assessing fracture risk. Techniques such as spectral shaping and virtual monoenergetic imaging further optimize the technology, minimizing artefacts and enhancing material decomposition. These capabilities extend to conditions like gout and haematologic malignancies, offering improved detection and assessment. The integration of artificial intelligence could enhance PCD-CT’s performance by reducing image noise and improving quantitative assessments. Ultimately, PCD-CT’s superior resolution, reduced dose protocols, and multi-energy imaging capabilities will likely have a transformative impact on MSK imaging, improving diagnostic accuracy, patient care, and clinical outcomes.

Objective: To establish comprehensive recommendations on the management of perihilar cholangiocarcinoma (pCCA) and to identify areas in need of future investigation. Summary Background Data: The lack of consensus in management of pCCA across institutions worldwide impairs optimal patient care and best-achievable oncological outcome. A holistic and critical assessment of the body of evidence and collaborative guidance are required. Methods: The Consensus4pCCA conference developed unbiased consensus using the Zurich-Danish model. An impartial and multidisciplinary jury adopted comprehensive recommendations grounded on the work of eight expert panels answering predefined clinical questions and considering the best-quality evidence through a systematic review. The development of recommendations complied with GRADE and SIGN50 methodologies. Results: Seventy-one international experts considered 570 studies. Ten jury members concluded 71 recommendations covering definition and diagnosis, preoperative assessment and optimization, surgical resection, liver transplantation, and outcome reporting for pCCA patients. The consensus underscored that making patients amenable to high-quality curative resection and reducing its associated morbidity must be of highest priority. As such, multidisciplinary expertise and centralized care at all stages of disease management are critical to ensure both safety and oncological adequacy. To overcome the evidence-gap for rare diseases like pCCA, the jury urged large-scale registries to address open questions across the disease continuum and highlighted priorities for future investigation. Conclusion: The Consensus4pCCA represents an unprecedented commitment to collectively harmonize global treatment strategies for pCCA. This collective effort bridges the gap between expert opinions and clinical evidence and holds great promise to improve patient outcomes in the future.