Contact X-ray Brachytherapy as a sole treatment in selected patients with early rectal cancer - Multi-centre study.

Background and purpose: Radical surgery is the standard of care for early rectal cancer. However, alternative organ-preserving approaches are attractive, especially in frail or elderly patients as these avoid surgical complications. We have assessed the efficacy of sole Contact X-ray Brachytherapy (CXB) treatment in stage-1 rectal cancer patients who were unsuitable for or declined surgery. Materials and methods: This retrospective multi-centre study (2009-2021) evaluated 76 patients with T1/2-N0-M0 rectal adenocarcinomas who were treated with CXB alone. Outcomes were assessed for the entire cohort and sub-groups based on the T-stage and the criteria for receiving CXB alone; Group A: patients who were fit enough for surgery but declined, Group B: patients who were high-risk for surgery and Group C: patients who had received prior pelvic radiation for a different cancer. Results: With a median follow-up of 26(IQR:12-49) months, initial clinical Complete Response (cCR) was 82(70-93)% with rates of local regrowth 18(8-29)%, 3-year actuarial local control (LC) 84(75-95)%, distant relapse 3 %, and no nodal relapse. 5-year disease-free survival (DFS) and overall survival (OS) were 66(48-78)% and 58(44-75)%. Lower OS was observed in Groups B [HR:2.54(95 %CI:1.17, 5.59), p = 0.02] and C [HR:2.75(95 %CI:1.15, 6.58), p = 0.03]. Previous pelvic radiation predicted lower cCR and OS. The main toxicity was G1-2 rectal bleeding (26 %) and symptoms of impaired anal sphincter function were not reported in any patients. Conclusion: CXB treatment alone achieved a high cCR rate with satisfactory LC and DFS. Inferior oncological outcomes were observed in patients who had received prior pelvic radiotherapy. CXB alone, with its favourable toxicity profile and avoidance of general anaesthesia and surgery risks, therefore, can be considered for patients who are unsuitable for or refuse surgery.

Complexity and Challenges of Cross-Cover Care in Graduate Medical Education: A Qualitative Study.

PURPOSE: Cross-cover care (care for hospitalized patients when the primary team is absent) is a common graduate medical education responsibility; however, it may lead to increased preventable adverse events. Despite understanding the difficulties of cross-cover care, medical educators lack comprehensive knowledge of specific challenges that residents face and how they handle these challenges. This study explores the challenges residents experience when providing cross-cover care. METHOD: The authors conducted 60 semistructured, qualitative interviews with 20 internal medicine and surgery residents at a single academic institution between October 2021 and April 2022. Each resident participated in 3 interviews, 2 immediately after a shift. Working inductively, the authors generated codes for important themes. Study design and data collection were guided by interpretive description, a qualitative approach for health care research focused on experiences and perceptions to develop meaningful findings. To illustrate residents' workflow and aid in quality improvement efforts, the authors created a process map. RESULTS: Seventeen cross-cover challenges were organized into 7 interrelated and overlapping themes: lack of baseline knowledge, inadequate or inaccurate information transfer from the primary team, unfamiliarity with cross-cover patients, high task volume leading to increased interruptions, ill-defined roles leading to unmet expectations from others, perceived decreased access to resources, and fatigue. The process map illustrates 4 cross-cover workflow components: information transfer from the primary team to the cross-cover team, direct handling of cross-cover tasks that are assigned by the primary team or that arise during the time of cross-cover, information transfer back to primary team and other care team members, and responsibilities that residents have overnight that are not directly related to cross-cover. CONCLUSIONS: Residents face substantial challenges when providing cross-cover care, which have important implications for patient safety and resident well-being. The medical community should strive to develop educational and structural interventions to improve this process.

When the first try fails: re-implementation of SIMPL in a general surgery residency.

