De Novo Malignancies Research Articles

Comparative Review of Standardized Incidence Ratio of Nonlymphoid, De Novo Malignancies After Liver Transplant Versus After Kidney Transplant.

De novo malignancies are the most common cause of death after solid-organ transplant. Here, we aimed to summarize standard incidence ratios of de novo malignancies after liver and kidney transplant within the same geographical locations, compare these ratios among differenttypes of de novo malignancies after liver and kidney transplant, and elucidate differences in de novo malignancies between liver and kidney transplant recipients. We performed a systematic review to identify studies on standard incidence ratios of de novo malignancies after liver and kidney transplant in the United Kingdom, Sweden, South Korea, and Taiwan. Four articles reported standard incidence ratios of de novo malignancies in 14 016 liver transplant recipients (mean follow-up 4.3 ± 0.7 y) and 48179 kidney transplant recipients (mean follow-up 6.1 ± 2.1 y). Mean ratios of oropharyngeal, pulmonary, colorectal, renal, and breast malignancies were 5.3, 1.6, 1.9, 1.8, and 1.1,respectively, after liver transplant and 3.2, 1.7, 1.5, 17.0, and 1.3, respectively, after kidney transplant. Mean ratios of bladder, cervixuterus, and stomach de novo malignancies were 1.8, 2.0, and 2.9, respectively, after liver transplant and 13.0, 1.9, and 1.9,respectively, after kidney transplant. Mean ratios of prostatic and esophageal malignancies were 1.6 and 1.8 after liver transplant and 1.2 and 1.1 after kidney transplant. Mean ratio of ovarian cancer was 1.2 and 2.9, respectively, after liver and kidney transplant. Low-frequency and lower standard incidence ratios were observed for testicular, ovarian and central nervous system malignancies after kidney and liver transplant. Standard incidence ratios of oropharyngeal and hepatic malignancies were higher after liver transplant compared with kidney transplant. After kidney transplant, standardized ration for renal malignancy were 9.4 times and bladder malignancies were 7.2 times higher compared with liver transplant recipients.

A Comparative Review of Standardized Incidence Ratios of De Novo Malignancies Post Liver Transplantation in Males Versus Females

After liver transplantation (LTx), the most common cause of death in the long-term is de-novo malignancy (DNM). The aim is to review the gender differences in the standardized incidence ratio (SIR) of DNM within the same geographical locations. MethodsFour studies were identified comparing post-LTx SIR between males and females. ResultsFrom 6663 males and 2780 females LTx recipients, the mean SIR from each of the four studies for males is 2.8, 2.0, 1.94, and 3.4, and 3.5, 1.3, 1.95, and 2.3 for females. On meta-analysis using a random effect model for each gender group. No significant difference was revealed after logarithmic transformation and subgroup meta-analysis. Overall mean SIR with 95% Confidence Interval (CI) for males is 2.53 (95% CI 1.65-3.88) and 2.3 (1.25-4.24) for females. lung malignancy, 1.97 (1.14-3.41) for males and 2.65 (0.67-10.47) for females. For colorectal malignancy, the combined SIR for males is 1.98 (0.58-6.78) and 1.85 (1.02-3.37) for females. The SIR for female gender-specific malignancies; SIR for breast is 1.1±4.4, cervix 2.9±1.9, uterus 2.8, and ovarian 0.7, and for males, testis 1.6±1.3, prostate 1.2±0.4. However, rare malignancies, male breast cancers (n=1, SIR, 22.6), and Kaposi's sarcoma, in males (n=6) and in females (n=1), had SIR 120. and 212.7, respectively ConclusionOverall, there are no statistical differences between male and female DNM. Female-specific cervix, uterus, ovarian, and male-specific testis and prostate have similar SIR. Rare malignancies have very high SIR.

Chronological alterations in de novo malignancies after living-donor liver transplantation: A cohort study of 1781 recipients using annual comparisons of standardized incidence ratios.

