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Background:VEXAS is a hemato-inflammatory syndrome that occurs in older males with an acquired somatic mutation in the UBA1 gene in myeloid lineage cells [1]. The most common variant is usually p.M41T, while p.M41V and p.M41L are less prevalent [1,2]. Several reports have found evidence for a genotype-phenotype interaction pointing to a worse prognosis in p.M41V pathogenic variant carriers [2,3].Objectives:To characterize the epidemiology of VEXAS in Israel.Methods:This is a descriptive cross-sectional multicenter national study done in January 2024 in Israel. We gathered the results of UBA1 gene testing for the diagnosis of VEXAS from genetic centers performing this test in Israel. We reached out to the medical centers treating VEXAS patients and collected anonymized data including demographic and clinical data, laboratory tests, treatments, and response to therapy. Categorical variables are presented as number (percent) and continuous variables are presented as mean±standard deviation and (range).Results:Altogether 24 VEXAS patients were included, with a mean follow-up time from diagnosis of 1.8±1 (0-4) years. All patients were Jewish and male, age at diagnosis was 76.0±6.8 (56-88) years. Disease duration at the time of diagnosis was 1.5±1.5 years. The most prevalent pathogenic variant was the p.M41V (n=10, 42%) (Figure 2). Of 10 patients carrying the p.M41V mutation, 3 died (30%), as well as a 4th patient with a splice-site mutation. Time from 1st symptom to death was 1-3 years for the patients with p.M41V and 5 years for the splice-site patient. The mortality rate in the Israeli cohort was 16.7%. Myelodysplastic syndrome was concomitantly diagnosed in 10 patients (5 with p.M41T, 4 p.M41V, 1 p.M41L), and 2 additional patients had inconclusive bone marrow biopsies (p.M41V and Splice). Clinical manifestations (n=23) included constitutional symptoms (n=21, 91.3%), rashes (n=16, 69.6%), chondritis (n=6, 26.1% in 3 p.M41T, 2 splice, 1 p.M41V), inflammatory eye disease (n=6, 26.1%, including 2 patients with dacryoadenitis), thromboembolism (n=7, 30.4%, including one dying of cerebral sinus vein thrombosis, see abstract CR.517, and another with a mesenteric event). Special manifestations of interest included 7 patients with pitting edema of hands or lower limbs and 2 patients who had parotitis, symptoms which have not been previousy described VEXAS; and a patient who had pathologic evidence for renal and gastrointestinal amyloidosis. All patients were treated with prednisone (8 (34.7%) received it as a sole treatment). The maximal daily dose was 52.0±22.5 mg (15-80), and the current dose was 19.4±21.3 mg (0-80). Additional therapies included: tocilizumab (TOC), in 7 patients, (1 deceased); canakinumab in another deceased patient; azacitidine in 3 patients; ruxolitinib in 1 patient, who experienced severe cutaneous injection site reaction to subcutaneous TOC and an anaphylactic reaction to a TOC infusion. Eight patients were treated with anakinra prior to VEXAS diagnosis, and at least 5 of them had severe cutaneous injection site reactions. One patient was treated with anakinra after diagnosis, but had a flare of his Sweet-like rash and was switched to TOC. This patient had a severe cutaneous injection site reaction to a BNT162b2 vaccine. Other treatments used before and after diagnosis included sarilumab, infliximab, canakinumab, colchicine, hydroxychloroquine, methotrexate, azathioprine, leflunomide, mycophenolate, dapsone and cyclosporine. Overall, response to current therapies was partial – both in lab tests and clinically (Table 1).Conclusion:The genetic milieu of the Israeli population may differ from other western countries. In this cross-sectional national study, we found that the UBA1 p.M41V pathogenic variant, which carries a worse prognosis, was more prevalent in Israeli Jewish patients than is reported from other cohorts around the world. This may explain the low rate of chondritis in our cohort.REFERENCES:[1] Beck DB, et al.. NEJM. 2020;383:2628–38.[2] Georgin-Lavialle S, et al.. BJD. doi: 10.1111/bjd.20805[3] Ferrada MA, et al. Blood. 2022;140:1496–506.Acknowledgements:We would like to thank Michal Rosenzwaig, MA, the Genetic Institute, Tel Aviv Sourasky Medical Center and Haike Reznik Wolf, PhD, The Danek Gertner Institute of human genetics, Sheba Medical Center for their contribution.Disclosure of Interests:Tali Eviatar GSK, Abbvie, AstraZeneca, Abbvie, AstraZeneca, Michael Zisapel: None declared, Neta Feinstein Goren: None declared, Iftach Sagy: None declared, Shaye Kivity: None declared, Merav Lidar: None declared, Amir Bieber: None declared, Oshrat Tayer-Shifman: None declared, Hagit Peleg: None declared, David Ozeri: None declared, Jana Shamash: None declared, Elon Pras: None declared, Hagit Baris-Feldman: None declared, Yonatan Edel: None declared, Ariela Dortort Lazar: None declared, Ofir Wolach: None declared, Yair Molad: None declared, Galia Stremer: None declared, Mohammad E. Naffa: None declared, Tzika Porges: None declared, Ori Elkayam: None declared.

