Lung Protective Mechanical Ventilation in Severe Acute Brain Injured Patients: A Multicenter, Randomized Clinical Trial (PROLABI).

BACKGROUND: Lung protective strategies using low tidal volumes and moderate positive end expiratory pressures (PEEP) are considered best practice in critical care, but interventional trials have never been conducted in acutely brain-injured patients due to concerns about carbon dioxide control and effect of PEEP on cerebral hemodynamic. METHODS: In this multicenter, open-label, controlled clinical trial 190 adult acute brain injured patients were assigned to receive either a lung-protective or a conventional ventilatory strategy. The primary outcome was a composite endpoint of death, ventilator dependency and ARDS at day 28. Neurological outcome was assessed at intensive care unit discharge by Oxford Handicap Scale and at six months by Glasgow Outcome Scale. FINDINGS: The two study arms had similar characteristics at baseline. In the lung-protective and conventional strategy groups, using an intention-to-treat approach, the composite outcome at 28 days was 61.5% and 45.3% (RR 1.35; 95%CI 1.03-1.79; p=0.025). Mortality was 28.9% and 15.1% (RR 1.91; 95%CI 1.06-3.42; p=0.02), ventilator dependency was 42.3% and 27.9% (RR 1.52; 95%CI 1.01-2.28; p=0.039), and incidence of ARDS was 30.8% and 22.1% (RR 1.39; 95%CI 0.85-2.27; p=0.179) respectively. The trial was stopped after enrolling 190 subjects because of termination of funding. INTERPRETATION: In acutely brain-injured patients without ARDS a lung-protective ventilatory strategy as compared to a conventional strategy did not reduce mortality, percentage of patients weaned from mechanical ventilation, incidence of ARDS and was not beneficial in terms of neurological outcomes. Due to the early termination, these preliminary results require confirmation in larger trials. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT01690819.

Discovered cancers at postmortem donor examination: A starting point for quality improvement of donor assessment.

BACKGROUND: clinical and imaging investigations allow a detailed assessment of an organ donor, but a quota of cancer still elude detection. Complete autopsy of donors is even less frequently performed, due to economic issues and increasing availability of high-quality imaging. The aim of this study is to gather evidence from the literature on donor malignancy discovered at autopsy following organ donation and to discuss the utility and limitations of autopsy practice in the field of transplantation. METHODS: A systematic search according to PRISMA guidelines was carried out in Pubmed and Embase databases until September 2020 to select articles with reporting of cancer discovered in a donor at postmortem examination. Cancer discover in not-transplant setting were excluded. A descriptive synthesis was provided. RESULTS: Of 7388 articles after duplicates removal, 56 were included. Fifty-one studies reported on complete autopsy, while 5 dealt only with limited autopsy (prostate and central nervous system). The number of autopsies ranged between 1 and 246 with a total of 823 autopsies performed. The most frequent cancer discovered at autopsy was lymphoma (n = 13, 15%), followed by renal cell carcinoma (RCC) (n = 11, 13%), non-small cell lung cancer (NSCLC) (n = 10, 11%), melanoma (n = 10, 11%), choriocarcinoma (n = 6, 7%) and glioblastoma (GBM) (n = 6, 7%). CONCLUSIONS: Lymphoma and melanoma are still difficult-to-detect cancers both during donor investigation and at procurement, whilst prostate cancer and choriocarcinoma are almost always easily detected nowadays thank to blood markers and clinical examination. There have been improvements with time in pre-donation detection procedures which are now working well, particularly when complete imaging investigations are performed, given that detection rate of CT/MRI is high and accurate. Autopsy can play a role to help to establish the correct donor management pathways in case of cancer discover. Furthermore, it helps to better understand which cancers are still eluding detection and consequently to refine guidelines' assessment procedures.

Histopathology and Long-Term Outcome of Kidneys Transplanted From Donors With Severe Acute Kidney Injury.

BACKGROUND: Acute kidney injury is a treatable entity although difficult to recognize without diagnostic biopsy. We investigated the potential association between clinically defined deceased donors and acute kidney injury with preimplantation histological findings and recipient outcomes. METHODS: Kidney biopsies from donors were classified using the Acute Kidney Injury Network criteria and assessed for percentage glomerulosclerosis, tubular atrophy, interstitial fibrosis, and vascular narrowing with the Remuzzi score and for acute tubular necrosis. Differences in incidence rates of delayed graft function (DGF) and cumulative rejection episodes were compared between recipients transplanted with normal and 3 levels of acute kidney injury using the analysis of variance with Bonferroni correction ( P = .0012). RESULTS: Sixteen out of 335 donors showed a severe acute kidney injury level 3 with a median serum creatinine of 458 µmol/L. Fourteen (88%) had 0-3 Remuzzi score and were used for single kidney transplantation and 2 (12%) were used for dual kidney transplantation (score: 4-6). Recipients who received a kidney from a donor with level 3 acute kidney injury had a higher percentage of DGF (47%) without statistical significance ( P = .008). The rate of cumulative rejection (45%) at 2 years was not significantly increased ( P = .09). CONCLUSIONS: Recipients receiving level 3 acute kidney injury kidneys, selected with Remuzzi histopathological score and acute tubular necrosis assessment, had a greater incidence of DGF but a similar long-term cumulative rejection compared to no injury and level 1 and level 2 acute kidney injury donors. The application of the histopathological examination allowed expansion of the kidney donor pool.

