Schwarzites and Triply Periodic Minimal Surfaces: From Pure Topology Mathematics to Macroscale Applications.

Schwarzites are porous (spongy-like) carbon allotropes with negative Gaussian curvatures. They are proposed by Mackay and Terrones inspired by the works of the German mathematician Hermann Schwarz on Triply-Periodic Minimal Surfaces (TPMS). This review presents and discusses the history of schwarzites and their place among curved carbon nanomaterials. The main works on schwarzites are summarized and are available in the literature. Their unique structural, electronic, thermal, and mechanical properties are discussed. Although the synthesis of carbon-based schwarzites remains elusive, recent advances in the synthesis of zeolite-templates nanomaterials have brought them closer to reality. Atomic-based models of schwarzites are translated into macroscale ones that are 3D-printed. These 3D-printed models are exploited in many real-world applications, including water remediation and biomedical ones.

A Targeted, Personalized Management Strategy in Advanced Penile Squamous Cell Carcinoma.

Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor outcomes in advanced stages, with dismal response and survival rates using conventional surgical and systemic options. Additionally, the ability to detect and monitor residual disease with current imaging modalities remains difficult. Therefore, advances in multimodal management and disease monitoring are desperately needed. We present a case of advanced PSCC utilizing multimodal management informed by next-generation sequencing and circulating tumor DNA monitoring. These genomic techniques were valuable in guiding management and deserve further evaluation in the management of PSCC and other rare malignancies.

Current opinions on the management of prolonged ischemic priapism: does penoscrotal decompression outperform corporoglanular tunneling?

Prolonged ischemic priapism presents a treatment challenge given the difficulty in achieving detumescence and effects on sexual function. To evaluate current practice patterns, an open, web-based multi-institutional survey querying surgeons' experience with and perceived efficacy of tunneling maneuvers (corporoglanular tunneling and penoscrotal decompression), as well as impressions of erectile recovery, was administered to members of societies specializing in male genital surgery. Following distribution, 141 responses were received. Tunneling procedures were the favored first-line surgical intervention in the prolonged setting (99/139, 71.2% tunneling vs. 14/139, 10.1% implant, p < .001). Although respondents were more likely to have performed corporoglanular tunneling than penoscrotal decompression (124/138, 89.9% vs. 86/137, 62.8%, p < .001), penoscrotal decompression was perceived as more effective among those who had performed both (47.3% Very or Extremely Effective for penoscrotal decompression vs. 18.7% for corporoglanular tunneling; p < .001). Many respondents who had performed both tunneling procedures felt that most regained meaningful sexual function after either corporoglanular tunneling or penoscrotal decompression (33/75, 44.0% vs. 33/74, 44.6%, p = .942). While further patient-centered investigation is warranted, this study suggests that penoscrotal decompression may outperform corporoglanular tunneling for prolonged priapism, and that recovery of sexual function may be higher than previously thought after tunneling procedures.

Static in vitro digestion model adapted to the general older adult population: an INFOGEST international consensus.

Understanding the mechanisms of food digestion is of paramount importance to determine the effect foods have on human health. Significant knowledge on the fate of food during digestion has been generated in healthy adults due to the development of physiologically-relevant in vitro digestion models. However, it appears that the performance of the oro-gastrointestinal tract is affected by ageing and that a model simulating the digestive conditions found in a younger adult (<65 years) is not relevant for an older adult (>65 years). The objectives of the present paper were: (1) to conduct an exhaustive literature search to find data on the physiological parameters of the older adult oro-gastrointestinal tract, (2) to define the parameters of an in vitro digestion model adapted to the older adult. International experts have discussed all the parameters during a dedicated workshop organized within the INFOGEST network. Data on food bolus properties collected in the older adult were gathered, including food particle size found in older adult boluses. In the stomach and small intestine, data suggest that significant physiological changes are observed between younger and older adults. In the latter, the rate of gastric emptying is slowed down, the pH of the stomach content is higher, the amount of secretions and thus the hydrolytic activities of gastric and intestinal digestive enzymes are reduced and the concentration of bile salts lower. The consensus in vitro digestion model of the older adult proposed here will allow significant progress to be made in understanding the fate of food in this specific population, facilitating the development of foods adapted to their nutritional needs. Nevertheless, better foundational data when available and further refinement of the parameters will be needed to implement the proposed model in the future.

