HCV resistance compartmentalization within tumoral and non-tumoral liver in transplanted patients with hepatocellular carcinoma.

BACKGROUND & AIMS: We investigated the HCV-RNA amount, variability and prevalence of resistance-associated substitutions (RASs), in plasma, hepatic tumoral and non-tumoral tissue samples in patients undergoing liver-transplant/hepatic-resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. METHODS: Eighteen HCV-infected patients undergoing LT/HR, 94.0% naïve to direct-acting antivirals (DAAs), were analysed. HCV-RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non-tumoral tissues were analysed using Sanger and Ultra-deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic-variability and phylogenetic analysis were evaluated. RESULTS: At the time of LT/HR, HCV-RNA was quantifiable in all compartments of DAA-naïve patients and was generally lower in tumoral than in non-tumoral tissues (median [IQR] = 4.0 [1.2-4.3] vs 4.3[3.1-4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV-RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non-tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected-patients, and by UDPS in other two patients. HCV-compartmentalization resulted to be associated with HBcAb-positivity (P = 0.013). UDPS showed approximately higher genetic-variability in NS3/NS5A sequences in all compartments. Phylogenetic-analysis showed defined and intermixed HCV-clusters among/within all compartments, and were strongly evident in the only non-cirrhotic patient, with plasma and non-tumoral sequences generally more closely related. CONCLUSIONS: Hepatic compartments showed differences in HCV-RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV-strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs.

Risk of virus and non-virus related malignancies following immunosuppression in a cohort of liver transplant recipients. Italy, 1985-2014.

This cohort study assessed, in Italy, the overall pattern of risk of de novo malignancies following liver transplantation (LT). The study group included 2,832 individuals who underwent LT between 1985 and 2014 in nine centers all over Italy. Person-years (PYs) at cancer risk were computed from 30 days after LT to the date of cancer diagnosis, to the date of death or to the end of follow-up. Excess cancer risk, as compared to the general population, was estimated using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). During 18,642 PYs, 246 LT recipients developed 266 de novo malignancies, corresponding to a 1.8-fold higher cancer risk (95% CI: 1.6-2.0). SIRs were particularly elevated for virus-related malignancies, including Kaposi's sarcoma (SIR = 53.6, 95% CI: 30.0-88.5), non-Hodgkin lymphomas (SIR = 7.1, 95% CI: 4.8-10.1) and cervix uteri (SIR = 5.4, 95% CI: 1.1-15.8). Among virus-unrelated malignancies, elevated risks emerged for head and neck (SIR = 4.4, 95% CI: 3.1-6.2), esophagus (SIR = 6.7, 95% CI: 2.9-13.3) and adrenal gland (SIR = 22.9, 95% CI: 2.8-82.7). Borderline statistically significant elevated risks were found for lung cancer (SIR = 1.4, 95% CI: 1.0-2.1) and skin melanoma (SIR = 2.6, 95% CI: 1.0-5.3). A reduced risk emerged for prostate cancer (SIR = 0.1, 95% CI: 0.0-0.5). These findings underline the need of preventive interventions and early detection of malignancies, specifically tailored to LT recipients.

Longterm Survival and Cost-Effectiveness of Immunosuppression Withdrawal After Liver Transplantation.

Lifelong immunosuppression (IS) after liver transplantation is associated with severe adverse effects and increased recipients' morbidity and mortality. Clinical operational tolerance has been reported in up to 40% in very well-selected recipients. Longterm survival and cost savings within the Italian national health system in operational tolerant recipients is reported. Seventy-five liver recipients were enrolled for IS withdrawal at our institution during the period from April 1998 to December 2015. The study population comprised 32 (42.7%) tolerant patients; 41 (54.7%) nontolerant patients needing uptake of IS after clinical or biopsy-proven rejection; and 2 (2.7%) immediate nontolerant patients who developed early rejection after the first drug reduction. The primary endpoint of the study was to assess the longterm patients and graft outcome; the secondary endpoint was the assessment of cost savings in the context of IS withdrawal. The follow-up was 95.0 months (interquartile range, 22.5-108.5 months). IS withdrawal did not result in patient nor graft loss and resulted in a major cost savings reaching about €630,000. In conclusion, longterm IS withdrawal represents a remarkable cost savings in the health care of liver recipients without exposing them to graft loss.

Head and neck and esophageal cancers after liver transplant: results from a multicenter cohort study. Italy, 1997-2010.