BACKGROUND: Workplace-based assessment (WBA) can facilitate evaluation of operative performance; however, implementation of WBA is sometimes unsuccessful. The American Board of Surgery Entrustable Professional Activities WBA project was launched in July 2023. Some programs will face the challenge of re-implementation of a WBA following previous failures. It is unknown what interventions are most effective for WBA re-implementation. Our goal is to identify barriers and facilitators to re-implementing SIMPL, an operative performance WBA. METHODS: The System for Improving and Measuring Procedural Learning (SIMPL) was implemented at our residency in 2018, but usage rates were low. We interviewed residents and faculty to identify barriers to usage and opportunities for improvement. Residents reported that SIMPL usage declined because of several factors, including a low faculty response rate, while some faculty reported not responding because they were unable to login to the app and because usage was not mandated. We then re-implemented SIMPL using a plan based on Kotter's Model of Change. To evaluate impact, we analyzed rates of SIMPL usage when it was first implemented, as well as before and after the date of re-implementation. RESULTS: In September 2022, we re-implemented SIMPL at our program with measures addressing the identified barriers. We found that, in the six months after re-implementation, an average of 145.8 evaluations were submitted by residents per month, compared with 47 evaluations per month at the start of the original implementation and 5.8 evaluations per month just prior to re-implementation. Faculty completed 60.6% of evaluations and dictated feedback for 59.1% of these evaluations, compared with 69.1% at implementation (44% dictated) and 43% prior to re-implementation (53% dictated). CONCLUSIONS: After identifying barriers to implementation of a WBA, we re-implemented it with significantly higher usage by faculty and residents. Future opportunities exist to implement or re-implement assessment tools within general surgery programs. These opportunities may have a significant impact in the setting of national standardization of workplace-based assessment among general surgery residencies.

Lower hepatocellular carcinoma surveillance in metabolic dysfunction-associated steatotic liver disease: Impact on treatment eligibility.

BACKGROUND AND AIM: This study aimed to compare the determinants and impact of hepatocellular carcinoma (HCC) surveillance rates for people with metabolic dysfunction-associated steatotic liver disease (MASLD) versus other chronic liver diseases. METHODS: A dataset of HCC patients from a UK hospital (2007-2022) was analyzed. The Mann-Whitney U-test compared continuous variables. The χ2 and two-tailed Fisher exact tests compared categorical data. Regression modeling analyzed the impact of MASLD on the size and number of HCC nodules and curative treatment. The Cox proportional hazards model assessed the influence of MASLD on overall survival. RESULTS: A total of 176 of 687 (25.6%) HCC patients had MASLD. Fewer people with MASLD HCC were enrolled in HCC surveillance compared to non-MASLD HCC (38 [21.6%] vs 215 [42.1%], P < 0.001). Patients with MASLD HCC were less likely to have been under secondary care (n = 57 [32.4%] vs 259 [50.7%], P < 0.001) and less likely to have cirrhosis (n = 113 [64.2%] vs 417 [81.6%], P < 0.001). MASLD was associated with a 12.3-mm (95% confidence interval [CI] 10.8-14.0 mm) greater tumor diameter compared to people without MASLD (P = 0.002). Patients with MASLD HCC had 0.62 reduced odds (95% CI 0.43-0.91) of receiving curative treatment compared to non-MASLD HCC (P = 0.014). Overall survival was similar for patients with MASLD HCC versus non-MASLD HCC (hazard ratio 1.03, 95% CI 0.85-1.25, P = 0.748). CONCLUSION: Patients with MASLD are less likely to have been enrolled in HCC surveillance due to undiagnosed cirrhosis or presenting with non-cirrhotic HCC. Patients with MASLD HCC present with larger tumors and are less likely to receive curative treatment.

Pre-diagnostic plasma advanced glycation end-products and soluble receptor for advanced glycation end-products and mortality in colorectal cancer patients.

