Urachal carcinoma: a large retrospective multicentric study from the French Genito-Urinary Tumor Group.

Introduction: Urachal cancer (UrC) is a rare, non-urothelial malignancy. Its natural history and management are poorly understood. Although localized to the bladder dome, the most common histological subtype of UrC is adenocarcinoma. UrC develops from an embryonic remnant, and is frequently diagnosed in advanced stage with poor prognosis. The treatment is not standardized, and based only on case reports and small series. This large retrospective multicentric study was conducted by the French Genito-Urinary Tumor Group to gain a better understanding of UrC. Material and Methods: data has been collected retrospectively on 97 patients treated at 22 French Cancer Centers between 1996 and 2020. Results: The median follow-up was 59 months (range 44-96). The median age at diagnosis was 53 years (range 20-86), 45% were females and 23% had tobacco exposure. For patients with localized disease (Mayo I-II, n=46) and with lymph-node invasion (Mayo III, n=13) median progression-free-survival (mPFS) was 31 months (95% CI: 20-67) and 7 months (95% CI: 6-not reached (NR)), and median overall survival (mOS) was 73 months (95% CI: 57-NR) and 22 months (95% CI: 21-NR) respectively. For 45 patients with Mayo I-III had secondary metastatic progression, and 20 patients were metastatic at diagnosis. Metastatic localization was peritoneal for 54% of patients. Most patients with localized tumor were treated with partial cystectomy, with mPFS of 20 months (95% CI: 14-49), and only 12 patients received adjuvant therapy. Metastatic patients (Mayo IV) had a mOS of 23 months (95% CI: 19-33) and 69% received a platin-fluorouracil combination treatment. Conclusion: UrC is a rare tumor of the bladder where patients are younger with a higher number of females, and a lower tobacco exposure than in standard urothelial carcinoma. For localized tumor, partial cystectomy is recommended. The mOS and mPFS were low, notably for patients with lymph node invasion. For metastatic patients the prognosis is poor and standard therapy is not well-defined. Further clinical and biological knowledge are needed.

Stereotactic Pelvic Reirradiation for Locoregional Cancer Relapse.

AIMS: Up to 40% of patients who have received radiation for a pelvic malignancy will develop locoregional recurrence in the previously irradiated volume. Stereotactic body radiotherapy (SBRT) has been used in the oligometastatic setting, and provides an ablative approach ideal for reirradiation. The purpose of this study was to evaluate the outcomes after SBRT reirradiation of extraosseous recurrences in the pelvis. MATERIALS AND METHODS: This single institution retrospective study evaluated patients treated with SBRT reirradiation in the pelvis from January 2011 to February 2018. Patients with more than five oligometastatic lesions, >7 cm in size, and recurrence within the prostate were excluded. RESULTS: In total, 30 patients were treated with SBRT with a median follow-up of 29.4 months. The primary tumour sites were most commonly rectum (30.8%) and prostate (30.8%). The median time interval between irradiation for the primary and SBRT reirradiation was 48 months (3-245). The typical reirradiation treatment was 35 Gy in five fractions, the median gross tumour volume size was 10.2 (0.3-110.5) ml and the most common target was the iliac nodes (40%). There were three (10%) acute grade 3 toxicities and no late grade 3 or more toxicities. At 12/24 months, local relapse-free survival, metastasis-free survival, progression-free survival and overall survival were 67.7%/50.7%, 67%/41.7%, 34.8%/14.9% and 83.2%/62.5%, respectively. On univariate analysis, improved local control was associated with low gross tumour volume (<10 ml) (P = 0.003) and prostate primary (P = 0.02), but was no longer significant on multivariate analysis. The proximity of organ at risk to the target did not significantly correlate with worse toxicity (P = 0.14) or tumour coverage (gross tumour volume: P = 0.8, planning target volume: P = 0.4). CONCLUSION: SBRT pelvic reirradiation in oligometastatic patients is a safe and effective treatment modality. Careful consideration should be taken with larger tumour size, as it may be associated with worse oncological and toxicity outcome.

Variation in neutrophil to lymphocyte ratio (NLR) as predictor of outcomes in metastatic renal cell carcinoma (mRCC) and non-small cell lung cancer (mNSCLC) patients treated with nivolumab.