This study quantified the risk of head and neck (HN) and esophageal cancers in 2770 Italian liver transplant (LT) recipients. A total of 186 post-transplant cancers were diagnosed-including 32 cases of HN cancers and nine cases of esophageal carcinoma. The 10-year cumulative risk for HN and esophageal carcinoma was 2.59%. Overall, HN cancers were nearly fivefold more frequent in LT recipients than expected (standardized incidence ratios - SIR=4.7, 95% CI: 3.2-6.6), while esophageal carcinoma was ninefold more frequent (SIR=9.1, 95% CI: 4.1-17.2). SIRs ranged from 11.8 in LT with alcoholic liver disease (ALD) to 1.8 for LT without ALD for HN cancers, and from 23.7 to 2.9, respectively, for esophageal carcinoma. Particularly elevated SIRs in LT with ALD were noted for carcinomas of tongue (23.0) or larynx (13.7). Our findings confirmed and quantified the large cancer excess risk in LT recipients with ALD. The risk magnitude and the prevalence of ALD herein documented stress the need of timely and specifically organized programs for the early diagnosis of cancer among LT recipients, particularly for high-risk recipients like those with ALD.

Bilateral native kidney neoplasia detected by ultrasound in functionning renal allograft recipient.

We report the case of bilateral renal clear cell carcinoma in the native kidney, occurring fouryears after renal transplantation. Renal Doppler duplex sonography revealed large solid bilateral neoformation. Total-body computed tomography confirmed the presence of bilateral kidney lesions and also showed the presence of concomitant gross dyscariocinetic lesion of left hemotorax. The patient underwent bilateral native nephrectomy and the histological diagnosis was renal cell carcinoma. Subsequent left upper lobectomy revealed necrotic keratinizing squamous cell carcinoma. Then, the patients was switched tacrolimus to everolimus treatment and mycophenolate mofetil was reduced.

Acute Appendicitis During Coronavirus Disease 2019 (COVID-19): Increasing Incidence of Complicate Appendicitis, Severity and Length of Hospitalization.

BACKGROUND/AIM: COVID-19 is rapidly spreading, and due to the high morbidity and mortality caused by the pandemic many Governments have introduced social restrictions. Those measures combined with infection-related patient anxiety, led to hiding other diseases. The aim of this study was to evaluate the impact of COVID-19 on numbers and severity of acute appendicitis cases referred during the pandemic. PATIENTS AND METHODS: Between March 2019 and March 2021, all patients who underwent appendectomy in Tor Vergata Hospital, Rome were included. Patients were divided in two groups (COVID-19/pre-COVID-19). Clinical features, intraoperative findings, hospital stay, and histologic examination data were included in the retrospective analysis. RESULTS: Out of 334 admitted patients, 36 (10.7%) had a diagnosis of acute appendicitis (COVID-19 group) vs. 59(11.2%) in the pre-COVID-19 group. The COVID-19 group presented significantly longer hospitalization, incidence of appendicular abscess, perforation, and severity of inflammation at univariate analysis p=0.002, p=0.021, p=0.001, p=0.006, p=0.001, respectively. At multivariate analysis, appendicular abscess (p=0.015) and higher serum levels of C reactive protein (p<0.008) were associated with prolonged hospital stay. CONCLUSION: This study highlights the correlation between COVID-19 pandemic and the severity of acute appendicitis presentations.

Long-term, maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (LT) is universal. We designed a retrospective case-control study to evaluate the effect of mycophenolate mofetil (MMF) monotherapy in patients with recurrent hepatitis C. Fifteen patients with histologically proven hepatitis C recurrence after LT were switched from calcineurin inhibitors (CNIs) to MMF monotherapy because of impairment of kidney function and/or metabolic side effects, and treated for 48 months (MMF group). Fifteen well-matched LT recipients who continued to receive CNIs therapy over the same period served as control group. Demographics, clinical data, time after LT, and baseline liver biopsies were similar in the two groups. There was no worsening of hepatic fibrosis during the study in the MMF group [2.6 ± 1.5 (baseline) Ishak Units vs. 2.7 ± 1.8 (after 48 months of MMF treatment), P = 0.6]. In contrast, a significant increase in the fibrosis score [2 ± 1.1 (baseline) vs. 3.2 ± 1.7 (after 48 months of CNI treatment), P = 0.0002] was observed in the control group. The yearly fibrosis progression rate was of 0.05 ± 0.44 in the MMF group and 0.33 ± 0.24 in the CNI group (P = 0.04). MMF monotherapy is associated with a favourable effect on hepatic fibrosis progression in HCV liver transplant recipients.