De novo malignancies (DNMs) are a major adverse event after solid organ transplantation; however, their characteristics and recent trends after living-donor liver transplantation (LDLT) remain unclear. We retrospectively reviewed 1781 primary LDLT recipients (1990-2020) and annually calculated standardized incidence ratios (SIRs) of DNMs compared to the age-adjusted Japanese general population. After 21 845 person-years follow-up, 153 DNM lesions (8.6%) were identified in 131 patients (7.4%). The incidence was 0.007 person-years. DNMs included 81 post-transplant lymphoproliferative disorders (PTLDs), 14 colorectal, 12 lung, and 12 gastric cancers, and so on. Comorbid DNMs significantly worsened recipient survival than those without (p < .001). The 5- and 10-year recipient survival after DNM diagnosis were 65% and 58%, respectively. Notably, SIR1993-1995: 8.12 (95% CI: 3.71-15.4, p < .001) and SIR1996-1998: 3.11 (1.34-6.12, p = .01) were significantly high, but had decreased time-dependently to SIR2005-2007: 1.31 (0.68-2.29, p = .42) and SIR2008-2010: 1.34 (0.75-2.20, p = .33), indicating no longer significant difference in DNMs development. Currently, however, SIR2014-2016: 2.27 (1.54-3.22, p < .001) and SIR2017-2019: 2.07 (1.40-2.96, p < .001) have become significantly higher again, reflecting recent aging of recipients (>50 years) and resultant increases in non-PTLD DNMs. Furthermore, characteristically in LDLT, the fewer the donor-recipient HLA-mismatches, the less the post-transplant DNMs development. DNM development after LDLT was significantly higher than in the general population due to higher PTLD incidence (1993-1998), but once became equivalent (2005-2013), then significantly increased again (2014-2019) due to recent recipient aging and resultant increase in solid cancers.

Outcomes of liver transplant recipients with pretransplant malignancies: Insights from a single institution’s experience.

11173 Background: Increasing liver transplantation (LT) utilization has resulted in more and more patients with a history of a non-hepatobiliary malignancy. Rather than deny such patients a lifesaving therapy the benefits must be weighed against risk of tumor recurrence and de novo malignancies (DNM) post-LT, especially with the immunosuppression required. While data has been presented on outcomes of pre transplant malignancies (PTM) in kidney and heart transplants, LT data is lacking. Our aim is to characterize rates of recurrence, DNM, and overall survival (OS) post-LT at a single, high volume American center. Methods: This retrospective study at Houston Methodist Hospital included patients who underwent LT with known history of PTM. Data was extracted from electronic health records, and descriptive statistics performed. Institutional IRB approval is obtained. Results: Between 01/1999- 12/2022, 1617 LTs were performed at our institute. We identified 261 LT recipients with 297 PTM, including 91 non- and 206 hepatobiliary cancers (See Table). Follow-up period ranged from 1 to 23 years. Post-LT malignancies were observed in 66 patients, 25% of the study population. Tumor recurrences accounted for 44 (17%) cases, and DNM were seen in 22 (8%). The DNMs included skin non-melanoma (n=8 cases), head &amp; neck (3), PTLD (2), prostate (2), renal (1), lung (1), CRC (1), pancreatic (1), gynecologic (2), and poorly differentiated (1). The OS rate at 1-, 5-years (excluding those less than 5 years follow-up and unknown), and at time of last follow-up were 86.6%, 60-65% and 70%, respectively. Patients with post-LT malignancies had lower OS compared to those without (46% vs. 77.7%). Conclusions: To our knowledge, this study is the first to assess post-LT outcomes in patients with PTM. This study of LT recipients with PTM demonstrates post-LT malignancy rates of 25%, including 17% with recurrences and 8% with DNM. The latter is within the previously reported range of 3-14% DNM in the general post-LT population and dominated by skin cancers. Post-LT OS is excellent in these recipients and comparable to all LT patients. However, OS is lower in those with post-LT malignancies, implying a possible role for increased cancer surveillance. Limitations include retrospective design and potential chart bias. Future work in this cohort will focus on immunosuppression effects for this high-risk population. [Table: see text]

Incidence, Risk Factors, and Outcomes of De Novo Malignancy following Kidney Transplantation.

