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Replicative crisis is a senescence-independent process that acts as a final barrier against oncogenic transformation by eliminating pre-cancerous cells with disrupted cell cycle checkpoints 1 . It functions as a potent tumour suppressor and culminates in extensive cell death. Cells rarely evade elimination and evolve towards malignancy, but the mechanisms that underlie cell death in crisis are not well understood. Here we show that macroautophagy has a dominant role in the death of fibroblasts and epithelial cells during crisis. Activation of autophagy is critical for cell death, as its suppression promoted bypass of crisis, continued proliferation and accumulation of genome instability. Telomere dysfunction specifically triggers autophagy, implicating a telomere-driven autophagy pathway that is not induced by intrachromosomal breaks. Telomeric DNA damage generates cytosolic DNA species with fragile nuclear envelopes that undergo spontaneous disruption. The cytosolic chromatin fragments activate the cGAS–STING (cyclic GMP-AMP synthase–stimulator of interferon genes) pathway and engage the autophagy machinery. Our data suggest that autophagy is an integral component of the tumour suppressive crisis mechanism and that loss of autophagy function is required for the initiation of cancer. Cell death during replicative crisis involves autophagy induced by telomere dysfunction.

Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane’s tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as “low” due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.

The main characteristic of senescence is its stability which relies on the persistence of DNA damage. We show that unlike fibroblasts, senescent epithelial cells do not activate an ATM-or ATR-dependent DNA damage response (DDR), but accumulate oxidative-stress-induced DNA single-strand breaks (SSBs). These breaks remain unrepaired because of a decrease in PARP1 expression and activity. This leads to the formation of abnormally large and persistent XRCC1 foci that engage a signalling cascade involving the p38MAPK and leading to p16 upregulation and cell cycle arrest. Importantly, the default in SSB repair also leads to the emergence of post-senescent transformed and mutated precancerous cells. In human-aged skin, XRCC1 foci accumulate in the epidermal cells in correlation with a decline of PARP1, whereas DDR foci accumulate mainly in dermal fibroblasts. These findings point SSBs as a DNA damage encountered by epithelial cells with aging which could fuel the very first steps of carcinogenesis. It is recognized that cellular senescence is triggered by DNA damage as a protective mechanism against tumorigenesis. Here the authors show that DNA single-strand breaks of oxidative origin can induce a transient senescent state followed by the emergence of clonal transformed cells.

Telomeres pose challenges during replication, with converging forks unlikely to resolve issues. Depleting TRF1 results in fragile telomeres, yet its exact role in telomere replication remains unclear. In our cellular model, insufficient TRF1 density at long telomeres leads to telomere fragility that is alleviated by restoring telomeric TRF1 levels. Our findings indicate that TRF1 mitigates lagging strand telomere fragility through fork reversal in a process involving telomerase activity, rather than merely alleviating fork barriers. Additionally, TFIIH, a crucial partner of TRF1, aids in restarting replication on the leading strand after fork reversal. When fork reversal is compromised, PrimPol-mediated repriming rescues fragility at leading strand telomeres, revealing a new role for this enzyme in human telomere replication. Lastly, our findings indicate that the TRF1-mediated decrease in telomere fragility is dependent on RNA:DNA hybrids, likely facilitating fork restart. Telomere replication poses unique challenges. Here, the authors show that TRF1 prevents telomere fragility by promoting replication fork reversal, a process dependent on RNA:DNA hybrids and necessary for TFIIH-mediated restart of leading strand synthesis. When fork reversal is impaired, PrimPol serves as a compensatory mechanism.

Introduction Accurate grading at the time of diagnosis is fundamental to risk stratification and treatment decision making, particularly for men being considered for Active Surveillance (AS). With the introduction of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) there has been considerable improvement in sensitivity and specificity for the detection and staging of clinically significant prostate cancer. Our study aims to determine the role of PSMA PET/CT in men with newly diagnosed low or favourable intermediate risk prostate cancer to better select men for AS. Method This is a retrospective single centre study performed from January 2019 and October 2022. This study includes men identified from electronic medical record system who had undergone a PSMA PET/CT following newly diagnosed low or favourable-intermediate risk prostate cancer. Primary outcome was to assess the change in management for men being considered for AS following PSMA PET/CT results on the basis of PSMA PET characteristics. Results In total, there were 11 of 30 men (36.67%) who were assigned management by AS and 19 of 30 men (63.33%) who had definitive treatment. 15 of the 19 men that needed treatment had concerning features on PSMA PET/CT results. Of the 15 men with concerning features on PSMA PET, 9 (60%) men were found to have adverse pathological features on final prostatectomy features. Conclusion This retrospective study suggests that PSMA PET/CT has potential to influence the management of men with newly diagnosed prostate cancer that would otherwise be appropriate for active surveillance.