Specificities of Meningitis and Meningo-Encephalitis After Kidney Transplantation: A French Retrospective Cohort Study.

Kidney transplant recipients develop atypical infections in their epidemiology, presentation and outcome. Among these, meningitis and meningoencephalitis require urgent and adapted anti-infectious therapy, but published data is scarce in KTRs. The aim of this study was to describe their epidemiology, presentation and outcome, in order to improve their diagnostic and management. We performed a retrospective, multicentric cohort study in 15 French hospitals that included all 199 cases of M/ME in KTRs between 2007 and 2018 (0.9 case per 1,000 KTRs annually). Epidemiology was different from that in the general population: 20% were due to Cryptococcus neoformans, 13.5% to varicella-zoster virus, 5.5% to Mycobacterium tuberculosis, and 4.5% to Enterobacteria (half of which produced extended spectrum beta-lactamases), and 5% were Post Transplant Lymphoproliferative Disorders. Microorganisms causing M/ME in the general population were infrequent (2%, for Streptococcus pneumoniae) or absent (Neisseria meningitidis). M/ME caused by Enterobacteria, Staphylococci or filamentous fungi were associated with high and early mortality (50%-70% at 1 year). Graft survival was not associated with the etiology of M/ME, nor was impacted by immunosuppression reduction. Based on these results, we suggest international studies to adapt guidelines in order to improve the diagnosis and the probabilistic treatment of M/ME in SOTRs.

Evaluating remote facilitation intensity for multi-national translation of nurse-initiated stroke protocols (QASC Australasia): a protocol for a cluster randomised controlled trial.

BACKGROUND: Facilitated implementation of nurse-initiated protocols to manage fever, hyperglycaemia (sugar) and swallowing difficulties (FeSS Protocols) in 19 Australian stroke units resulted in reduced death and dependency for stroke patients. However, a significant gap remains in translating this evidence-based care bundle protocol into standard practice in Australia and New Zealand. Facilitation is a key component for increasing implementation. However, its contribution to evidence translation initiatives requires further investigation. We aim to evaluate two levels of intensity of external remote facilitation as part of a multifaceted intervention to improve FeSS Protocol uptake and quality of care for patients with stroke in Australian and New Zealand acute care hospitals. METHODS: A three-arm cluster randomised controlled trial with a process evaluation and economic evaluation. Australian and New Zealand hospitals with a stroke unit or service will be recruited and randomised in blocks of five to one of the three study arms-high- or low-intensity external remote facilitation or a no facilitation control group-in a 2:2:1 ratio. The multicomponent implementation strategy will incorporate implementation science frameworks (Theoretical Domains Framework, Capability, Opportunity, Motivation - Behaviour Model and the Consolidated Framework for Implementation Research) and include an online education package, audit and feedback reports, local clinical champions, barrier and enabler assessments, action plans, reminders and external remote facilitation. The primary outcome is implementation effectiveness using a composite measure comprising six monitoring and treatment elements of the FeSS Protocols. Secondary outcome measures are as follows: composite outcome of adherence to each of the combined monitoring and treatment elements for (i) fever (n=5); (ii) hyperglycaemia (n=6); and (iii) swallowing protocols (n=7); adherence to the individual elements that make up each of these protocols; comparison for composite outcomes between (i) metropolitan and rural/remote hospitals; and (ii) stroke units and stroke services. A process evaluation will examine contextual factors influencing intervention uptake. An economic evaluation will describe cost differences relative to each intervention and study outcomes. DISCUSSION: We will generate new evidence on the most effective facilitation intensity to support implementation of nurse-initiated stroke protocols nationwide, reducing geographical barriers for those in rural and remote areas. TRIAL REGISTRATION: ACTRN12622000028707. Registered 14 January, 2022.