Background: The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS). Methods: From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan–Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance. Results: At study entry, the median age was 76 years (inter-quartile range: 70–80 years), the median PSA was 79 ng ml −1 , and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different ( P =0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups ( P >0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) ( P =0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) ( P <0.001). Multivariable analysis showed that patients with previous haemoglobin ⩾11 g dl −1 decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25–0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno–thromboembolic events was 22% ( n =28) in DAiS and 11% ( n =14) in the DA arm ( P =0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS ( P =0.001). Conclusion: Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.

The objective of the study is to define selection parameters for RRPLND and evaluate the outcomes from cases selected via this method. Patients undergoing RRPLND from 2017 to 2023 ( n  = 57) were included. Initial criteria for robotic case selection were defined via ‘B-SAFE’ parameters. Safety was assessed via complication rate and oncological outcome. Analysis of both robotic and open RPLND outcomes including data from across the Anglican Germ Cell Cancer Collaborative Group was done. Mean lesion size was 30 mm (9–72). No cases required open conversion. Positive margin rate was 5.2%. Median length of stay (LOS) was 2 days (1–5). Overall complication rate was 15.7%. One patient required radiological intervention via embolization for a post-operative bleed. No in-field recurrences was observed at a median follow-up of 25 months (1–81). Analysis of parallel open RPLND cohort ( n  = 57) showed some differences in LOS (2 vs 6 [ p  =  < 0.05]) and bloods loss (130 vs 865 [ p  =  < 0.05]) likely explained by case complexity. Nodal yield higher in RRPLND (23 vs 10 [ p  =  < 0.05]). No significant difference in operation time (4.5 vs 4.6 [ p  = 0.5]), positive margins (5.2 vs 15.8% [ p  = 0.06]) or complication rates (15.7 vs 17% [ p  = 0.85]). This series proposed six parameters that can be used to appropriately select cases for RRPLND which we have defined using the ‘B-SAFE’ system. Our results using this framework are encouraging, with no instances of open conversion, excellent short-term oncological outcomes and no compromise of peri-operative morbidity with a short LOS. We also demonstrate an evolution in our practice towards more complex cases suggesting that as unit experience grows, initial selection criteria can be expanded to tackle more complex lesions.

Background: We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability. Methods: Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP. Results: Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72–1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1–6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64–100%). Conclusion: Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.

There is no consensus as to the management of untreated poor prognosis or relapsed/refractory germ cell tumours. We have studied an intensive cisplatin-based regimen that incorporates high-dose methotrexate (HD MTX) and actinomycin-D and etoposide every 14 days (GAMEC). Sixty-two patients were enrolled in a phase 2 study including 27 who were untreated (IGCCCG, poor prognosis) and 35 with progression despite conventional platinum based chemotherapy. The pharmacokinetics of the drugs were correlated with standard outcome measures. Twenty of the untreated patients were progression free following GAMEC and appropriate surgery, as were 18 individuals in the pretreated group. None of the established prognostic factors for therapy for pretreated patients could identify a poor-prognosis group. Five out of nine late relapses to prior chemotherapy were progression free following GAMEC and appropriate surgery. All patients had at least one episode of febrile neutropenia and there were five (8%) treatment-related deaths. PK values were not predictive of efficacy or toxicity, although the dose intensity in the pretreated group of patients, especially of HD MTX, was significantly correlated with progression-free survival (PFS). GAMEC is a novel intensive regimen for this group of patients producing encouraging responses, although with significant toxicity. For those in whom it fails, further therapy is still possible with durable responses being seen.