A 66-year-old Australian male farmer was referred for management of an asymptomatic, rapidly expanding, anterior abdominal wall mass. It was firm and well circumscribed. There were no overlying skin changes, constitutional symptoms or weight loss. His medical history included small bowel obstruction and resection from a Meckel’s diverticulitis and a 40-pack-year smoking history. Core biopsy was suggestive of a neuroendocrine tumour and Gallium-68-Dodecane-Tetraacetic-Acid (68GaTate) positron emission tomography revealed an avid solitary lesion confined to the subcutaneous space in the left anterior abdominal wall. Wide local excision was performed, and histopathology revealed Merkel cell carcinoma (MCC). Although classically regarded as a primary cutaneous neuroendocrine tumour, MCC may originate from the subcutaneous fat without obvious skin involvement. Older patients with asymptomatic, rapidly enlarging lesions, particularly if immunosuppressed, with significant ultraviolet sunlight exposure, should raise a high index of suspicion for MCC. Like melanoma, non-metastatic MCC should be treated aggressively for best prognosis.

A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1–40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient’s treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.

A 63-year-old woman with multiple endocrine neoplasia type 2A (MEN2A) presented with recurrent spells of headaches, sweats and palpitations decades after right adrenalectomy for phaeochromocytoma, and total thyroidectomy for medullary thyroid cancer. She was hypertensive and in sinus rhythm. DOTA-TATE positron-emission tomography (PET) demonstrated a 12mm enhancing left adrenal incidentaloma. 24 hours urine catecholamines, and multiple plasma metanephrine and normetanephrine measurements were all within normal reference ranges. Based on her symptoms and imaging findings, left adrenalectomy was performed and found a 40 mm phaeochromocytoma. Her symptoms have since completely resolved and plasma metanephrine is now undetectable MEN2-associated phaeochromocytomas are often bilateral and may be metachronous. Patients at high risk of phaeochromocytoma who develop symptoms of catecholamine excess should be carefully evaluated even if plasma or urinary metanephrines are within the normal reference range. Biochemical reference ranges for metanephrines need to be adjusted accordingly in patients who have had prior unilateral total adrenalectomy.

Background: The maximum standardised uptake value (SUVmax) can potentially be affected by the uptake period during PSMA PET imaging. The optimal image acquisition period for 2-(3-1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl-ureido)-pentanedioic acid (18F-DCFPyL)PSMA PET/CT is yet to be established. This study aims to evaluate the effect of the uptake period on the SUVmax in diagnosing localised, clinically significant prostate cancer using 18F-DCFPyL-PSMA PET/CT. Methods: Sixty biopsy-naive men with one or more PI-RADS 4 or 5 lesions of at least 10 mm on multiparametric MRI (mpMRI) were enrolled to undergo 18F-DCFPyL-PSMA PET/CT. SUVmax was prospectively measured following an uptake period of 60, 90 and 120 min post injection of 18F-DCFPyL-PSMA radiotracer. Concordance with biopsy results or final histopathology was recorded. Results: Mean absolute differences in SUVmax at 60 vs. 90, 60 vs. 120, and 90 vs. 120 min uptake periods were 3.23 (SD 4.76), 4.53 (SD 7.33), and 3.24 (SD 4.56), respectively. This represents a statistically significant systematic increase in SUVmax (p-value < 0.001) with increasing uptake period. The interval between the uptake period of 60 vs. 120 min represented the largest SUVmax change of 29.98%. Conclusions: The SUVmax is a dynamic variable significantly affected by uptake period. Our study supports image acquisition at 120 min following injection of 18F-DCFPyL radiotracer. Further studies are needed to determine if this acquisition period can be applied to other Fluorine-18 based PSMA radiotracers.

Knotted ureteric stents remain a rare complication, with only 34 cases reported to date. They require prompt recognition and skilful management to avoid ureteric injury. Knots more often occur at the proximal end of stents, have a male preponderance, are associated with multi-length stents and relate to the J-coil configuration, which is affected by the renal pelvis anatomy, hydroureter and presence of urolithiasis. We present our experience of a knotted stent managed using holmium:yttrium aluminium garnet laser and traction. We also provide an updated literature review and recommend a treatment algorithm for this rare but important complication.