The Role of the Extrafibrillar Volume on the Mechanical Properties of Molecular Models of Mineralized Bone Microfibrils.

Bones are responsible for body support, structure, motion, and several other functions that enable and facilitate life for many different animal species. They exhibit a complex network of distinct physical structures and mechanical properties, which ultimately depend on the fraction of their primary constituents at the molecular scale. However, the relationship between structure and mechanical properties in bones are still not fully understood. Here, we investigate structural and mechanical properties of all-atom bone molecular models composed of type-I collagen, hydroxyapatite (HA), and water by means of fully atomistic molecular dynamics simulations. Our models encompass an extrafibrillar volume (EFV) and consider mineral content in both the EFV and intrafibrillar volume (IFV), consistent with experimental observations. We investigate solvation structures and elastic properties of bone microfibril models with different degrees of mineralization, ranging from highly mineralized to weakly mineralized and nonmineralized models. We find that the local tetrahedral order of water is lost in similar ways in the EFV and IFV regions for all HA containing models, as calcium and phosphate ions are strongly coordinated with water molecules. We also subject our models to tensile loads and analyze the spatial stress distribution over the nanostructure of the material. Our results show that both mineral and water contents accumulate significantly higher stress levels, most notably in the EFV, thus revealing that this region, which has been only recently incorporated in all-atom molecular models, is fundamental for studying the mechanical properties of bones at the nanoscale. Furthermore, our results corroborate the well-established finding that high mineral content makes bone stiffer.

The Hunter-8 Scale Prehospital Triage Workflow for Identification of Large Vessel Occlusion and Brain Haemorrhage.

OBJECTIVE: The Hunter-8 prehospital stroke scale predicts large vessel occlusion in hyperacute ischemic stroke patients (LVO) at hospital admission. We wished to test its performance in the hands of paramedics as part of a prehospital triage algorithm. We aimed to determine (a) the proportion of patients identified by the Hunter-8 algorithm, receiving reperfusion therapies, (b) whether a call to stroke team improved this, and (c) performance for LVO detection using an expanded LVO definition. METHODS: A prehospital workflow combining pre-morbid functional status, time from symptom onset, and the Hunter-8 scale was implemented from July 2019. A telephone call to the stroke team was prompted for potential treatment candidates. Classic LVO was defined as a proximal middle cerebral artery (MCA-M1), terminal internal carotid artery, or tandem occlusion. Extended LVO added proximal MCA-M2 and basilar occlusions. RESULTS: From July 2019 to April 2021, there were 363 Hunter-8 activations, 320 analyzed: 181 (56.6%) had confirmed ischemic strokes, 13 (4.1%) transient ischemic attack, 91 (28.5%) stroke mimics, and 35 (10.9%) intracranial hemorrhage. Fifty-two patients (16.3%) received reperfusion therapies, 35 with Hunter-8 ≥ 8. The stroke doctor changed the final destination for 76 patients (23.7%), and five received reperfusion therapies. The AUCs for classic and extended LVO were 0.73 (95% CI 0.66-0.79) and 0.72 (95% CI 0.65-0.77), respectively. CONCLUSION: The Hunter-8 workflow resulted in 28.7% of confirmed ischemic stroke patients receiving reperfusion therapies, with no secondary transfers to the comprehensive stroke center. The role of communication with stroke team needs to be further explored.

The effect of supraphysiological dose of nandrolone decanoate administration on the inflammatory, neurotrophin and behavioral response in adult and old male mice.