Introduction: Post-transplant malignancy is a significant cause of morbidity and mortality following kidney transplantation often emerging after medium- to long-term follow-up. To understand the risk factors for the development of de novo post-transplant malignancy (DPTM), this study aimed to assess the incidence, risk factors, and outcomes of DPTM at a single nephrology centre over two decades. Methods: This retrospective cohort study included 963 kidney transplant recipients who underwent kidney transplantation between January 2000 and December 2020 and followed up over a median follow-up of 7.1 years (IQR 3.9-11.4). Cox regression models were used to identify the significant risk factors of DPTM development, the association of DPTM with graft survival, and mortality with a functioning graft. Results: In total, 8.1% of transplant recipients developed DPTM, and the DPTM incidence rate was 14.7 per 100 patient-years. There was a higher mean age observed in the DPTM group (53 vs. 47 years, p < 0.001). The most affected organ systems were genitourinary (32.1%), gastrointestinal (24.4%), and lymphoproliferative (20.5%). Multivariate Cox analysis identified older age at transplant (aHR 9.51, 95%CI: 2.60-34.87, p < 0.001) and pre-existing glomerulonephritis (aHR 3.27, 95%CI: 1.10-9.77, p = 0.03) as significant risk factors for DPTM. Older age was significantly associated with poorer graft survival (aHR 8.71, 95%CI: 3.77-20.20, p < 0.001). When age was excluded from the multivariate Cox model, DPTM emerged as a significant risk factor for poor survival (aHR 1.76, 95%CI: 1.17-2.63, p = 0.006). Conclusion: These findings underscore the need for tailored screening, prevention, and management strategies to address DPTM in an aging and immunosuppressed kidney transplant population.

Tacrolimus Drug Exposure Level and Smoking Are Modifiable Risk Factors for Early De Novo Malignancy After Liver Transplantation for Alcohol-Related Liver Disease.

De novo malignancy (DNM) is the primary cause of mortality after liver transplantation (LT) for alcohol-related liver disease (ALD). However, data on risk factors for DNM development after LT are limited, specifically in patients with ALD. Therefore, we retrospectively analyzed all patients transplanted for ALD at our center before October 2016. Patients with a post-LT follow-up of <12months, DNM within 12months after LT, patients not on tacrolimus in the 1st year post-LT, and unknown smoking habits were excluded. Tacrolimus drug exposure level (TDEL) was calculated by area under the curve of trough levels in the 1st year post-LT. 174 patients received tacrolimus of which 19 (10.9%) patients developed a DNM between 12 and 60months post-LT. Multivariate cox regression analysis identified TDEL [HR: 1.710 (1.211-2.414); p = 0.002], age [1.158 (1.076-1.246); p < 0.001], number of pack years pre-LT [HR: 1.021 (1.004-1.038); p = 0.014] and active smoking at LT [HR: 3.056 (1.072-8.715); p = 0.037] as independent risk factors for DNM. Tacrolimus dose minimization in the 1st year after LT and smoking cessation before LT might lower DNM risk in patients transplanted for ALD.

Long Term Complications of Immunosuppression Post Liver Transplant

Improvement in immunosuppression has led to a remarkable improvement in short-term and long-term outcomes post-liver transplant (LT). However, with improvements in long-term survival, complications related to immunosuppressive drugs, either directly or indirectly, have also increased. The adverse events could be drug-specific, class-specific, or generic. Calcineurin inhibitors (cyclosporine and tacrolimus) are the backbone of the immunosuppression after LT and the main culprit associated with most of the complications, including renal failure, post-transplant diabetes mellitus (PTDM), and metabolic syndrome. Steroids are also implicated in the development of diabetes, osteoporosis, and metabolic syndrome post-LT. The development of infections and de novo malignancies (DNMs) is a generic effectlinked to the overall cumulative immunosuppression. The development of these complications significantly hampers the quality of life and leads to increased morbidity and mortality post-LT. Thus, it is important to minimize the cumulative immunosuppression dosewhile simultaneously preventing allograft rejection. This review provides up-to-date, comprehensive knowledge of the complications of long-term immunosuppression post-LT along with associated risk factors and strategies to minimize the risk of complications.

