Gastrointestinal metastases in renal cell carcinoma: A retrospective multicenter GETUG (Groupe d'Étude des Tumeurs Uro-Génitales) study.

BACKGROUND: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood. OBJECTIVES: To report clinical presentations, patient characteristics, therapeutic strategies, and prognosis of GIMs from RCC. METHODS: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021. RESULTS: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of patients already had other metastases. GIMs occurred after a median duration of 5.4 years (IC95%=[4.2-7.1]) and 1.9 years (IC95%=[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. GIM management consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months. CONCLUSION: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether or not they are symptomatic.

No Difference in the Phenotypic Expression of Frailty among Elderly Patients Recently Diagnosed with Cancer Vs Cancer Free Patients.

OBJECTIVES: To examine frailty determinants differences in patients with a recent diagnosis of cancer compared to non-cancer patients among older adult. Revealing those differences will allow us to individualize the exact frailty management in those patients diagnosed with cancer. DESIGN: This is an observational cross-sectional, monocentric study. SETTING: Patients were evaluated at the Geriatric Frailty Clinic (GFC), in the Toulouse University Hospital, France, between October 2011 and February 2016. PARTICIPANTS: 1996 patients aged 65 and older were included (1578 patients without cancer and 418 patients with solid and hematological cancer recently diagnosed). MEASUREMENTS: Frailty was established according to the frailty phenotype. The frailty phenotype measures five components of frailty: weight loss, exhaustion, low physical activity, weakness and slow gait. Frailty phenotype was categorized as robust, pre-frail and frail. RESULTS: In a multinomial logistic regression, cancer, compared to the non-cancer group, is not associated with an increased likelihood of being classified as pre frail (RRR 0.9, 95% CI [0.5 ; 1.6 ], p 0.9) or frail (RRR 1.2, 95% CI [0.7 ; 2.0], p 0.4) rather than robust. When considering each Fried criterion, a significant higher odd of weight loss was observed in older patients with cancer compared to the non-cancer patients (OR 2.3, 95% CI [1.8; 3.0], p <0.001) but no statistically significant differences was found among the four other Fried criteria. Sensitivity analysis on the frailty index showed that cancer was not associated with a higher FI score compared to non-cancer (ß 0.002, 95%CI [-0.009; 0.01], p 0.6). CONCLUSION: In this real-life study evaluating elderly patients with and without cancer, we didn't confirm our hypothesis, in fact we found that cancer was not associated with frailty severity using both a phenotypic model and a deficit accumulation approach. Cancer may contribute, at least additively, to the development of frailty, like any other comorbidity, rather than a global underlying condition of vulnerability.

Multidisciplinary development of the Geriatric Core Dataset for clinical research in older patients with cancer: A French initiative with international survey.

BACKGROUND: To define a core set of geriatric data to be methodically collected in clinical cancer trials of older adults, enabling comparison across trials. PATIENTS AND METHODS: Following a consensus approach, a panel of 14 geriatricians from oncology clinics identified seven domains of importance in geriatric assessment. Based on the international recommendations, geriatricians selected the mostly commonly used tools/items for geriatric assessment by domain (January-October 2015). The Geriatric Core Dataset (G-CODE) was progressively developed according to RAND appropriateness ratings and feedback during three successive Delphi rounds (July-September 2016). The face validity of the G-CODE was assessed with two large panels of health professionals (55 national and 42 international experts) involved both in clinical practice and cancer trials (March-September 2017). RESULTS AND DISCUSSION: After the last Delphi round, the tools/items proposed for the G-CODE were the following: (1) social assessment: living alone or support requested to stay at home; (2) functional autonomy: Activities of Daily Living (ADL) questionnaire and short instrumental ADL questionnaire; (3) mobility: Timed Up and Go test; (4) nutrition: weight loss during the past 6 months and body mass index; (5) cognition: Mini-Cog test; (6) mood: mini-Geriatric Depression Scale and (7) comorbidity: updated Charlson Comorbidity Index. More than 70% of national experts (42 from 20 cities) and international experts (31 from 13 countries) participated. National and international surveys showed good acceptability of the G-CODE. Specific points discussed included age-year cut-off, threshold of each tool/item and information about social support, but no additional item was proposed. CONCLUSION: We achieved formal consensus on a set of geriatric data to be collected in cancer trials of older patients. The dissemination and prospective use of the G-CODE is needed to assess its utility.

Robot-assisted post-chemotherapy retroperitoneal lymph node dissection in germ cell tumor: is the single-docking with lateral approach relevant?