This study examined the effect of 6 weeks of supraphysiological nandrolone decanoate (ND) administration in adult mice (7 months) on cognitive function and neuroinflammation during aging. Male C57BL/6 mice were randomized into ND (10 mg·kg-1·wk-1) or control (CTL) groups. Half of the mice were tested at a young (Y) age (ND-Y and CTL-Y), 1 week following final ND administration, while the remaining mice were tested at 16 months (O) (ND-O and CTL-O). Learning and memory were better in young mice compared to older mice, regardless of treatment. ND-O displayed decreased anxiety as compared to all other groups. TNFα and IL1ß expression were higher in older mice, regardless of treatment. ND administration in young mice appeared to attenuate the neuroinflammatory response in aging mice as evidenced by decreased COX2, IL-4 and increased IL-10 expression in ND-O compared to CTL-O. BDNF AR and ER expression increased in ND-O compared to CTL-O. Results of the study indicated that supraphysiological ND administration had no negative effect on learning and memory but may attenuate anxiety in older mice. In addition, ND administration in young adult mice may attenuate the inflammatory response during aging, which may be related to elevations in both AR and ER expression.

Guided fractures in graphene mechanical diode-like structures.

The concept of a diode is usually applied to electronic and thermal devices but very rarely for mechanical ones. A recently proposed fracture rectification effect in polymer-based structures with triangular void defects has motivated us to test these ideas at the nanoscale using graphene membranes. Using fully-atomistic reactive molecular dynamics simulations we showed that robust rectification-like effects exist. The fracture can be 'guided' to more easily propagate along one specific direction than its opposite. We also observed that there is an optimal value for the spacing between each void for the rectification effect.

Devising Bone Molecular Models at the Nanoscale: From Usual Mineralized Collagen Fibrils to the First Bone Fibers Including Hydroxyapatite in the Extra-Fibrillar Volume.

At the molecular scale, bone is mainly constituted of type-I collagen, hydroxyapatite, and water. Different fractions of these constituents compose different composite materials that exhibit different mechanical properties at the nanoscale, where the bone is characterized as a fiber, i.e., a bundle of mineralized collagen fibrils surrounded by water and hydroxyapatite in the extra-fibrillar volume. The literature presents only models that resemble mineralized collagen fibrils, including hydroxyapatite in the intra-fibrillar volume only, and lacks a detailed prescription on how to devise such models. Here, we present all-atom bone molecular models at the nanoscale, which, differently from previous bone models, include hydroxyapatite both in the intra-fibrillar volume and in the extra-fibrillar volume, resembling fibers in bones. Our main goal is to provide a detailed prescription on how to devise such models with different fractions of the constituents, and for that reason, we have made step-by-step scripts and files for reproducing these models available. To validate the models, we assessed their elastic properties by performing molecular dynamics simulations that resemble tensile tests, and compared the computed values against the literature (both experimental and computational results). Our results corroborate previous findings, as Young's Modulus values increase with higher fractions of hydroxyapatite, revealing all-atom bone models that include hydroxyapatite in both the intra-fibrillar volume and in the extra-fibrillar volume as a path towards realistic bone modeling at the nanoscale.

Renal and overall outcomes of double-positive (ANCA and anti-GBM antibodies) patients compared to ANCA-associated vasculitis patients with severe renal involvement: A multicenter retrospective study with systematic renal pathology analysis.