De Novo Malignancy After Adult-to-Adult Living Donor Liver Transplantation: A Single-Center Long-Term Experience

The incidence of de novo malignancy (DNM) after liver transplantation (LT) is reported to be 3.1% to 14.4%. It is a known cause of death in long-term recipients. This study aimed to clarify the clinical features and risk factors of DNM. Recipients who underwent adult-to-adult living-donor LT (LDLT) and survived for >6 months were investigated. The medical records were retrospectively reviewed. This study was approved by the institutional review board. In total, 180 patients were included. The indications for LDLT were hepatocellular disease (n=62), metabolic liver disease (n=50), cholestatic disease (n=46), acute liver failure (n=12), and others (n=10). The median age at LDLT was 48 (18-71) years, and the follow-up period was 15 (0-29) years. De novo malignancy was diagnosed in 24 recipients (28 sites), including the digestive tract (n=9), genitourinary (n=5), gynecologic (n=5), lung (n=4), hematological (n=3), and others (n=2). The median duration from LDLT to DNM was 7 (0-19) years. Four patients were lost to follow-up due to advanced-stage cancer. R0 (curative treatment) for non-hematological DNM was achieved in 19 lesions (95%). The 10- and 20-year DNM incidence rates were 11% and 20%, respectively. The 20-year survival rates of DNM (59.6%) and non-DNM (59.9%) patients were not significantly different. De novo malignancy was significantly higher in patients with primary sclerosing cholangitis than in others (P < .05). Even in DNM recipients, early detection of malignancy and R0 treatment promises long-term outcomes comparable to those of non-DNM recipients.

De Novo Malignancies After Kidney Transplant: Where Do We Stand and Does the Head and Neck Region Require More Caution?

The aim of this study was to investigate the characteristics of de novo malignancies arising in kidney transplant recipients followed in a tertiary hospital in Turkey and to examine the tumors in the head and neck region as a subgroup. Data from kidney transplant recipients treated at our institution between January 2010 and July 2022 were retrospectively analyzed in this single-center study. Data regarding malignancies were noted according to the pathologists' reports. In situ malignancies and those arising after graft loss were not evaluated. The study population comprised 231 patients (165 men; 71.4%) with a median follow-up of 11 years (2853 patient-years). The recipients had a higher cancer risk than the general population (standardized incidence rate = 3.04; 95% CI, 1.82-4.26). Thirty de novo malignant tumors were detected in 24 patients (10.4%). The mean age at diagnosis of cancer was 54.88 ± 11.44 years. The median time from transplant to cancer diagnosis was 11.5 years (range, 7-18.8 y). Nonmelanoma skin cancers (56.7% of all tumors) were the most common malignancies. Twenty-two lesions (73.3%) that developed in 17 patients (7.4%) were localized to the head and neck region: 15 (68.2%) were cutaneous and 7 (31.8%) were noncutaneous. The median time from transplant to head and neck cancer diagnosis was 12 years (range, 7.5-17.5 y). Mortality rate was higher in cancer patients (10 [41.7%] vs 17 [8.2%]; P < 0.01). The incidence of de novo malignancy in kidney transplant recipients was relatively higher compared with previous data. Nonmelanoma skin cancers were the most common type. Three-quarters of all lesions were in the head and neck region, and two-thirds were of cutaneous origin.

Clinical adoptive regulatory T Cell therapy: State of the art, challenges, and prospective.