Advanced glycation end-products (AGEs), formed endogenously or obtained exogenously from diet, may contribute to chronic inflammation, intracellular signaling alterations, and pathogenesis of several chronic diseases including colorectal cancer (CRC). However, the role of AGEs in CRC survival is less known. The associations of pre-diagnostic circulating AGEs and their soluble receptor (sRAGE) with CRC-specific and overall mortality were estimated using multivariable-adjusted Cox proportional hazards regression among 1369 CRC cases in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Concentrations of major plasma AGEs, Nε-[carboxy-methyl]lysine (CML), Nε-[carboxy-ethyl]lysine (CEL) and Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), were measured using ultra-performance liquid chromatography mass-spectrometry. sRAGE was assessed by enzyme-linked immunosorbent assay. Over a mean follow-up period of 96 months, 693 deaths occurred of which 541 were due to CRC. Individual and combined AGEs were not statistically significantly associated with CRC-specific or overall mortality. However, there was a possible interaction by sex for CEL (Pinteraction = .05). Participants with higher sRAGE had a higher risk of dying from CRC (HRQ5vs.Q1 = 1.67, 95% CI: 1.21-2.30, Ptrend = .02) or any cause (HRQ5vs.Q1 = 1.38, 95% CI: 1.05-1.83, Ptrend = .09). These associations tended to be stronger among cases with diabetes (Pinteraction = .03) and pre-diabetes (Pinteraction <.01) before CRC diagnosis. Pre-diagnostic AGEs were not associated with CRC-specific and overall mortality in individuals with CRC. However, a positive association was observed for sRAGE. Our findings may stimulate further research on the role of AGEs and sRAGE in survival among cancer patients with special emphasis on potential effect modifications by sex and diabetes.

Kv1.3-induced hyperpolarization is required for efficient Kaposi's sarcoma-associated herpesvirus lytic replication.

Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus that is linked directly to the development of Kaposi's sarcoma. KSHV establishes a latent infection in B cells, which can be reactivated to initiate lytic replication, producing infectious virions. Using pharmacological and genetic silencing approaches, we showed that the voltage-gated K+ channel Kv1.3 in B cells enhanced KSHV lytic replication. The KSHV replication and transcription activator (RTA) protein increased the abundance of Kv1.3 and led to enhanced K+ channel activity and hyperpolarization of the B cell membrane. Enhanced Kv1.3 activity promoted intracellular Ca2+ influx, leading to the Ca2+-driven nuclear localization of KSHV RTA and host nuclear factor of activated T cells (NFAT) proteins and subsequently increased the expression of NFAT1 target genes. KSHV lytic replication and infectious virion production were inhibited by Kv1.3 blockers or silencing. These findings highlight Kv1.3 as a druggable host factor that is key to the successful completion of KSHV lytic replication.

Sequence of Contact X-ray Brachytherapy (CXB) and External Beam Radiation (EBRT) in organ-preserving treatment for small rectal cancer.

BACKGROUND AND PURPOSE: External Beam Radiotherapy (EBRT) followed by Contact X-ray Brachytherapy (CXB) and vice versa are viable alternatives to surgery for selected rectal cancer patients who have small tumours (≤3 cm). However, the optimal sequence of treatment needs to be established. We compared two approaches using Propensity Score (PS) matching and inverse probability treatment weighting (IPTW) analyses to investigate whether the sequence of treatment affected patient outcomes. MATERIALS AND METHODS: This retrospective analysis (2008-2019) included patients with rectal adenocarcinoma (cT1-3,N0-1,M0, grade 1-2, size ≤ 3 cm) who received both EBRT and CXB, irrespective of treatment sequence. PS matching and IPTW were conducted to balance covariate standardised mean differences between groups. Oncological outcomes and rate of post-treatment rectal bleeding were assessed. RESULTS: Following PS matching and IPTW analyses from 251 eligible patients; 103 starting with EBRT (median follow-up: 37 [IQR:18-56] months) and 148 with CXB (median follow-up: 32 [IQR:16-54] months, a significant improvement in 3-year overall survival (77% vs 85%, p = 0.02, [HR:0.58 (95% CI:0.37-0.91)]) and a higher risk of post-treatment rectal bleeding (grade 1 (26%) and grade 2 (6%)) were found in patients who started with CXB (p = 0.08). No significant differences were observed in local regrowth (18% vs 12%, p = 0.47), distant relapse (10% vs 6%, p = 0.53), 3-year organ preservation rates (70% vs 75%, p = 0.20, [HR:0.66 (95% CI: 0.35-1.26)]), or disease-free survival (78% vs 82%, p = 0.17, [HR: 0.47 (95% CI: 0.16-1.38)]) CONCLUSION: In patients with rectal cancer (≤3 cm), commencing with CXB rather than EBRT, was associated with improved overall survival, but had a higher risk of G1/2 rectal bleeding. No statistically significant differences were observed in other oncological outcomes.