BACKGROUND: An elevated pre-treatment neutrophil to lymphocytes ratio (NLR) is associated with poor prognosis in various malignancies. Optimal cut-off is highly variable across studies and could not be determined individually for a patient to inform his prognosis. We hypothesize that NLR variations could be more useful than baseline NLR to predict progression-free survival (PFS) and overall survival (OS) in patients (pts) receiving anti-PD1 treatment. PATIENTS AND METHODS: All pts with metastatic renal cell carcinoma (mRCC) and metastatic non-small cell lung cancer (mNSCLC) who received anti-PD1 nivolumab monotherapy in second-line setting or later were included in this French multicentric retrospective study. NLR values were prospectively collected prior to each nivolumab administration. Clinical characteristics were recorded. Associations between baseline NLR, NLR variations and survival outcomes were determined using Kaplan-Meier's method and multivariable Cox regression models. RESULTS: 161 pts (86 mRCC and 75 mNSCLC) were included with a median follow-up of 18 months. On the whole cohort, any NLR increase at week 6 was significantly associated with worse outcomes compared to NLR decrease, with a median PFS of 11 months vs 3.7 months (p < 0.0001), and a median OS of 28.5 months vs. 18 months (p = 0.013), respectively. In multivariate analysis, NLR increase was significantly associated with worse PFS (HR 2.2; p = 6.10-5) and OS (HR 2.1; p = 0.005). Consistent results were observed in each cohort when analyzed separately. CONCLUSION: Any NLR increase at week 6 was associated with worse PFS and OS outcomes. NLR variation is an inexpensive and dynamic marker easily obtained to monitor anti-PD1 efficacy.

Iron deficiency during first-line chemotherapy in metastatic cancers: a prospective epidemiological study.

PURPOSE: Anemia is common in oncology and negatively impacts quality of life. However, there is lack of knowledge about iron deficiency (ID) epidemiology. The aim of this study was to prospectively assess iron status in patients with locally advanced or metastatic cancer beginning chemotherapy. METHODS: In this prospective, multicenter cohort study, anemia and ID were evaluated in patients with locally advanced or metastatic solid tumors and lymphoma before starting chemotherapy. Blood samples were collected at inclusion (W0), 6 weeks (W6), and 12 weeks (W12). Prevalence was evaluated in the general population, according to tumor location and was correlated with tumor response. RESULTS: One hundred twenty-nine patients were enrolled between 2013 and 2015; 119 had solid tumors and 10 lymphomas. At W0, there were no significant difference between locations with a prevalence around 50-60% (range 47.2-70.4%) and only a trend for colorectal cancer (70.4%, P = 0.069) due to a higher prevalence of absolute ID (18.5%). Prevalence of ID+ decreased between W0 and W6 and remained stable until W12 due to the proportion of patients with ID and without anemia. However, anemia prevalence increased during W0 and W6 and remained stable to W6 from W12 due to patients with anemia but without ID. A significant correlation between tumor response and ID prevalence was found (P = 0.036). CONCLUSIONS: We confirm the high prevalence of ID and anemia in cancer patients. ID status is correlated to tumor response providing a strong rationale for iron monitoring during cancer management.

18FDG PET/CT in the early assessment of non-small cell lung cancer response to immunotherapy: frequency and clinical significance of atypical evolutive patterns.

PURPOSE: This prospective study aimed (1) to assess the non-small cell lung cancer (NSCLC) evolutive patterns to immunotherapy using FDG-PET and (2) to describe their association with clinical outcome. DESIGN: Fifty patients with metastatic NSCLC were included before pembrolizumab or nivolumab initiation. FDG-PET scan was performed at baseline and after 7 weeks of treatment (PETinterim1) and different criteria/parameters of tumor response were assessed, including PET response criteria in solid tumors (PERCIST). If a first PERCIST progressive disease (PD) without clinical worsening was observed, treatment was continued and a subsequent FDG-PET (PETinterim2) was performed at 3 months of treatment. Pseudo-progression (PsPD) was defined as a PERCIST response/stability on PETinterim2 after an initial PD. If a second PERCIST PD was assessed on PETinterim2, a homogeneous progression of lesions (termed immune homogeneous progressive-disease: iPDhomogeneous) was distinguished from a heterogeneous evolution (termed immune dissociated-response: iDR). A durable clinical benefit (DCB) of immunotherapy was defined as treatment continuation over a 6-month period. The association between PET evolutive profiles and DCB was assessed. RESULTS: Using PERCIST on PETinterim1, 42% (21/50) of patients showed a response or stable disease, most of them (18/21) reached a DCB. In contrast, 58% (29/50) showed a PD, but more than one-third (11/29) were misclassified as they finally reached a DCB. No standard PETinterim1 criteria could accurately distinguished responding from non-responding patients. Treatment was continued in 19/29 of patients with a first PERCIST PD; the subsequent PETinterim2 demonstrated iPDhomogeneous, iDR and PsPD in 42% (8/19), 26% (5/19), and 32% (6/19), respectively. Whereas no patients with iPDhomogeneous experienced a DCB, all patients with iDR and PsPD reached a clinical benefit to immunotherapy. CONCLUSION: In patients with a first PD on PERCIST and treatment continuation, a subsequent PET identifies more than half of them with iDR and PsPD, both patterns being strongly associated with a clinical benefit of immunotherapy.