INTRODUCTION: Surgical treatment of post-chemotherapy residual mass of germ cell tumor (GCT) may be performed in various techniques. We assess the feasibility, safety, and efficacy of single-docking with lateral approach robot-assisted retroperitoneal lymph node dissection (R-RPLND) in residual mass of GCT in our center. MATERIALS AND METHODS: A retrospective review of patients undergoing R-RPLND for residual mass of CGT was performed between January 2014 and April 2017. Patients with residual mass < 3 cm for seminoma or < 1 cm for non-seminoma were eligible. All surgeries were performed with single-docking RPNLD technique in lateral decubitus. We assessed preoperative characteristics (age, testicular pathology, template, chemotherapy regimen, lesion size, and clinical stage), peroperative (operative time, estimated blood loss, intraoperative complication, node count, pathology, and number of positive node), and postoperative outcomes (postoperative complications, hospital length of stay, recurrence-free survival at 2 year, and ejaculation dysfunction). RESULTS: Eleven patients underwent R-RPLND with a median size of the residual mass of 20 mm. Median operative time was 153 min with 120 ml of estimated blood loss, without intraoperative complication. Median nodes count was 7 [1; 24]. Two patients had post-chemotherapy necrotic nodes and one no tumorous node. One patient had postoperative Clavien I complication (chyloperitoneum). We report 72.7% of antegrade ejaculation at 1 month from the surgery. Median clinical recurrence-free survival was 100% after 2 years from the surgery (n = 6). CONCLUSION: Lateral approach with single-docking R-RPLND for residual mass of GCT is feasible and safe, with satisfying functional and oncologic outcomes.

Methodology of phase II clinical trials in metastatic elderly breast cancer: a literature review.

PURPOSE: As the incidence of invasive breast cancer will increase with age, the number of elderly patients with a diagnosis metastatic breast cancer will also rise. But the use of cytotoxic drugs in elderly metastatic breast cancer patients is not systematic and is dreaded by medical oncologists. The need for prospective oncologic data from this population seems increasingly obvious. The main objective of this review is to investigate design and characteristics of phase II trials that assess activity and feasibility of chemotherapies in elderly advanced/metastatic breast cancer patients. METHODS: An electronic search in PUBMED allowed us to retrieve articles published in English language on phase II trials in elderly metastatic breast cancer between January 2002 and May 2016. Sixteen publications were finally included in this review. RESULTS: The primary endpoint was a simple, a composite, and a co-primary endpoints in 11, three, and two studies, respectively. Efficacy was the primary objective in 15 studies: simple (n = 10), composite (n = 3), co-primary endpoints (n = 2). Composite or co-primary endpoints combined efficacy and toxicity. Thirteen studies used multistage designs. CONCLUSIONS: Only five studies evaluated the feasibility, i.e., to jointly assess efficacy and tolerance to treatment (toxicity, quality of life, etc) as primary endpoint. Development of elderly specific phase III clinical trials might be challenging, it therefore seems essential to conduct phase II clinical trials evaluating jointly efficacy and toxicity in a well-defined geriatric population. Use of multistage designs that take into account heterogeneity would allow to identify a subpopulation at interim analysis and to reduce the number of patients exposed to an inefficient or a toxic treatment regimen. It is crucial to evaluate new therapies (targeted therapies, immunotherapies) using adequate methodologies (Study design, endpoint).

Body Composition and Anti-Neoplastic Treatment in Adult and Older Subjects - A Systematic Review.

BACKGROUND: The estimation of the risk of poor tolerance and overdose of antineoplastic agents protocols represents a major challenge in oncology, particularly in older patients. We hypothesize that age-related modifications of body composition (i.e. increased fat mass and decreased lean mass) may significantly affect tolerance to chemotherapy. METHOD: We conducted a systematic review for the last 25 years (between 1990 and 2015), using US National library of Medicine Medline electronic bibliographic database and Embase database of cohorts or clinical trials exploring (i) the interactions of body composition (assessed by Dual X-ray Absorptiometry, Bioelectrical Impedance Analyses, or Computerized Tomography) with pharmacokinetics parameters, (ii) the tolerance to chemotherapy, and (iii) the consequences of chemotherapies or targeted therapies on body composition. RESULTS: Our search identified 1504 articles. After a selection (using pre-established criteria) on titles and abstract, 24 original articles were selected with 3 domains of interest: impact of body composition on pharmacokinetics (7 articles), relationship between body composition and chemotoxicity (14 articles), and effect of anti-cancer chemotherapy on body composition (11 articles). The selected studies suggested that pharmacokinetic was influenced by lean mass, that lower lean mass could be correlated with toxicity, and that sarcopenic patients experienced more toxicities that non-sarcopenic patients. Regarding fat mass, results were less conclusive. No studies specifically explored the topic of body composition in older cancer patients. CONCLUSIONS: Plausible pathophysiological pathways linking body composition, toxicity, and pharmacokinetics are sustained by the actual review. However, despite the growing number of older cancer patients, our review highlighted the lack of specific studies in the field of anti-neoplastic agents toxicity regarding body composition conducted in elderly.