A Rare Case of Xanthogranulomatous Pyelonephritis with Spontaneous Renocolic Fistula and IVC Thrombosis.

Xanthogranulomatous pyelonephritis (XGPN) is a rare disorder affecting the kidney which can fistulise to the colon in exceptional cases. We herein report a case of XGPN with renocolic fistula and large vessel thrombosis presenting with sepsis and pulmonary embolism. Preoperative diagnosis and strategic planning resulted in successful management. A 64-year-old woman presented to the emergency department with abdominal pain and a septic condition, corroborated by venous thromboembolism. Workup diagnosed a left renal abscess with calicocolic fistula. Scintigraphy confirmed a nonfunctioning left kidney. The patient underwent inferior vena cava filter placement and staged surgery. The first, damage control procedure was a loop ileostomy. Ten days later, when the patient's conditions improved, she underwent left nephrectomy and left colectomy with primary anastomosis. Finally, a year later, the ileostomy was closed. At follow-up, the patient was well, with unremarkable renal function. Scrupulous diagnostics, multidisciplinary decision making, and staged intervention have been key to optimal outcome.

A Low-Grade Appendiceal Mucinous Neoplasia and Neuroendocrine Appendiceal Collision Tumor: A Case Report and Review of the Literature.

BACKGROUND Incidental appendiceal neoplasms account for 1-2% of appendectomies. Mucinous neoplasms and carcinoids are the most frequent lesions, with an incidence of 0.6% and 0.3-0.9%, respectively. Appendiceal collision tumors are extremely rare and result from the proliferation of 2 different cellular lines. This report describes a young woman with a collision tumor composed of a low-grade appendiceal mucinous neoplasia (LAMN) and an appendiceal neuroendocrine tumor (ANET). CASE REPORT A 31-year-old woman was admitted to our institution presenting with abdominal pain and dysuria. After ultrasound assessment of a dilated appendix with wall thickening and distension by anechogenic material, a diagnosis of acute appendicitis was made. The patient, after a period of antibiotic therapy and observation, underwent an urgent laparoscopic appendectomy due to worsening condition. Surprisingly, the histological exam revealed a Tis LAMN extending from the base of the appendix to the resection margins, and a T3 grade-1 ANET, chromogranin-A and synaptophysin-positive, with a Ki67 less than 1%. On the basis of histological examination and European Neuroendocrine Tumor Network guidelines, in light of the positive LAMN resection margin and ANET mesoappendiceal invasion, after multidisciplinary team discussion, an elective laparoscopic hemicolectomy was indicated. The patient is now in good condition following a regular 5-year follow-up. CONCLUSIONS A collision LAMN and ANET is an exceedingly rare condition. The heterogeneity of clinical presentation and lack of solid evidence seem to recommend a tailored management. Laparoscopy is a safe and useful tool in localized mass excision.

Ileal Neuroendocrine Tumor in a Patient with Sclerosing Mesenteritis: Which Came First?

BACKGROUND Jejunoileal neuroendocrine tumors (JI-NETs) are rare tumors that can be associated with mesenteric fibrosis. This case report is of an incidental finding of a JI-NET in a patient who was previously misdiagnosed with sclerosing mesenteritis. CASE REPORT A 42-year-old man was admitted to our institution with diffuse abdominal pain and clinical and radiographic signs of bowel obstruction. He had a previous diagnosis of sclerosing mesenteritis, which had been histologically diagnosed after an exploratory laparoscopy performed in 2009 for recurrent acute abdominal pain. He was also annually monitored through computed tomography scans for an incidentally discovered, gradually enlarging mesenteric mass for which a "wait and watch" management approach was adopted. After a period of fasting and observation, the patient underwent an urgent exploratory laparotomy because of his worsening condition. Intraoperatively, an ileocecal resection was performed, along with excision of the known mesenteric mass. The pathology report revealed an ileal NET with nodal metastases within the mesentery and mesenteric tumor deposits (pT3N1). CONCLUSIONS JI-NETs are rare entities, which are usually encountered as incidental findings or in patients with unspecific abdominal pain. Our case represents a probable delayed diagnosis of JI-NET in the context of sclerosing mesenteritis; therefore, a possible association between these 2 conditions should be investigated.