Immune checkpoint inhibitors in MITF family translocation renal cell carcinomas and genetic correlates of exceptional responders.

BACKGROUND: Microphthalmia Transcription Factor (MITF)family translocation renal cell carcinoma (tRCC) is a rare RCC subtype harboring TFE3/TFEB translocations. The prognosis in the metastatic (m) setting is poor. Programmed death ligand-1 expression was reported in 90% of cases, prompting us to analyze the benefit of immune checkpoint inhibitors (ICI) in this population. PATIENTS AND METHODS: This multicenter retrospective study identified patients with MITF family mtRCC who had received an ICI in any of 12 referral centers in France or the USA. Response rate according to RECIST criteria, progression-free survival (PFS), and overall survival (OS) were analyzed. Genomic alterations associated with response were determined for 8 patients. RESULTS: Overall, 24 patients with metastatic disease who received an ICI as second or later line of treatment were identified. Nineteen (82.6%) of these patients had received a VEGFR inhibitor as first-line treatment, with a median PFS of 3 months (range, 1-22 months). The median PFS for patients during first ICI treatment was 2.5 months (range, 1-40 months); 4 patients experienced partial response (16,7%) and 3 (12,5%) had stable disease. Of the patients whose genomic alterations were analyzed, two patients with mutations in bromodomain-containing genes (PBRM1 and BRD8) had a clinical benefit. Resistant clones in a patient with exceptional response to ipilimumab showed loss of BRD8 mutations and increased mutational load driven by parallel evolution affecting 17 genes (median mutations per gene, 3), which were enriched mainly for O-glycan processing (29.4%, FDR = 9.7 × 10- 6). CONCLUSIONS: MITF family tRCC is an aggressive disease with similar responses to ICIs as clear-cell RCC. Mutations in bromodomain-containing genes might be associated with clinical benefit. The unexpected observation about parallel evolution of genes involved in O-glycosylation as a mechanism of resistance to ICI warrants exploration.

Candidate apoptotic and DNA repair gene approach confirms involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer.

INTRODUCTION: Single nucleotide polymorphisms (SNPs) of DNA repair and apoptosis genes have been associated with outcome in head and neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy (RT). Our goal was to conduct a candidate gene study in HNSCC patients receiving RT or chemoRT. METHODS: 122 non-resectable HNSCC patients undergoing RT (N=38) or chemoRT (N=84) between 1992 and 2006 were retrospectively analyzed. ERCC1 Lys259Thr (rs735482), ERCC2 Lys751Gln (rs13181), ERCC5 His46His C>T (rs1047768), XRCC1 Arg399Gln (rs25487), TP53 Arg72Pro (rs1042522) and MDM2 309T>G (rs2279744) were analyzed on tumor DNA. SNP profile was considered to assess RT-related toxicity. RESULTS: All 120 evaluable patients experienced RT-related toxicity at any time. Among them, 83% had G3-4 acute side-effects during RT, mainly dysphagia, mucositis, epithelitis and/or xerostomia (DMEX). 28/105 patients (27%) had early G3-4 toxicity up to 3months after the end of RT. 29/96 patients (30%) had G3-4 late toxicity thereafter. The presence of G allele of MDM2 or Thr allele of ERCC1 was associated with a significantly higher risk of acute and/or early DMEX toxicity. The MDM2 309GG genotype was linked to a higher risk of acute G3-4 dermatitis. The ERCC5 TT genotype was associated with more frequent G3-4 late cervical skin fibrosis or xerostomia. Pro allele of TP53 72 was associated with a higher risk of G3-4 osteoradionecrosis. CONCLUSION: Relevant SNPs in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might influence the severity of radiation-related side-effects in HNSCC patients. Prospective clinical SNP-based validation studies are needed on these bases.

Blastic plasmacytoid dendritic cell neoplasm: a report of four cases and review of the literature.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN), formerly known as agranular CD4(+) /CD56(+) haematodermic neoplasm (CD4/CD56 HN), is a rare distinct form of lymphoma-like entity known of dermatologists because of its marked predilection for cutaneous involvement, and its aggressive behaviour. Moreover, the association or the evolution to an acute leukaemia entity that still expresses CD4 and CD56 markers is almost systematic. This new described entity of 'CD4(+) /CD56(+) leukaemia' or 'leukaemia of plasmacytoid dendritic cell lineage' has a poor prognostic and may lead to include haematopoietic stem cell transplantation in the treatment strategy as early as possible. REPORT OF CASES: We report here four cases presenting with skin lesions and haematological signs. One of the patients underwent allogeneic stem cell transplantation, with a relapse-free survival of 40 months. We discuss the diagnosis features as well as the treatment options. CONCLUSION: A collaborative work between dermatologists and onco-haematologists is essential to give patients the best chance of complete and long-term response.