Introduction
Epstein‐Barr virus (EBV) is a herpesvirus linked to pre‐malignant lymphoproliferative diseases and up to nine distinct human tumors. The most frequent EBV‐associated malignancies are ...lymphomas and nasopharyngeal carcinoma. By promoting smooth muscle proliferation, EBV can induce EBV‐associated smooth muscle tumors (SMT) which remain a very rare oncological entity. This study reports one case report of SMT and aims to offer the largest review of literature on post‐transplantation‐SMT (PT‐SMT) in kidney transplant recipients, with a focus on therapeutic management and evolution of graft function.
Methods
Case reports and case series of PT‐SMT in kidney transplant recipients were collected from 1996 to 2019.
Results
A total of 59 PT‐SMT were evaluated. The median time at diagnosis was 74.6 months after kidney transplantation. The most frequent localizations were liver and lung. EBV seroconversion was notified in all six patients with previously negative status. Preferred therapeutic option was surgery (65.9%), associated with a reduction in immunosuppression (77.2%), which includes switch to mTOR inhibitors (29.5%), and discontinuation of MMF (32%). In our review, 13% of patients experienced rejection, 8.7% lost their graft and went back on hemodialysis; 8.8% of patients died of PT‐SMT.
Conclusion
PT‐SMT is a rare but serious condition in kidney transplant recipients. EBV seroconversion following transplantation appears as a risk factor in developing PT‐SMT in solid‐organ recipients. In the absence of guidelines, therapeutic management for PT‐SMT is challenging and exposes the patient to high risk of graft loss.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
After failure of first line FOLFOX‐bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second‐line FOLFIRI increases survival compared to FOLFIRI alone. ...In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI‐aflibercept or FOLFIRI‐bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression‐free survival (PFS), disease control rate (DCR: CR + PR + SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2 years and 45.2% of patients were men. Most patients had RAS‐mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2 months, median OS was 13.0 months (95% CI: 11.3‐14.7) and 10.4 months (95% CI: 8.8‐11.4) in the bevacizumab and aflibercept groups, respectively (P < .0001). Median PFS was 6.0 months (95% CI: 5.4‐6.5) and 5.1 months (95% CI: 4.3‐5.6) (P < .0001). After adjustment on age, PS, PFS of first line, primary tumor resection, metastasis location and RAS/BRAF status, bevacizumab was still associated with better OS (HR: 0.71, 95% CI: 0.59‐0.86, P = .0003). FOLFIRI‐bevacizumab combination was associated with longer OS and PFS, and a better tolerability, as compared to FOLFIRI‐aflibercept after progression on FOLFOX‐bevacizumab.
What's new?
Second‐line treatment with chemotherapy plus an antiangiogenic agent such as bevacizumab or aflibercept is associated with improved survival among patients with metastatic colorectal cancer (mCRC) who failed first‐line therapy. Here, the efficacy of FOLFIRI plus bevacizumab or aflibercept was investigated in a retrospective, real‐world study in French mCRC patients. Compared to patients who received FOLFIRI plus aflibercept, those who received FOLFIRI plus bevacizumab had significantly improved overall and progression‐free survivals. FOLFIRI plus bevacizumab was also associated with superior tolerability. The findings warrant further investigation to determine whether FOLFIRI plus bevacizumab should be the second‐line therapy of choice for mCRC.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Chemotherapy (three cycles of bleomycin + etoposide + cisplatin or four of etoposide + cisplatin) cures the vast majority of stage II seminomas. Retroperitoneal lymph node dissection (RPLND) is safe ...in early-stage seminoma, but the risk of relapse is not negligible. Long-term chemotherapy side effects are a reality but may be reduced using de-escalation strategies such as in the SEMITEP trial design, motivated by growing interest in survivorship. RPLND may be an option for well-informed select patients who understand that it may be associated with a higher rate of relapse than with cisplatin-based chemotherapy. In any case, local and systemic treatment should not be performed outside high-volume centers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients ...enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.
According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses.
Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1;
= 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5;
< 0.001) and a reduction of 1-year overall survival rate (OR = 7.0;
= 0.02).
This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA.
.
Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with ...estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency.
ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels (D15/baseline and D30/baseline) were then correlated with prospectively registered patient characteristics and outcomes.
Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (N
= 21, N
= 2, N
= 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a D30/baseline ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested.
Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.
Checkpoints inhibitors anti-programmed death 1 (PD1) and anti-programmed death ligand 1 (PD-L1) restore immunity against tumour. By their mechanism of action, they could induce immune-related adverse ...events (irAEs) that can theoretically involve all organs. These irAEs, especially those that are rare, remain incompletely described. Immune-related eosinophilia has been described with ipilimumab and was interestingly associated with favourable response to immunotherapy. We report here the first series of patients who experienced immune-related eosinophilia due to anti-PDI or anti-PD-L1 antibodies. Immune-related eosinophilia is a new biological immune-related adverse effect with anti-PD-1 or anti-PD-Ll. To the best of our knowledge, we report here the first case series of immune-related eosinophilia with anti-PDl or anti-PD-Ll. Importantly, we show that kinetics of leukocyte changes was restricted to the eosinophil lineage. This immune-related eosinophilia was rare (estimated frequency of 2.9%), began at 3.0 months with a peak achieved at 6.4 months. Patients with immune-related eosinophilia remain asymptomatic. Larger prospective studies are required to search for a link with favourable anti-tumour response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Ultrasound imaging of the testis represents the standard-of-care initial imaging for the diagnosis of TGCT, whereas computed tomography (CT) plays an integral role in the initial accurate disease ...staging (organ-confined, regional lymph nodes, or sites of distant metastases), in monitoring the response to therapy in patients who initially present with non-confined disease, in planning surgical approaches for residual masses, in conducting follow-up surveillance and in determining the extent of recurrence in patients who relapse after treatment completion. CT imaging has also an important place in diagnosing complications of treatments. The aims of this article are to review these different roles of CT in primary TGCT and focus on different pitfalls that radiologists need to be aware of.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
5060 Background: ODM-209 is a novel, oral selective inhibitor of CYP11A1, that blocks production of all steroid hormones and precursors that may activate hormone receptor (e.g. androgen or estrogen) ...signaling pathways. It’s mode of action is similar to ODM-208/MK-5684 currently in phase 3 clinical development in patients with metastatic castration resistant prostate cancer (mCRPC). We report the results of the first-in-man phase I STESIDES study (NCT03878823). Methods: STESIDES was a dose finding Phase 1 trial with a 3+3 design in patients with progressive mCRPC who had previously received ≥1 line of AR signalling inhibitor and ≥1 line of taxane-based chemotherapy. Four patients with ER-positive/HER2 negative (ER+/HER2-) breast cancer (BC) were also enrolled. ODM-209 was administered once or twice daily with glucocorticoid and mineralocorticoid replacement therapy and androgen deprivation therapy (in men with mCRPC). Endpoints included dose-limiting toxicities (DLTs), adverse events (AE’s), pharmacokinetics, pharmacodynamics, PSA and RECIST response, and exploratory molecular profiling. Patients with and without androgen receptor ligand-binding domain ( AR-LBD) activating mutations were included. Results: 38 patients (median age 67 yrs.) received ODM-209 in doses ranging from 10 to 20 mg/day. Of 34 patients with mCRPC, 18 (53%) had previously received both abiraterone and enzalutamide, and 18 (53%) patients both docetaxel and cabazitaxel; 19 patients (56%) had activating AR-LBD mutations detected at baseline. All 4 BC patients had ESR1 mutations. Steroid hormone concentrations were mostly undetectable on treatment as expected. Patients generally tolerated the treatment well. The most commonly reported AE’s were fatigue (53%) and peripheral oedema (34%). Adrenal insufficiency was recorded in 4 patients (11%), of which 2 were considered serious, 1 case being a DLT in a patient with BC at 15 mg/day. Hyponatremia (21%) and hyperkalemia (16%) were also common and used as an indication to increase corticosteroid replacement dose. In patients with mCRPC serum testosterone was undetectable (limit of detection 0.2 ng/dL) in almost all patients in all dose groups at Day 8 and remained so at 16 weeks. 10 (29%) patients with mCRPC achieved a PSA decline of ≥50%, being 9/19 (47%) and 1/15 (7%) in patients with and without AR-LBD mutations respectively. 3/11 (27%) evaluable patients with mCRPC achieved a partial response by RECIST (1 in an AR-LBD wild-type patient). No responses were seen in patients with BC. The median duration of treatment was 4.8 and 3.7 months in mCRPC patients with and without activating AR-LBD mutations. Conclusions: Phase 1 results of ODM-209 suggest activity in heavily pre-treated patients with mCRPC particularly in those with activating AR-LBD mutations, with expected on-target AE’s. Similar findings were recently reported with ODM-208/MK-5684 (NEJM Evidence 2023). Clinical trial information: NCT03878823 .