Contact X-ray brachytherapy (CXB) as a salvage treatment for rectal cancer patients who developed local tumor re-growth after watch-and-wait approach.

Purpose: A watch-and-wait approach is an alternative to surgery for rectal cancer patients who have achieved a clinical complete response (cCR) following neoadjuvant (chemo)radiotherapy. However, approximately 25-38% of patients experience subsequent local tumor re-growth that requires salvage surgery. We evaluated the effectiveness of contact X-ray brachytherapy (CXB) as an alternative method of salvage therapy for those patients who were either unfit for or refused surgery. Oncological outcomes, tolerability, and feasibility of subsequent surgery for local treatment failure following CXB were reported. Material and methods: From 2009-2021, all patients treated with CXB as salvage therapy for local rectal cancer re-growth after watch-and-wait approach at our center were analyzed. Results: Contact X-ray brachytherapy as a salvage treatment (range, 90-110 Gy) was offered to 56 patients who experienced tumor re-growth following (chemo)radiation and watch-and-wait protocol. Median age was 76 (IQR = 66-83) years. Most patients (82%) had early-stage re-growth (ycT1/ycT2, ycN0), and 18% had more advanced stages (ycT3/ycT4, ycN0). After a median of 37-month follow-up (IQR = 19-53), 48% of patients who had early-stage re-growth achieved a sustained complete remission after CXB compared with 20% of those who had more advanced tumor stages. Disease-free and overall survivals for the whole cohort were 69% and 100% at 1-year, 51% and 82% at 3-year, and 51% and 65% at 5-years. CXB effectively controlled local re-growth-related symptoms. Mild post-CXB side effects occurred in 18% of cases. All (100%) eight patients who developed further local relapse, and 29% of those who had residual disease post-CXB salvage were successfully managed with subsequent surgery. Conclusions: Contact X-ray brachytherapy offers a new treatment option for patients in this situation whose other therapy options are not suitable for or refused initial surgery. Early local tumor re-growth responded best with minimal treatment-related toxicity and excellent symptom control. Disease-free and overall survival rates were acceptable, and delaying surgical salvage for local re-growth did not compromise patients' eventual long-term outcomes.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Letter: Estimating the baseline local recurrence rate for a brain metastasis after neurosurgical resection.

Brain metastases represent a growing healthcare challenge with a rising incidence attributed to earlier detection and improved systemic cancer treatments. We conducted a systematic review and meta-analysis to investigate the local recurrence rate following surgical resection of a brain metastasis without adjuvant therapy. The analysis included four studies with a total of 235 cases. It was found that the rate of local recurrence by 12-months was 48.1% (95% CI 41.2-58.9). These findings underscore the high rate of patients who will experience local recurrence within 12-months of surgery, emphasising the need for vigilant surveillance when omitting adjuvant radiotherapy in favour of systemic treatments with potential but unproven CNS penetrance. The analysis highlights unmet needs in this patient population.

Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetes.

BACKGROUND: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. METHODS: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. FINDINGS: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value <0.05). Mendelian randomization analyses indicated a causal relationship between predicted circulating furin and glycoprotein Nmb on breast cancer risk (odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.67-0.99, P-value = 0.03; and OR = 0.88, 95% CI = 0.78-0.99, P-value = 0.04 respectively), though these results were not supported in sensitivity analyses examining violations of MR assumptions. INTERPRETATION: Intentional weight loss among individuals with recently diagnosed diabetes may modify levels of cancer-related proteins in serum. Further evaluation of the proteins identified in this analysis could reveal molecular pathways that mediate the effect of adiposity and type 2 diabetes on cancer risk. FUNDING: The main sources of funding for this work were Diabetes UK, Cancer Research UK, World Cancer Research Fund, and Wellcome.