Long-Term SARS-CoV-2 Infection Associated with Viral Dissemination in Different Body Fluids Including Bile in Two Patients with Acute Cholecystitis.

Our study aimed to investigate the kinetics of SARS-CoV-2 RNA in bile and in different body fluids of two SARS-CoV-2 positive patients with acute cholecystitis by innovative droplet digital PCR (ddPCR) assays. For each patient, nasopharyngeal- and rectal swabs, bile, urine, and plasma samples were collected at different time points for SARS-CoV-2 RNA quantification by two ddPCR assays. For both patients, ddPCR revealed persistent and prolonged detection of viral RNA in the nasopharyngeal swab despite triple-negative or single-positive results by qRT-PCR. In Patient 1, SARS-CoV-2 RNA dropped more rapidly in bile and rectal-swab and declined slowly in nasopharyngeal swab and plasma, becoming undetectable in all compartments 97 days after symptoms started. Conversely, in patient 2, SARS-CoV-2 RNA was detected, even if at low copies, in all body samples (with the exception of urine) up to 75 days after the onset of symptoms. This study highlights that SARS-CoV-2 RNA can persist for a prolonged time in respiratory samples and in several biological samples despite negativity to qRT-PCR, supporting SARS-CoV-2's ability to provoke persistent and disseminated infection and therefore to contribute to extra-pulmonary clinical manifestations.

Native Nephrectomy in Patients With Autosomal Dominant Polycystic Kidney Disease Evaluated for Kidney Transplantation.

Native nephrectomy (NN) in patients with autosomal dominant polycystic kidney disease (ADPKD) is indicated in cases of recurrent urinary tract infections and hematuria, neoplastic degeneration, and encumbrance. Timing, indication, and surgical approach of NN depends on the symptoms or policy of the center. The aim of our study is to evaluate our experience. In our retrospective study, we included 130 patients with a diagnosis of ADPKD from 530 patients evaluated for renal transplantation from 2011 to 2017. We analyzed the etiologic indication, the timing, and the complications of NN. In our cohort, 53 patients underwent open NN, 85% pre-kidney transplantation (KT), 13% post-KT, and only 1 case simultaneous with KT. In the pre-KT group, indications included: major indication was encumbrance in the. In the post-KT group, the major indication was infection followed by encumbrance, which developed after KT. Complications were: 3 cases of bleeding (1 required relaparotomy, 2 evolved into hematoma and radiological derange); 1 iatrogenic iliac artery injury, which was contextually repaired, and 5 cases of incisional hernia. At 35 ± 7.2 months follow-up, patients' survival was 96%; 1 patient died at the induction of anesthesia and 1 patient from sepsis after double NN and removal of nonfunctional transplanted kidney. NN is not without complications and should be performed when clearly indicated. In our experience, we preferred to perform NN before KT.

Prostate Cancer Recurrence in Kidney Transplant Recipient 15 Years After Radical Prostatectomy: A Case Report.

Incidence of malignant tumors in kidney transplant recipients is higher than nontransplanted population due to many factors, such as immunosuppression therapy and complex donor-recipient interaction. Genitourinary malignancies have been reported as the second most common malignancy in kidney transplant recipients. In this regard, prostate cancer is the most common neoplasm. Herein, we describe a rare case of prostate cancer recurrence after 15 years in a patient who underwent kidney transplant after radical prostatectomy.

Erythrocyte glutathione transferase in kidney transplantation: a probe for kidney detoxification efficiency.

Erythrocyte glutathione transferase (e-GST) is overexpressed in case of increased blood toxicity and its level correlates with the kidney disease progression. Thus, it represents a probe of kidney efficiency against circulating toxins. We measured the activity of e-GST in patients with transplant kidney from living and cadaver donors, correlated its level to biochemical parameters of kidney function, and measured the level of oxidized albumin as a probe of oxidative stress using a new simple procedure. Interestingly, the activity of e-GST in transplant patients from cadaver donors (N = 153) is very high (11.7 U/gHb) compared to healthy subjects (N = 80) ( 5.6 U/gHb). Lower values were observed in transplant patients with kidney from living donors (N = 16) (9.8 U/gHb). Except for steroids, no correlation has been found with the immunosuppressive therapies and routine clinical and laboratory parameters. Also serum oxidized albumin, which reveals oxidative stress, is significantly higher in transplant patients from cadaver donors (53%) compared to that from living donors (36%). Overall, these data indicate that most of transplant kidneys from cadavers lost part of the detoxifying power against circulating toxins and suffer a relevant oxidative stress compared to those coming from living donors. A case report suggests that e-GST could represent a very early marker of incipient graft rejection. In conclusion, e-GST may be used to check the decline or maintenance of the kidney detoxification competence during post-transplantation course.