OBJECTIVE: Double-positive patients (DPPs), combining serum and/or histological findings for glomerular basement membrane (GBM) disease and anti-neutrophil cytoplasmic antibodies (ANCAs), are rare and poorly described. This study aimed to compare characteristics between DPPs and ANCA-associated vasculitis (AAV) patients with severe renal involvement. METHOD: This retrospective multicentre study compared 33 DPPs and 45 AAV patients with severe renal involvement (serum creatinine > 300 µmol/L), all with biopsy-proven nephropathy. RESULTS: All DPPs (including 18% exhibiting negative serum anti-GBM antibodies) presented severe acute kidney failure with histological GBM involvement. Compared to AAV patients, they had higher serum creatinine (719 vs 501 µmol/L; p = 0.006) and a higher proportion of patients requiring initial renal replacement therapy (82% vs 36%; p < 0.001). Berden classification differed significantly (p = 0.003), with more crescentic glomerulonephritis and fewer sclerotic lesions in DPPs. One-year renal survival was significantly lower in DPPs than in AAV patients (27% vs 64%; p < 0.0002). With comparable proportions of ANCA subtypes (two-thirds with anti-myeloperoxidase autoantibodies), numbers of extrarenal manifestations (mostly pulmonary in two-thirds), remission-inducing immunosuppressants, and median follow-ups (3 years) between groups, relapse rates were similar: 9.1% of DPPs and 10% of AAV patients. CONCLUSION: Although DPPs have features of both kinds of vasculitis, the anti-GBM component is the dominant phenotype, with more severe renal presentation and prognosis compared to AAV patients with severe renal failure. Simultaneous testing of both antibodies and systematically performed renal biopsy should be recommended in all rapidly progressing glomerulonephritis patients to recognize this difficult-to-treat, rare disease.

Synthesis, Self-Assembly and In Vitro Cellular Uptake Kinetics of Nanosized Drug Carriers Based on Aggregates of Amphiphilic Oligomers of N-Vinyl-2-pyrrolidone.

Development of nanocarrier-based drug delivery systems is a major breakthrough in pharmacology, promising targeted delivery and reduction in drug toxicity. On the cellular level, encapsulation of a drug substantially affects the endocytic processes due to nanocarrier-membrane interaction. In this study we synthesized and characterized nanocarriers assembled from amphiphilic oligomers of N-vinyl-2-pyrrolidone with a terminal thiooctadecyl group (PVP-OD). It was found that the dissolution free energy of PVP-OD depends linearly on the molecular mass of its hydrophilic part up to M¯n = 2 × 104, leading to an exponential dependence of critical aggregation concentration (CAC) on the molar mass. A model hydrophobic compound (DiI dye) was loaded into the nanocarriers and exhibited slow release into the aqueous phase on a scale of 18 h. Cellular uptake of the loaded nanocarriers and that of free DiI were compared in vitro using glioblastoma (U87) and fibroblast (CRL2429) cells. While the uptake of both DiI/PVP-OD nanocarriers and free DiI was inhibited by dynasore, indicating a dynamin-dependent endocytic pathway as a major mechanism, a decrease in the uptake rate of free DiI was observed in the presence of wortmannin. This suggests that while macropinocytosis plays a role in the uptake of low-molecular components, this pathway might be circumvented by incorporation of DiI into nanocarriers.

Complex nonverbal response inhibition and stopping impulsivity in childhood stuttering.

PURPOSE: The primary purpose of this study was to examine complex nonverbal response inhibition and stopping impulsivity in children who do (CWS) and do not stutter (CWNS). METHOD: A total of 30 CWS and 30 CWNS between the ages of 3;1 and 6;0 (years; months) performed the Peg-Tapping Task (PTT; Diamond & Taylor, 1996; Luria, 1966), in which children were required to tap a dowel once when an examiner taps twice and vice versa. The main dependent variables were the number of practice trials, response accuracy, response latency for accurate responses, and the number of extra taps (i.e., tapping more than two times). RESULTS: The CWS were less accurate and slower on the PTT than the CWNS, with no differences in the number of practice trials. Furthermore, the CWS, especially boys, produced more extra taps than the CWNS. CONCLUSIONS: Findings revealed that preschool CWS have weaknesses in complex response inhibition and stopping impulsivity in the nonverbal domain compared to CWNS. Taken together, these findings along with those of previous studies indicate that CWS may have weaknesses in inhibition and impulsivity in the nonverbal domain as well as the verbal domain, suggesting a domain-general weakness.

ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost.