One-year Thyroglobulin Levels as a Predictive Measure for Recurrence and Need for Continued Surveillance in Treated Differentiated Thyroid Cancer.

PURPOSE: Patients with differentiated thyroid cancer (DTC) undergo posttreatment surveillance for several years. We aim to better define an excellent response to therapy using thyroglobulin (TG) and thyroglobulin antibody (TGab) levels at 1-year to tailor appropriate length of surveillance. METHODS: Patients with DTC who underwent surgical treatment with or without adjuvant radioiodine therapy were followed with standard American Thyroid Association surveillance. TG and TGab levels at 1-year posttreatment were used to define 3 cohorts: undetectable TG (<0.5 ng/mL), detectable TG (≥0.5 ng/mL), and positive TGab (>1 IU/mL). The rates of structural recurrence and the trends of TG and TGab were compared. RESULTS: Of the 268 study patients at 1-year, 210 (78%) had undetectable TG, 29 (11%) had detectable TG, and 29 (11%) had positive TGab. The overall structural recurrence rate was 18/268 (7%): undetectable TG at 1 year, 3/210 (1%), detectable TG at 1-year, 11/29 (38%), and positive TGab at 1-year, 4/29 (13%). At the last follow-up, 196/210 (93%) patients with undetectable TG at 1-year continued to have undetectable TG levels. Regarding patients with detectable TG at 1-year, in 11/29 (38%), detectable TG was converted to undetectable TG at the last follow-up without additional treatments. Of those with positive TGab at 1 year, 6/29 (21%) had resolution of TGab and undetectable TG levels at the last follow-up without additional treatments. CONCLUSION: One year after treatment of DTC, TG levels <0.5 ng/mL, in the absence of TGab, are associated with an exceedingly low risk of recurrence suggesting that further surveillance may not be warranted.

Programmed Death Ligand 1-Expressing Macrophages and Their Protective Role in the Joint During Arthritis.

OBJECTIVE: Arthritis associated with immune checkpoint inhibitor therapies highlights the importance of immune checkpoint expression for joint homeostasis. We investigated the role of programmed death ligand (PD-L) 1 in the synovium using a collagen-induced arthritis (CIA) mouse model. METHODS: We blocked PD-L1 using blocking antibodies during CIA and assessed the arthritis severity by clinical and histologic scoring. PD-L1 expression and the origin of synovial macrophages were investigated using flow cytometry and parabiosis. We used Cre-Lox mice to ascertain the protective role of PD-L1-expressing macrophages in arthritis. The immune profile of human and murine synovial PD-L1+ macrophages was determined by reverse transcriptase-polymerase chain reaction, flow cytometry, and single-cell RNA sequencing. RESULTS: Anti-PD-L1 antibody treatment during CIA worsened arthritis with increased immune cell infiltration compared with isotype control, supporting the regulatory role of PD-L1 in the joint. The main cells expressing PD-L1 in the synovium were macrophages. Using parabiosis, we showed that synovial PD-L1+ macrophages were both locally proliferating and partially replaced by the circulation. PD-L1+ macrophages had increased levels of MER proto-oncogene tyrosine kinase (MerTK) and interleukin (IL)-10 expression during acute CIA. Genetic depletion of PD-L1 on macrophages in LyzcrePD-L1fl/fl mice resulted in worsened CIA compared with controls. We found that human PD-L1+ macrophages in the synovium of healthy individuals and patients with rheumatoid arthritis express MerTK and IL-10. CONCLUSION: PD-L1+ macrophages with efferocytotic and anti-inflammatory characteristics protect the synovium from severe arthritis in the CIA mouse model. Tissue-protective, PD-L1-expressing macrophages are also present in the human synovium at homeostasis and during rheumatoid arthritis.

Exploring the potential of steel slag waste for carbon sequestration through mineral carbonation: A comparative study of blast-furnace slag and ladle slag.