HCV-RNA quantification in liver bioptic samples and extrahepatic compartments, using the abbott RealTime HCV assay.

BACKGROUND & AIMS: We evaluated the performance of a rapid method to quantify HCV-RNA in the hepatic and extrahepatic compartments, by using for the first time the Abbott RealTime HCV-assay. METHODS: Non-tumoral (NT), tumoral (TT) liver samples, lymph nodes and ascitic fluid from patients undergoing orthotopic-liver-transplantation (N=18) or liver resection (N=4) were used for the HCV-RNA quantification; 5/22 patients were tested after or during direct acting antivirals (DAA) treatment. Total RNA and DNA quantification from tissue-biopsies allowed normalization of HCV-RNA concentrations in IU/µg of total RNA and IU/106 liver-cells, respectively. RESULTS: HCV-RNA was successfully quantified with high reliability in liver biopsies, lymph nodes and ascitic fluid samples. Among the 17 untreated patients, a positive and significant HCV-RNA correlation between serum and NT liver-samples was observed (Pearson: rho=0.544, p=0.024). Three DAA-treated patients were HCV-RNA "undetectable" in serum, but still "detectable" in all tested liver-tissues. Differently, only one DAA-treated patient, tested after sustained-virological-response, showed HCV-RNA "undetectability" in liver-tissue. CONCLUSIONS: HCV-RNA was successfully quantified with high reliability in liver bioptic samples and extrahepatic compartments, even when HCV-RNA was "undetectable" in serum. Abbott RealTime HCV-assay is a good diagnostic tool for HCV quantification in intra- and extra-hepatic compartments, whenever a bioptic sample is available.

The efficacy and safety of mammalian target of rapamycin inhibitors ab initio after liver transplantation without corticosteroids or induction therapy.

BACKGROUND: Mammalian target of rapamycin inhibitors have been used along with corticosteroids and/or induction therapy immediately after liver transplantation. Our aim was to assess the safety and tolerability of everolimus ab initio after liver transplantation without corticosteroids or induction, as well as efficacy in terms of liver function, rejection and graft loss. METHODS: A retrospective observational study of 50 adult patients (86% males, median age 54 years, range 25-68) who were liver transplanted between 2009 and 2013 and followed for 12 months. All recipients received everolimus plus low doses of calcineurin inhibitors (n=38) or mycophenolate (n=12) without corticosteroids and/or induction from the day of transplant. RESULTS: The overall patient and graft survival was 80%. Liver function was stable during one year follow-up. No rejections or graft loss were observed. Only five patients (10%) required therapy for onset dyslipidemia. CONCLUSION: Everolimus-based immunosuppression regimen without corticosteroids and/or induction immediately after liver transplantation seems to be safe and effective when administered with low doses of calcineurin-inhibitor or mycophenolate; although these findings require further investigation, these regimens could avoid adverse effects of standard immunosuppression regimens with higher doses.

One-shot versus multidose perioperative antibiotic prophylaxis after kidney transplantation: a randomized, controlled clinical trial.

BACKGROUND: There is no consensus on the optimal perioperative antibiotic prophylaxis regimen for renal transplant recipients. Some studies have reported that irrigation of the wound at the time of closure without systemic antibiotics may suffice to minimize the risk for surgical site infection (SSI), but many centers still use long-term, multidose regimens in which antibiotics are administered until removal of foreign bodies occur, such as the urethral catheter, drain and central line. METHODS: We designed a prospective, randomized, multicenter, controlled trial to compare a single dose versus a multidose regimen of systemic antibiotic prophylaxis in adult, nondiabetic, non-morbidly obese patients undergoing renal transplantation. The primary endpoint was the incidence of SSI; the assessment of other infection in the first postoperative month was the secondary endpoint. RESULTS: Two hundred five patients were enrolled and randomized to receive either a single (n = 103) or multidose antibiotic regimen (n = 102) for prophylaxis. The incidences of SSI and urinary tract infection were similar in both groups. CONCLUSION: As the dramatic increase in antibiotic resistance has mandated the implementation of global programs to optimize the use of antibiotic agents in humans, we believe that the single dose regimen is preferred, at least in nondiabetic, non-morbidly obese, adult renal transplant recipients.