Up to 25% of patients with metastatic prostate cancer present with germline or somatic DNA damage repair alterations, some of which are associated with aggressive disease and poor outcomes. New data ...have brought poly(ADP-ribose) polymerase (PARP) inhibitors into sharp focus in the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Olaparib improved survival after at least one new hormonal therapy (NHT) in a cohort of patients harboring
BRCA1
,
BRCA2
or
ATM
mutations in the PROfound trial, while rucaparib, talazoparib and niraparib demonstrated compelling activity in phase II trials. While patients with prostate cancer and
BRCA1
or
BRCA2
mutations may derive greatest benefit of PARP inhibition, the magnitude of benefit seems much lower in the context of most other homologous recombination gene mutations. Several PARP inhibitors are currently developed in combination with conventional therapy, including chemotherapy, NHT, and alpha-particle emitters, at different disease stages. Herein, we review the rationale for PARP inhibition in patients with prostate cancer, discuss the impact of PARP inhibitors on outcomes, and explore underlying challenges for future developments.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
TPS5109 Background: Progression to metastatic castration-resistant prostate cancer (mCRPC) occurs in most patients treated with androgen receptor signaling inhibitors (ARSi) for advanced disease. ...Preclinical studies demonstrate that AR and PI3K - AKT - mTOR (PAM) pathways interact through reciprocal negative feedback, whereby inhibition of one pathway activates the other. Thus, combining a PAM inhibitor with an ARSi may deliver improved anti-cancer activity in patients with mCRPC. A Phase 2 trial in 129 patients with mCRPC who progressed on abiraterone demonstrated improved median radiographic progression-free survival (rPFS) when samotolisib, a dual PI3K-mTOR inhibitor, was added to enzalutamide. These results form the basis for this clinical trial of gedatolisib, a potent PAM inhibitor, in combination with darolutamide in men with mCRPC who have previously progressed on ARSi. Methods: This open-label, multicenter, Phase 1/2 study will evaluate the safety and efficacy of gedatolisib in combination with darolutamide in men with mCRPC who have progressed on ARSi. In Phase 1, 36 patients will be randomized to one of two dose arms to evaluate dose limiting toxicities (DLTs) and determine the recommended Phase 2 dose (RP2D). Gedatolisib will be administered once weekly for 3-weeks-on/1-week-off: Arm 1 – 120 mg and Arm 2 – 180 mg, with darolutamide 600 mg orally administered twice daily. Arm 2 may be dose de-escalated depending on the number of DLTs observed. In Phase 2, 12 additional patients will be enrolled at the RP2D (n= 30). Key inclusion criteria include adult males (≥ 18 years) with mCRPC who have progressed on or after treatment with one next-generation ARSi. Key exclusion criteria include males with adenocarcinoma with a small cell component and with ≥10% neuroendocrine type cells; prior treatment with PI3K, AKT, or mTOR inhibitor; prior chemotherapy or radiopharmaceutical therapy for mCRPC; uncontrolled type 1/2 diabetes; or active brain or leptomeningeal metastases. Primary endpoints for Phase 1 are safety and tolerability (incidence of DLTs, adverse events, and determination of maximum tolerated dose) determination of the recommended Phase 2 dose (RP2D), PK, and Bayesian Optimal Interval utility score. Primary endpoints for Phase 2 are rPFS rate at 6 months based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 with modifications as specified in Prostate Cancer Working Group 3 criteria. Secondary endpoints include rPFS rates at 9 and 12 months, overall rPFS, prostate-specific antigen response of ≥50% decrease from baseline at 4, 8, 12, and 16 weeks, overall response rate, duration of response, clinical benefit rate, overall survival rate at 18 and 24 months, and safety. The trial is currently open for enrollment (NCT06190899). Clinical trial information: NCT06190899 .
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