Steel slag is a by-product of steelmaking which has emerged as a potential CO2 sequestration material due to its high reactivity and abundance. This research investigates the use of steel slag waste for the direct capture of carbon from air and its storage through mineral carbonation. Two abundant wastes, blast-furnace slag (BFS) and ladle slag (LS), were tested for their carbon sequestration potential, and the effects of operational parameters such as reaction time between CO2 and slag waste, temperature, liquid-solid ratio, and pressure on CO2 sequestration were determined. Quantitative and qualitative results reveal that much higher CO2 sequestration was achieved using LS compared to BFS after exposure to CO2 for 1 day at room temperature. By increasing the exposure time to four days, levels of CO2 sequestration increased gradually from 2.71% to 4.19% and 23.46%-28.21% for BFS and LS respectively. Increasing the temperature from 20 ± 2 °C to 90 ± 2 °C positively influenced CO2 sequestration in BFS, resulting in an enhancement from 3.45% to 13.21%. However, the impact on LS was insignificant, with sequestration levels rising from 27.72% to 29.90%. Moreover, better CO2 sequestration was observed for BFS than LS when the liquid-to-solid ratio increased from 3:1 to 4:1, whereupon the sequestration potential reached approximately 15% for BFS and 30% for LS at 90 ± 2 °C. Meanwhile, higher pressure reduced the sequestration potential of slag. The results of this study suggest that there is potential for scaling up the process to industrial applications and contributing to the reduction of CO2 emissions in the steelmaking industry.

Calciphylaxis in a patient with hypoparathyroidism and MEN-1 syndrome.

Summary: Calciphylaxis is a rare disorder characterised by the development of painful necrotic skin lesions. Occlusion of cutaneous arterioles due to ectopic calcification leads to potentially life-threatening widespread skin loss. Most cases occur in patients with chronic renal disease, which leads to dysregulation of calcium and phosphate homeostasis. Only a handful of case reports exist describing calciphylaxis occurring in patients without chronic renal disease but with hypoparathyroidism. We report on a unique case of a 53-year-old man with multiple endocrine neoplasia type 1 syndrome and acquired hypoparathyroidism due to total parathyroidectomy who went on to develop calciphylaxis following cardiac surgery. Learning points: Calciphylaxis most commonly occurs in the context of chronic renal disease but can rarely occur in its absence as a consequence of calcium and phosphate dysregulation. Patients who develop necrotic skin lesions in the presence of hypoparathyroidism require an urgent dermatological opinion. Mortality from calciphylaxis is high, with the majority of deaths occurring secondary to sepsis. Management of calciphylaxis requires a multidisciplinary team approach to manage wound healing, infections and pain. Recovery with full rehabilitation from calciphylaxis can take months to years.

Infections in children following chimeric antigen receptor T-cell therapy for B-cell acute lymphoblastic leukemia.

BACKGROUND: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is transforming care for pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). There are limited pediatric-specific data concerning the infection risks associated with CD19 CAR-T therapy and the adequacy of current antimicrobial prophylaxis guidelines for these patients. METHODS: We describe the antimicrobial prophylaxis used and the types of infectious occurring in the first 100 days following CAR-T therapy for relapsed or refractory B-cell ALL in children and adolescents (≤18 years) at our centre. RESULTS: Twenty-seven patients received their first CAR-T infusion (CTI) during the study period. Almost all patients (96%) had a comprehensive Infectious Diseases review prior to CTI, which informed a personalised prophylaxis or fever/sepsis plan in six (22%). Overall, six (22%) patients had one or more infections during the study period including five (19%, 0.9 per 100 days-at-risk) from days 0-30 and three (n = 20, 15%, 0.6 per 100 days-at-risk) from days 31-100. Bacterial blood stream infections were the most common type of infection encountered during both time periods, and one patient had probable pulmonary aspergillosis. There were no infection-related deaths. CONCLUSION: Our study contributes important information on the spectrum of infections encountered in pediatric patients with B-ALL post CAR-T therapy. Overall, the burden of infectious complications post CAR-T therapy in our cohort is lower than previously reported in the literature. Results suggest that our prophylaxis recommendations are effective in this population.