Vinflunine-gemcitabine versus vinflunine-carboplatin as first-line chemotherapy in cisplatin-unfit patients with advanced urothelial carcinoma: results of an international randomized phase II trial (JASINT1).

BACKGROUND: There is no standard first-line chemotherapy for advanced urothelial carcinoma (aUC) in cisplatin-ineligible (cisplatin-unfit) patients. The study assessed the efficacy and tolerability profile of two vinflunine-based cytotoxic regimens in this setting. PATIENTS AND METHODS: Patients with aUC a creatinine clearance (CrCl) of <60 but ≥30 ml/min, performance status 0 or 1 and no prior chemotherapy for advanced disease were randomized (1 : 1). They received vinflunine 250 or 280 mg/m(2) (based on baseline CrCl) on day 1, plus either gemcitabine [750 mg/m(2) escalated to 1000 mg/m(2) in cycle 2 if no toxicity grade (G) ≥2 on days 1 and 8 (VG) or plus carboplatin area under the curve 4.5 day 1 (VC) every 21 days]. To detect a 22% improvement in each arm compared with H0 (41%) in the primary end point, disease control rate (DCR = complete response + partial response + stable disease), 31 assessable patients per arm were required (α = 5%, ß = 20%). RESULTS: Sixty-nine patients were enrolled (34 VG, 35 VC). Less G3/4 haematological adverse events (AEs) were reported with VG: neutropaenia was seen in 38% (versus 68% with VC) and febrile neutropaenia in 3% (versus 14% with VC) of patients. No major differences were observed for non-haematological AEs. DCR was 77% in both groups; overall response rate (ORR) was 44.1% versus 28.6%, with a median progression-free survival of 5.9 versus 6.1 months and median OS of 14.0 versus 12.8 months with VG and VC, respectively. CONCLUSION: Both vinflunine-based doublets offer a similar DCR, ORR and OS. The better haematological tolerance favours the VG combination, which warrants further study. CLINICALTRIALS.GOV PROTOCOL IDENTIFIER: NCT 01599013.

Guidelines for the definition of time-to-event end points in renal cell cancer clinical trials: results of the DATECAN project†.

BACKGROUND: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions. MATERIALS AND METHODS: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events. RESULTS: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression). CONCLUSIONS: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons.

[Mood and cognitive disorders, and androgen deprivation]. / Troubles de l'humeur et cognitifs et suppression androgénique.

Prostate cancer has become a chronic disease. In this context, it is important to take into account the quality of life of patients and their family in the therapeutic approach. Recent studies have demonstrated the importance of depression and the risk of suicide in patients with prostate cancer as well as the repercussions of the disease on the spouse and their relationship. The implication of hormonal treatment in the increase in risk of depression is difficult to affirm. Few studies have investigated this subject and they present methodological biases. Some authors report an increased risk of cognitive decline in patients on androgen deprivation. However, even if certain physiopathological hypotheses have been put forward, the imputability of the treatment on the alteration of cognitive functions has not been clearly established. Urologists are at the forefront of diagnosis and treatment of prostate cancer occurring most often in elderly subjects. Therefore, given the prevalence of depression syndromes and/or the alteration of cognitive functions in this population, the urologist must be aware of these different factors, which are potentially aggravated by the introduction of androgen deprivation. Based on a review of the recent literature, the authors suggest using a simple depression screening tool: confirmation of the diagnosis and management is within the competence of the general practitioner. As for the risk of cognitive decline, it seems difficult to imagine, and not necessarily relevant, to systematically propose a battery of neuropsychometric screening tests. On the other hand, giving the patient the G8 screening test can allow the urologist to assess whether the patient needs a geriatric consultation or not.

Routine FDG PET-CT in patients with a high-risk localized melanoma has a high predictive positive value for nodal disease and high negative predictive value for the presence of distant metastases.