Rapid screening for malignancy in organ donors: 15-year experience with the Verona "Alert" protocol and review of the literature.

BACKGROUND: Prevention of transmission of malignancy from donors to recipients is an aim of donor assessment. We report the most stringent interpretation of the Italian National Guidelines. METHODS: A two-step ALERT process was used: ALERT1 consisting of clinical, radiological, and laboratory tests; ALERT2, consisting of intraoperative assessment in suspicious lesions. RESULTS: Four hundred of 506 potential deceased donors entered the ALERT system. Forty-one of 400 (10%) donors were excluded due to unacceptable risk of transmission. Of the remaining 359 193 required histopathology, which excluded malignancy or determined acceptable risk in 161/193 (83%). Thirty-five malignancies were identified: 19 (54%) at ALERT1, four (11%) at ALERT2, nine (26%) picked up at ALERT1 and confirmed by ALERT2. Three (9%) were missed by ALERT and diagnosed at postmortem examination. Prostate (n=12%, 34%) and renal cell (n=7%, 20%) were the most frequent carcinomas. The majority (92%) of prostate adenocarcinomas were of low risk and donation proceeded compared to 43% of renal carcinomas. Four renal carcinomas, two breast carcinomas, and a single case of nine different malignancies excluded donation. Positive ALERT donors had statistically more malignant reports than negative ALERT donors (P=<.05). CONCLUSION: Histopathology is an essential component of the multidisciplinary assessment of donors.

De Novo Renal Neoplasia After Kidney Transplantation According to New 2016 WHO Classification of Renal Tumors.

BACKGROUND De novo renal neoplasia developing after kidney transplantation at Verona Kidney Transplant Center were reviewed according to new 2016 WHO Renal Tumor Classification. MATERIAL AND METHODS Primary renal tumors developed in native or transplanted kidneys de novo following renal transplantation were retrieved and histologically reviewed by three expert uropathologists. Immunoexpression of the diagnostic antigens CD13, CD10, CK7, CK34bE12, AMACR, CAIX, AE1/AE3, CK14, GATA-3, HMB-45, cathepsin-k, S100A1, and parvalbumin was assessed. Predictive antigens ph-mTOR and ph-p70S6k were also tested. RESULTS Two thousands and sixteen kidney transplantations have been carried out from 1968-2015. Follow-up was available per 1,646 patients (mean 8.4 years). We observed 16 cases of de novo renal neoplasia arising in patients 16 to 286 months post-transplantation. Nine clear cell, two papillary RCCs and a single case of the new WHO entity denominated "acquired cystic disease-associated RCC" were identified in native kidneys. Another new WHO tumor entity called "clear cell papillary RCC" was diagnosed and a new variant of papillary RCC with diffuse clear cytoplasm was also identified. The majority of tumors were low stage and low grade according to the new ISUP grading system. Seven patients were additionally treated with mTOR inhibitors. Post-cancer follow-up ranged from 62 to 281 months. One patient showed a recurrence (a lung metastases) and died. Of the remaining patients, three died of non-cancer-related causes. CONCLUSIONS The application of the new WHO 2016 classification has importance as it identifies new (18% of tumors) morphotypes that are likely to behave in a less aggressive fashion.

Donor kidneys with miliary papillary renal cell neoplasia: the role of the pathologist in determining suitability for transplantation.

BACKGROUND: Kidneys with single or multiple tumors, provided that they have histological features recognized as being associated with low risk of recurrence, are considered suitable for transplantation. It is known that kidneys with multiple primary renal tumors show poor renal function and that function dramatically declines when tumors have a miliary configuration. Despite this, no guidelines are in place to differentiate between multifocal tumors and those that are miliary in nature. CASE REPORT: We report a case in which initial examination revealed papillary renal cell neoplasia in deceased donor kidneys, which were later confirmed on histological and genetic testing to be multiple and miliary in distribution. Gross examination showed closely opposed neoplasms, and on histological examination these were found to be papillary renal cell carcinomas and renal papillary adenomas. This ultimately led to the decision that both kidneys were unsuitable for transplantation. CONCLUSIONS: At present there are no recommendations as to how tumor-bearing donor kidneys should be handled in order to determine if miliary neoplasia is present. From our case it is apparent that, in addition to obvious tumor nodules, at least 3 samples of cortex should be examined. This case highlights the important role of the pathologist in assessing donor kidneys with evidence of neoplasia.