The predictive accuracy of cardiovascular risk prediction tools in inflammatory arthritis and psoriasis: an observational validation study using the Clinical Practice Research Datalink.

OBJECTIVES: Cardiovascular risk prediction tools developed for the general population often underperform for individuals with rheumatoid arthritis (RA), and their predictive accuracy are unclear for other inflammatory conditions that also have increased cardiovascular risk. We investigated performance of QRISK-3, Framingham Risk Score (FRS) and Reynolds Risk Score (RRS) in RA, psoriatic disease (psoriatic arthritis (PsA) and psoriasis) and ankylosing spondylitis (AS). We considered osteoarthritis as a non-inflammatory comparator. METHODS: We utilised primary care records from the Clinical Practice Research Datalink (CPRD) Aurum database to identify individuals with each condition and calculated 10-year cardiovascular risk using each prediction tool. Discrimination and calibration of each tool in each disease was assessed. RESULTS: Time-dependent AUC for QRISK3 was 0.752 for RA (95% CI 0.734-0.777), 0.794 for AS (95% CI 0.764-0.812), 0.764 for PsA (95% CI 0.741-0.791),0.815 for psoriasis (95% CI 0.789-0.835), and 0.698 for osteoarthritis (95% CI 0.670-0.717) indicating reasonably good predictive performance. AUC for FRS were similar, and slightly lower for RRS. FRS was reasonably well calibrated for each condition but underpredicted risk for patients with RA. RRS tended to underpredict CVD risk, whilst QRISK3 overpredicted CVD risk, especially for the most high-risk individuals. CONCLUSIONS: CVD risk for individuals with RA, AS and psoriatic disease were generally less accurately predicted using each of the 3 CVD risk prediction tools than reported accuracies in the original publications. Individuals with osteoarthritis also had less accurate predictions suggesting inflammation is not the sole reason for underperformance. Disease specific risk prediction tools may be required.

Evaluation of human papillomavirus DNA in colorectal cancer and adjacent mucosal tissue samples.

BACKGROUND: Although the role of viral agents, such as human papillomavirus (e.g. HPV16, HPV18) in colorectal cancer (CRC) has been previously investigated, results remain inconclusive. METHODS: To further evaluate the involvement of oncogenic HPV types in CRC, 40 frozen neoplastic and 40 adjacent colonic tissues collected from Italian patients were analyzed by Luminex-based assays that detect a broad spectrum of HPV types, i.e. Alpha (n = 21), Beta (n = 46) and Gamma HPVs (n = 52). In addition, 125 frozen CRC samples and 70 surrounding mucosal tissues were collected from Czech patients and analyzed by broad spectrum PCR protocols: (i) FAP59/64, (ii) FAPM1 and (iii) CUT combined with Next Generation Sequencing (NGS). RESULTS: Using Luminex-basedassays, DNA from HPV16 was detected in 5% (2/40) CRC tissues from Italian patients. One HPV16 DNA-positive CRC case was subsequently confirmed positive for E6*I mRNA. Cutaneous beta HPV types were detected in 10% (4/40) adjacent tissues only, namely HPV111 (n = 3) and HPV120 (n = 1), while gamma HPV168 (n = 1) and HPV199 (n = 1) types were detected in adjacent and in tumor tissues, respectively. The NGS analysis of the CRC Czech samples identified HPV sequences from mucosal alpha-3 (HPV89), alpha-7 (HPV18, 39, 68 and 70) and alpha-10 species (HPV11), as well as cutaneous beta-1 (HPV20, 24, 93, 98, 105,124) beta-2 (HPV23), beta-3 (HPV49) and gamma-1 species (HPV205). CONCLUSIONS: Our findings indicate that HPV types belonging to the mucosal alpha, and the 'cutaneous' beta and gamma genera can be detected in the colonic mucosal samples with a low prevalence rate and a low number of HPV reads by Luminex and NGS, respectively. However, additional studies are required to corroborate these findings.