BACKGROUND: FDG PET-CT is the superior imaging modality for the detection of visceral metastases (M+) in patients with melanoma. Conflicting evidence exists regarding its role for the initial staging of patients with high risk localized melanoma (large Breslow Thickness (BT) and/or ulceration). OBJECTIVE: To assess the role of routine staging with FDG PET-CT in melanoma patients with localized high risk melanoma. METHODS: Forty-eight consecutive patients with 1 < BT < 4 mm with ulceration and with BT ≥ 4 mm were staged with PET-CT. PET-CT procedures were performed on a GE Discovery ST® scanner. PET-CT findings for regional nodal status and presence of distant metastatic disease were collected. The gold standard for nodal assessment was pathological examination. The gold standard for M+ was conventional imaging and clinical follow-up, confirmed by biopsy whenever feasible. RESULTS: No patient had a positive PET-CT for M+. Six patients (13%) had a non-conclusive PET-CT; none of them presented with M+ within 6 months. Forty-three patients (90%) had a negative PET-CT, amongst them only one patient (2.5%) presented with M+ within a year. Six patients had FDG-avid lymph nodes in the drainage territory of the primary melanoma, either SLNB or lymph node dissection confirmed metastatic nodal involvement. The predictive positive value of PET for regional node involvement was 100%. COMMENTS: FDG PET-CT does not seem to be effective at detecting M+ at baseline staging in patients with high risk localized melanoma. However, it has a high negative predictive value for the presence of M+ at 6 months and a high positive predictive value for nodal involvement.

Crystal structure of the CheA histidine phosphotransfer domain that mediates response regulator phosphorylation in bacterial chemotaxis.

The x-ray crystal structure of the P1 or H domain of the Salmonella CheA protein has been solved at 2.1-A resolution. The structure is composed of an up-down up-down four-helix bundle that is typical of histidine phosphotransfer or HPt domains such as Escherichia coli ArcB(C) and Saccharomyces cerevisiae Ypd1. Loop regions and additional structural features distinguish all three proteins. The CheA domain has an additional C-terminal helix that lies over the surface formed by the C and D helices. The phosphoaccepting His-48 is located at a solvent-exposed position in the middle of the B helix where it is surrounded by several residues that are characteristic of other HPt domains. Mutagenesis studies indicate that conserved glutamate and lysine residues that are part of a hydrogen-bond network with His-48 are essential for the ATP-dependent phosphorylation reaction but not for the phosphotransfer reaction with CheY. These results suggest that the CheA-P1 domain may serve as a good model for understanding the general function of HPt domains in complex two-component phosphorelay systems.

The molecular puzzle of two-component signaling cascades.

Two-component systems constitute prevalent signaling pathways in bacteria and mediate a large variety of adaptative cellular responses. Signaling proceeds through His-Asp phosphorelay cascades that involve two central partners, the histidine protein kinase and the response regulator protein. Structural studies have provided insights into some design principles and activation mechanisms of these multi-domain proteins implicated in the control of virulence gene expression in several pathogens.

Detection and characterization of human herpesvirus-8-infected cells in bone marrow biopsies of human immunodeficiency virus-positive patients.

We studied 15 bone marrow biopsy specimens from patients with human immunodeficiency virus infection for detection of Kaposi sarcoma herpesvirus (KSHV/HHV-8) DNA sequences by a very sensitive and specific polymerase chain reaction (PCR) assay (with 3 different sets of primers). In addition, we used immunohistochemistry with antiviral interleukin-6 (vIL-6) and anti-latent nuclear antigen-1 (LNA-1) antibodies to localize the infected cells on tissue sections. Among the 15 samples, 6 had positive PCR results with the 3 sets of primers (orf26, orf72, orf75). Interestingly, in 2 of these 6 patients (both with Kaposi sarcoma) vIL-6 and LNA-1 were detected in mononuclear lymphoid cells but not in stromal cells of the bone marrow. The detection of vIL-6--positive lymphoid cells in bone marrow suggests a homing for HHV-8--infected elements in this tissue. The local release of vIL-6 may play some role in the plasmacytosis observed in bone marrow in the acquired immunodeficiency syndrome. HUM PATHOL 32:288-291.

Further insights into the mechanism of function of the response regulator CheY from crystallographic studies of the CheY--CheA(124--257) complex.