The impact of a compromised blood-brain barrier (BBB) on the drug treatment of intracranial tumors remains controversial. We characterize the BBB integrity in several intracranial tumor models using magnetic resonance imaging, fluorescent dyes, and autoradiography and determine the distribution and efficacy of docetaxel in brain tumors grafted in Abcb1-proficient and Abcb1-deficient mice. Leakiness of the tumor vasculature varies from extensive to absent. Regardless of the extent of leakiness, tumor blood vessels express ATP-binding cassette transporters (Abcb1 and Abcg2). A leaky vasculature results in higher docetaxel tumor levels compared to normal brain. Nevertheless, Abcb1 can reduce drug distribution and efficacy even in leaky models. Thus, BBB leakiness does not ensure the unimpeded access of ATP-binding cassette transporter substrate drugs. Therapeutic responses may be observed, but the full potential of such therapeutics may still be attenuated. Consequently, BBB-penetrable drugs with little to no affinity for efflux transporters are preferred for the treatment of intracranial tumors.

Intraoperative and early postoperative complications in postchemotherapy retroperitoneal lymphadenectomy among patients with germ cell tumors using validated grading classifications.

BACKGROUND: Postchemotherapy retroperitoneal lymphadenectomy (PC-RPLND) is an essential, yet potentially morbid, therapy for the management of patients with advanced germ cell tumors. In the current study, the authors sought to define the complication profile of PC-RPLND using validated grading systems for intraoperative adverse events (iAEs) and early postoperative complications. METHODS: Between 2000 and 2018, all patients who underwent PC-RPLND were analyzed for iAEs and early postoperative complications using the Kaafarani and Clavien-Dindo classifications, respectively. Logistic regression models were conducted to assess patient and tumor factors associated with iAEs and postoperative complications. RESULTS: Of the 453 patients identified, 115 patients (25%) and 252 patients (56%), respectively, experienced an iAE and postoperative complication. Major iAEs (grade ≥3) were observed in 15 patients (3%) and major postoperative complications (grade ≥3) were noted in 80 patients (18%). The most common iAE was vascular injury (112 of 132 events; 85%), which occurred in 92 patients (20%), and the most frequent postoperative complication was ileus, which occurred in 121 patients (27%). Original and postchemotherapy retroperitoneal mass size, nonretroperitoneal metastases, intermediate and/or poor International Germ Cell Cancer Collaborative Group classification, previous RPLND, elevated tumor markers at the time of RPLND, and anticipated adjuvant surgical procedures increased the risk of both iAEs and postoperative complications. Patients who experienced an iAE were significantly more likely to experience a postoperative complication (odds ratio, 2.50; 95% confidence interval, 1.58-3.97 [P < .001]). CONCLUSIONS: In what to the authors' knowledge is the first analysis of PC-RPLND using validated classifications for both iAEs and postoperative complications, advanced disease and surgical complexity significantly increased the risks of major iAEs and postoperative complications. Standardized reporting of adverse perioperative events allows providers and patients to appreciate the consequences of PC-RPLND during counseling and decision making.

Pulse pressure variability is associated with unfavorable outcomes in acute ischaemic stroke patients treated with intravenous thrombolysis.

BACKGROUND AND PURPOSE: Blood pressure (BP) variability has been associated with worse neurological outcomes in acute ischaemic stroke (AIS) patients receiving treatment with intravenous thrombolysis (IVT). However, no study to date has investigated whether pulse pressure (PP) variability may be a superior indicator of the total cardiovascular risk, as measured by clinical outcomes. METHODS: Pulse pressure variability was calculated from 24-h PP measurements following tissue plasminogen activator bolus in AIS patients enrolled in the Combined Lysis of Thrombus using Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization (CLOTBUST-ER) trial. The outcomes of interest were the pre-specified efficacy and safety end-points of CLOTBUST-ER. All associations were adjusted for potential confounders in multivariable regression models. RESULTS: Data from 674 participants was analyzed. PP variability was identified as the BP parameter with the most parsimonious fit in multivariable models of all outcomes, and was independently associated (P < 0.001) with lower likelihood of both 24-h neurological improvement and 90-day independent functional outcome. PP variability was also independently related to increased odds of any intracranial bleeding (P = 0.011) and 90-day mortality (P < 0.001). Every 5-mmHg increase in the 24-h PP variability was independently associated with a 36% decrease in the likelihood of 90-day independent functional outcome (adjusted odds ratio 0.64, 95% confidence interval 0.52-0.80) and a 60% increase in the odds of 90-day mortality (adjusted odds ratio 1.60, 95% confidence interval 1.23-2.07). PP variability was not associated with symptomatic intracranial bleeding at either 24 or 36 h after IVT administration. CONCLUSIONS: Increased PP variability appears to be independently associated with adverse short-term and long-term functional outcomes of AIS patients treated with IVT.

