Non-parametric estimation of survival probabilities with a time-dependent exposure switch: application to (simulated) heart transplant data

Background: To summarize the survival experience of patients waiting for heart transplant and to compare it with the post-transplant survival it is not possible to use the Kaplan-Meier estimator considering the intervention status as fixed in time because of the well known "immortaltime bias" issue.Methods: We reviewed and applied to a simulated dataset the available methods to perform a non-parametric analysis accounting for the time-varying nature of the transplant status. Specifically we considered the Simon-Makuch estimator and the recently proposed "clock-back" estimator.Results: We showed that the Simon-Makuch estimator for the survival of patients on list is unbiased but the corresponding estimator of the post-transplant survival is not reliable for non-markov contexts like the one considered. Instead, if the semi-Markov assumption could be postulated (the post-transplant mortality depends mainly on the time since transplant and not on the waiting time to the intervention), the "clock-back" estimator produces valid results.Conclusion: We enlightened the importance of testing the process memory assumptions (e.g. Markov properties) in order to choose the approach more reliable. Moreover, we recommend the use of the Simon-Makuch method to study the survival of patients before the interventionand the use of the "clock back" estimator for the post-intervention survival in semi-markovian contexts

Patterns of recurrences in sinonasal cancers undergoing an endoscopic surgery-based treatment: Results of the MUSES* on 940 patients: *MUlti-institutional collaborative Study on Endoscopically treated Sinonasal cancers

The improvements in survival with expansion of the survivors' population, along with evolution of endoscopically-based treatment modalities, have contributed to emphasize the clinical relevance of recurrences in sinonasal cancers. However, at present, literature is scant regarding the pattern of recurrences and the therapeutic strategies available to manage long survivors who experienced single or multiple failures. The aim of the present study was to analyze sinonasal cancers recurrences to provide data regarding rates and patterns of relapse, predictors of failure and prognostic impact of the recurrence

ERAS with or without supplemental artificial nutrition in open pancreatoduodenectomy for cancer. A multicenter, randomized, open labeled trial (RASTA study protocol)

PurposeThe role of supplemental artificial nutrition in patients perioperatively treated according to enhanced recovery programs (ERAS) on surgery-related morbidity is not known. Therefore, there is a need of a clinical trials specifically designed to explore whether given a full nutritional requirement by parenteral feeding after surgery coupled with oral food “at will” compared to oral food “at will” alone, within an established ERAS program, could achieve a reduction of the morbidity burden.Materials and analysisRASTA will be a multicenter, randomized, parallel-arm, open labeled, superiority trial. The trial will be conducted in five Italian Institutions with proven experience in pancreatic surgery and already applying an established ERAS program. Adult patients (age ≥ 18 and < 90 years of age) candidate to elective open pancreatoduodenectomy (PD) for any periampullary or pancreatic cancer will be randomized to receive a full ERAS protocol that establishes oral food “at will” plus parenteral nutrition (PN) from postoperative day 1 to day 5 (treatment arm), or to ERAS protocol without PN (control arm). The primary endpoint of the trial is the complication burden within 90 days after the day of surgery. The complication burden will be assessed by the Comprehensive Complication Index, that incorporates all complications and their severity as defined by the Clavien-Dindo classification, and summarizes postoperative morbidity with a numerical scale ranging from 0 to 100. The H0 hypothesis tested is that he administration of a parenteral nutrition added to the ERAS protocol will not affect the CCI as compared to standard of care (ERAS). The H1 hypothesis is that the administration of a parenteral nutrition added to the ERAS protocol will positively affect the CCI as compared to standard of care (ERAS). The trial has been registered at ClinicalTrials.gov (number: NCT04438447; date: 18/05/2020).ConclusionThis upcoming trial will permit to establish if early postoperative artificial nutritional support after PD may improve postoperative outcomes compared to oral nutrition alone within an established ERAS program