New crystallographic structures of the response regulator CheY in association with CheA(124--257), its binding domain in the kinase CheA, have been determined. In all crystal forms, the molecular interactions at the heterodimer interface are identical. Soaking experiments have been performed on the crystals using acetyl phosphate as phosphodonor to CheY. No phosphoryl group attached to Asp57 of CheY is visible from the electron density, but the response regulator in the CheY-CheA(124--257) complex may have undergone a phosphorylation-dephosphorylation process. The distribution of water molecules and the geometry of the active site have changed and are now similar to those of isolated CheY. In a second soaking experiment, imido-diphosphate, an inhibitor of the phosphorylation reaction, was used. This compound binds in the vicinity of the active site, close to the N-terminal part of the first alpha-helix. Together, these results suggest that the binding of CheY to CheA(124--257) generates a geometry of the active site that favours phosphorylation and that imido-diphosphate interferes with phosphorylation by precluding structural changes in this region.

Crystal structure of the F component of the Panton-Valentine leucocidin.

Leucocidins and gamma-hemolysins are bi-component staphylococcal toxins that form lytic transmembrane pores. Their cytotoxic activities involve the synergistic association of a class S and a class F component, produced as water-soluble monomers which assemble on the surface of specific cells. The structure of the F protein from Panton-Valentine leucocidin, solved at 2.0 A resolution, and sequence alignment suggest that it represents the fold of any secreted protein in this family of toxins. The comparison of this structure to that of the homoheptameric alpha-hemolysin provides some insights into the molecular events that may occur during pore formation.

6-(hydroxyalkyl)penicillanates as probes for mechanisms of beta-lactamases.

6-(Hydroxyalkyl)penicillanates have proven helpful as probes for the mechanisms of beta-lactamases, enzymes of resistance for beta-lactam antibiotics. The present report summarizes the concepts on design, syntheses and use of these molecules in mechanistic studies of beta-lactamases.

Discoupling the Ca(2+)-activation from the pore-forming function of the bi-component Panton-Valentine leucocidin in human PMNs.

The consecutive cell activation, including Ca(2+)-channel opening, and pore formation leading to human neutrophil lysis were the two functions of the staphylococcal Panton-Valentine leucocidin attempted to be discoupled by site-directed mutagenesis. In a first approach consisting in deletions of the cytoplasmic extremity of the transmembranous domain, we produced a LukF-PV DeltaSer125-Leu128 with a slightly reduced Ca(2+) induction but with a significantly lowered lytic activity when combined with its synergistic protein LukS-PV. The second approach consisted in the modification of charges and/or introduction of a steric hindrance inside the pore, which also led to interesting mutated proteins: LukF-PV G131D, G131W and G130D. The latter had an intact Ca(2+) induction ability while the lytic one was 20-fold diminished. Binding properties and intrinsic pore diameters of these discoupled toxins remained comparable to the wild-type protein. The mutated proteins promoted interleukin-8 secretion, but they were rather inactive in an experimental model. New insights are brought concerning the role of the two functions in the virulence of this bi-component leucotoxin.

Inhibition of the broad spectrum nonmetallocarbapenamase of class A (NMC-A) beta-lactamase from Enterobacter cloacae by monocyclic beta-lactams.

beta-Lactamases hydrolyze beta-lactam antibiotics, a reaction that destroys their antibacterial activity. These enzymes, of which four classes are known, are the primary cause of resistance to beta-lactam antibiotics. The class A beta-lactamases form the largest group. A novel class A beta-lactamase, named the nonmetallocarbapenamase of class A (NMC-A) beta-lactamase, has been discovered recently that has a broad substrate profile that included carbapenem antibiotics. This is a serious development, since carbapenems have been relatively immune to the action of these resistance enzymes. Inhibitors for this enzyme are sought. We describe herein that a type of monobactam molecule of our design inactivates the NMC-A beta-lactamase rapidly, efficiently, and irreversibly. The mechanism of inactivation was investigated by solving the x-ray structure of the inhibited NMC-A enzyme to 1.95 A resolution. The structure shed light on the nature of the fragmentation of the inhibitor on enzyme acylation and indicated that there are two acyl-enzyme species that account for enzyme inhibition. Each of these inhibited enzyme species is trapped in a distinct local energy minimum that does not predispose the inhibitor species for deacylation, accounting for the irreversible mode of enzyme inhibition. Molecular dynamics simulations provided evidence in favor of a dynamic motion for the acyl-enzyme species, which samples a considerable conformational space prior to the entrapment of the two stable acyl-enzyme species in the local energy minima. A discussion of the likelihood of such dynamic motion for turnover of substrates during the normal catalytic processes of the enzyme is presented.