On the structural stability and optical properties of germanium-based schwarzites: a density functional theory investigation.

Since graphene was synthesized the interest in building new 2D and 3D structures based on carbon allotropes has been growing every day. One of these 3D structures is know as carbon schwarzites. Schwarzites consist of carbon nanostructures possessing the shape of Triply-Periodic Minimal Surfaces (TPMS), which is characterized by a negative Gaussian curvature introduced by the presence of carbon rings with more than six atoms. Some examples of schwarzite families include: primitive (P), gyroid (G) and diamond (D). Previous studies considering different element species of schwarzites have investigated the mechanical, electrical and thermal properties. In this work, we investigated the stability of germanium (Ge) schwarzites using density functional theory with the GGA exchange-correlation functional. We chose one structure of each family (P8bal), (G688) and (D688). It was observed that regions usually flat in carbon schwarzites acquire buckled configurations as previously observed on silicene and germanene monolayers. The investigated structures presented a semiconducting bandgap ranging from 0.13 to 0.27 eV. We also performed calculations of optical properties within the linear regime, where it was shown that Ge schwarzite structures absorb light from infrared to ultra-violet frequencies. Therefore, our results open new perspectives of materials that can be used in optoelectronics device applications.

Optimizing patient selection for cytoreductive nephrectomy based on outcomes in the contemporary era of systemic therapy.

BACKGROUND: The management of metastatic renal cell carcinoma (mRCC) has evolved rapidly, and results from the Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques (CARMENA) trial bring into question the utility of cytoreductive nephrectomy (CN). The objective of this study was to examine overall survival (OS) and identify risk factors associated with patients less likely to benefit from CN in the targeted therapy era. METHODS: Patients with mRCC undergoing CN from 2005 to 2017 were identified. Kaplan-Meier methods and Cox proportional hazards regression analyses were used to assess OS and risk-stratify patients, respectively, on the basis of preoperative clinical and laboratory data. RESULTS: Six hundred eight patients were eligible with a median follow-up of 29.4 months. Ninety-five percent of the patients had an Eastern Cooperative Oncology Group performance status less than or equal to 1, and 70% had a single site of metastatic disease. In a multivariable analysis, risk factors significantly associated with decreased OS included systemic symptoms at diagnosis, retroperitoneal and supradiaphragmatic lymphadenopathy, bone metastasis, clinical T4 disease, a hemoglobin level less than the lower limit of normal (LLN), a serum albumin level less than the LLN, a serum lactate dehydrogenase level greater than the upper limit of normal, and a neutrophil/lymphocyte ratio greater than or equal to 4. Patients were stratified into 3 risk groups: low (fewer than 2 risk factors), intermediate (2-3 risk factors), and high (more than 3 risk factors). These groups had median OS of 58.9 months (95% confidence interval [CI], 44.3-66.6 months), 30.6 months (95% CI, 27.0-35.0 months), and 19.2 months (95% CI, 13.9-22.6 months), respectively (P < .0001). The median time to postoperative systemic therapy was 45 days (interquartile range, 30-90 days). CONCLUSIONS: Patients with more than 3 risk factors did not seem to benefit from CN. Importantly, OS in this group was equivalent to, if not higher than, OS for patients in the CN plus sunitinib arm of CARMENA, and this raises the possibility that a well-selected population might benefit from CN.