Placental pathology in perinatal asphyxia: a case–control study

IntroductionPlacentas of term infants with birth asphyxia are reported to have more lesion such as maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM) and chorioamnionitis with fetal response (FIR) than those of term infants without birth asphyxia. We compared the placental pathology of asphyxiated newborns, including those who developed hypoxic-ischemic encephalopathy (HIE), with non-asphyxiated controls.MethodsWe conducted a retrospective case–control study of placentas from neonates with a gestational age ≥ 35 weeks, a birthweight ≥ 1,800 g, and no malformations. Cases were asphyxiated newborns (defined as those with an umbilical artery pH ≤ 7.0 or base excess ≤ −12 mMol, 10-minute Apgar score ≤ 5, or the need for resuscitation lasting >10 min) from a previous cohort, with (n=32) and without (n=173) diagnosis of HIE. Controls were non-asphyxiated newborns from low-risk l (n= 50) or high-risk (n= 68) pregnancies. Placentas were analyzed according to the Amsterdam Placental Workshop Group Consensus Statement 2014.ResultsCases had a higher prevalence of nulliparity, BMI>25, thick meconium, abnormal fetal heart monitoring, and acute intrapartum events than controls (p<0.001). MVM and FVM were more frequent among non-asphyxiated than asphyxiated newborns (p<0.001). There was no significant difference in inflammatory lesions or abnormal umbilical insertion site. Histologic meconium-associated changes (MAC) were observed in asphyxiated newborns only (p= 0.039).DiscussionOur results confirm the role of antepartum and intrapartum risk factors in neonatal asphyxia and HIE. No association between neonatal asphyxia and placental lesions was found, except for in the case of MAC. The association between clinical and placental data is crucial to understanding and possibly preventing perinatal asphyxia in subsequent pregnancies

Altered adipocyte differentiation and unbalanced autophagy in type 2 Familial Partial Lipodystrophy: an in vitro and in vivo study of adipose tissue browning

Type-2 Familial Partial Lipodystrophy is caused by LMNA mutations. Patients gradually lose subcutaneous fat from the limbs, while they accumulate adipose tissue in the face and neck. Several studies have demonstrated that autophagy is involved in the regulation of adipocyte differentiation and the maintenance of the balance between white and brown adipose tissue. We identified deregulation of autophagy in laminopathic preadipocytes before induction of differentiation. Moreover, in differentiating white adipocyte precursors, we observed impairment of large lipid droplet formation, altered regulation of adipose tissue genes, and expression of the brown adipose tissue marker UCP1. Conversely, in lipodystrophic brown adipocyte precursors induced to differentiate, we noticed activation of autophagy, formation of enlarged lipid droplets typical of white adipocytes, and dysregulation of brown adipose tissue genes. In agreement with these in vitro results indicating conversion of FPLD2 brown preadipocytes toward the white lineage, adipose tissue from FPLD2 patient neck, an area of brown adipogenesis, showed a white phenotype reminiscent of its brown origin. Moreover, in vivo morpho-functional evaluation of fat depots in the neck area of three FPLD2 patients by PET/CT analysis with cold stimulation showed the absence of brown adipose tissue activity. These findings highlight a new pathogenetic mechanism leading to improper fat distribution in lamin A-linked lipodystrophies and show that both impaired white adipocyte turnover and failure of adipose tissue browning contribute to disease.We thank FPLD2 patients for donating biological samples. We thank the Italian Network for Laminopathies and the European Consortium of Lipodystrophies (ECLip) for support and helpful discussion. We thank Aurelio Valmori for the technical support. The studies were supported by Rizzoli Orthopedic Institute “5 per mille” 2014 project to MC, AIProSaB project 2016 and Fondazione Del Monte di Bologna e Ravenna grant 2015–2016 “New pharmacological approaches in bone laminopathies based on the use of antibodies neutralizing TGF beta 2” to GL. GL is also supported by PRIN MIUR project 2015FBNB5Y.S

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Description of survival data extended to the case of competing risks: a teaching approach based on frequency tables

Survival analysis is a powerful statistical tool to study failure-time data. In introductory courses students learn how to describe right-censored survival time data using the product-limit estimator of the survival function on a given end-point relying on a product of conditional survival probabilities. In the case of a composite end-point, the next step is to account for the presence of competing risks. The complement to one of the survival function is decomposed into the sum of cause-specific incidences, which are obtained as sum of unconditional probabilities due to the single competing risk. However, this algebraic decomposition is not straightforward, given the difference between the structure of the involved estimators. In addition, one is tempted to use the Kaplan-Meier estimator, leading to an erroneous decomposition of the overall incidence. Here we discuss a simple reinterpretation of the Kaplan-Meier formula in terms of sum of non-conditional probabilities of developing the end-point in time, adjusted for the presence of censoring. This approach could be used for describing survival data through simple frequency tables which are directly generalized to the case of competing risks. In addition, it makes clear how the estimation of the single cause-specific incidence through the Kaplan-Meier estimator, simply considering the occurrence of competing events as censored data, leads to an overestimation of the cause-specific incidence. Two examples are provided to support the explanation: the first one, could help to clarify the procedure described by the formulas; the second one, simulates real data in order to present graphically the results