When chemotherapy is used in androgen-independent prostate cancer (AIPC), androgen deprivation is continued despite its failure. In this study, we investigated whether it was possible to re-induce hormone sensitivity in previously castrate patients by stopping endocrine therapy during chemotherapy. A phase II prospective study investigated the effects of reintroduction of endocrine therapy after oral chemotherapy in 56 patients with AIPC, which was given without concurrent androgen deprivation. After chemotherapy, patients were given maximum androgen blockade until failure when treatment was switched to diethylstilbestrol and dexamethasone. Patients had already received these endocrine treatments in the same sequence before chemotherapy. All patients were castrate at the start of chemotherapy. Forty-three subsequently restarted endocrine therapy after the completion of chemotherapy. The median overall survival for these 43 patients from the time of restarting endocrine therapy was 7.7 months (95% confidence interval (CI): 3.7–10.9 months). Sixteen (37%) patients had a 50% PSA response to treatment, which was associated with improved overall survival (14.0 months vs 3.7 months P =0.003). Eight out of 12 patients who did not respond to diethylstilbestrol before chemotherapy did so post chemotherapy. Re-induction of hormone sensitivity can occur after chemotherapy in AIPC.

Malignant testicular germ cell tumours in the elderly are extremely rare with anecdotal accounts of their aggressive behaviour. Fifty cases of germ cell tumour, diagnosed at the age of 60 years or above, were pathologically reviewed. The oldest patient was 86 years of age, with 78% of cases presenting in men in their 60s. Forty-one (82%) of the tumours were seminomas with only nine cases (18%) of mixed or non-seminomatous germ cell tumour. However, all non-seminomatous types of tumour were represented in the series. The macroscopic tumour size was significantly larger (median=6 cm, range=2–11 cm) than comparable series in younger men. They were also of higher stage with more frequent vascular invasion and rete testis invasion than is typically seen in a younger population. The tumours were less associated with intratubular germ cell neoplasia than in younger men as it was present in only 47% of assessable cases. We conclude that germ cell tumours, in man aged 60 years or above, present at a later stage than in younger men, and although most are seminomas, non-seminomatous tumours may occur with a wide spectrum of morphology.

Summary Most patients with testis cancer are cured with treatment. However, the incidence of osteoporosis after prolonged follow-up is unknown. This study investigates the incidence of osteoporosis in 39 testis cancer patients with follow-up from 5 to 28 years. There was no increased incidence of osteoporosis. These initial data are reassuring but require further investigation. Introduction The majority of patients with testis cancer are cured with either a unilateral orchidectomy alone or orchidectomy and chemotherapy. However, the long-term incidence of osteoporosis following treatment for testicular cancer has not been established. Method This was a single-centre cross-sectional study, where bone mineral density (BMD) measurements were performed in male patients who were previously treated for testicular cancer. BMD measurements were made by dual-energy X-ray scanning (DXA) using a HOLOGIC imaging bone densitometer. The World Health Organisation criteria were used to define osteoporosis and osteopenia. Blood samples were taken from each patient at the time of the DXA scan. Statistical analyses were performed in STATA10. Results Neither orchidectomy alone nor orchidectomy and chemotherapy together predisposed to osteoporosis [p value = 0.4 (95%CI -0.1-0.8) and p value = 0.2 (95%CI -0.2-0.7), respectively]. Analysis also showed no evidence of an association between cases of osteopenia and length of follow-up (assessed by logistic regression). Conclusion This work found no association between treatment for testis cancer and the development of osteoporosis. Screening the whole population of testis cancer survivors for osteoporosis in the long term is not necessary; however, targeting specific patients with risk factors may be warranted.

The management of androgen independent prostate cancer is increasingly disputed. Diethylstilbestrol and steroids have useful second-line activity in its management. The value of chemotherapy still remains contentious. This paper reports a phase 2 study of two orally active chemotherapy drugs in patients who are absolutely hormone refractory having failed primary androgen blockade and combined oestrogens and corticosteroids. In total, 37 patients who were biochemically castrate with absolute hormone refractory prostate cancer and performance status of 0–3 were enrolled. Therapy consisted of chlorambucil 1 mg kg −1 given as 6 mg a day until the total dose was reached and lomustine 2 mg kg −1 given every 56 days (CL56). During this time all hormone therapy was stopped. One patient normalised his PSA with a further two having a greater than 50% decline leading to an objective response rate of 10%. The median time to progression was 3.6 months with an overall survival of 7.1 months. The median survival of this group of patients from first becoming androgen independent was 23.5 months. Eight of 17 (47%) patients who were subsequently re-challenged with hormonal therapy following failure of chemotherapy had a further PSA reduction, three (17%) of which were >50%. The median progression-free interval for the eight patients was 4 months. In conclusion, CL56 has a low objective response rate in the management of absolute hormone refractory prostate cancer. Toxicity was mild. Re-induction of hormone sensitivity following failure of chemotherapy was an unexpected finding that requires further study.