Rejection of solid organ transplant and graft versus host disease (GvHD) continue to be challenging in post transplantation management. The introduction of calcineurin inhibitors dramatically improved recipients' short-term prognosis. However, long-term clinical outlook remains poor, moreover, the lifelong dependency on these toxic drugs leads to chronic deterioration of graft function, in particular the renal function, infections and de-novo malignancies. These observations led investigators to identify alternative therapeutic options to promote long-term graft survival, which could be used concomitantly, but preferably, replace pharmacologic immunosuppression as standard of care. Adoptive T cell (ATC) therapy has evolved as one of the most promising approaches in regenerative medicine in the recent years. A range of cell types with disparate immunoregulatory and regenerative properties are actively being investigated as potential therapeutic agents for specific transplant rejection, autoimmunity or injury-related indications. A significant body of data from preclinical models pointed to efficacy of cellular therapies. Significantly, early clinical trial observations have confirmed safety and tolerability, and yielded promising data in support of efficacy of the cellular therapeutics. The first class of these therapeutic agents commonly referred to as advanced therapy medicinal products have been approved and are now available for clinical use. Specifically, clinical trials have supported the utility of CD4+CD25+FOXP3+ regulatory T cells (Tregs) to minimize unwanted or overshooting immune responses and reduce the level of pharmacological immunosuppression in transplant recipients. Tregs are recognized as the principal orchestrators of maintaining peripheral tolerance, thereby blocking excessive immune responses and prevent autoimmunity. Here, we summarize rationale for the adoptive Treg therapy, challenges in manufacturing and clinical experiences with this novel living drug and outline future perspectives of its use in transplantation.

563 - Outcomes of patients admitted to the hospital with disseminated intravascular coagulation with de-novo malignancies: a single institution experience

563 - Outcomes of patients admitted to the hospital with disseminated intravascular coagulation with de-novo malignancies: a single institution experience

498. MINIMALLY INVASIVE ESOPHAGECTOMY FOR PATIENTS WITH ESOPHAGEAL CANCER AND A HISTORY OF LIVER TRANSPLANTATION: A LITERATURE REVIEW AND CASE SERIES

Abstract The survival after liver transplantation is continually improving. With evidence of an increased risk of de-novo malignancies after liver transplantation, it is urgent to improve the treatment of an esophageal cancer in patients with a history of liver transplantation. With this study we wanted to show a case series of totally minimally invasive Esophagectomy for patients with a history of liver transplantation, as well as an literature review. We performed a systematic literature review according to the PRISMA guidance to identify the documented cases of an operative procedure in patients with a history of liver transplantation. Baseline characteristics, tumor stages as well as operative and postoperative management is compared with the case series of 2 cases operated minimally invasive in our center. Seven studies were identified, with a total of 15 patients who underwent esophagectomy after liver transplantation. In 67% of the cases, including our two patients, alcohol associated liver cirrhosis was the indication for the liver transplantation. All reported cases proceed an open surgical approach for the Esophagectomy, except for 1 case with an open abdominal approach and a thoracoscopic chest procedure. The two cases in our center underwent a totally minimally invasive esophagectomy. The mean length of stay in the hospital was 21.5 days, compared to 8 and 14 days in our presented cases. The importance of an optimal treatment of esophageal cancer after liver transplantation is evident. With this case series we showed that it is technically feasible to proceed a total minimally invasive Esophagectomy for patients with a history of liver transplantation in a curative intention. For a successful and radical treatment of malignancies after liver transplantation a multidisciplinary procedure is necessary.

MO986: Incidence And Predictors of Post-Transplant De-Novo Malignancy: A Single-Centre Retrospective Cohort Study

Abstract BACKGROUND AND AIMS Improvement in short to medium term kidney transplant outcomes and increasingly successful transplantation older patients have led to increasing occurrence of long-term complications of transplantation. Amongst these complications, cancer has become an important cause of mortality following kidney transplantation necessitating the need to better understand the risk factors for the development of de novo malignancy. This study aimed to evaluate the prevalence and the risk factors of de-novo malignancy in a single UK tertiary nephrology centre. METHOD This retrospective cohort study included all kidney transplant recipients (KTR) at our centre, that underwent kidney transplantation between 2000 and 2020 and followed up at our centre. The incidence and types of malignancies excluding non-melanoma skin cancer (NMSC) were analysed. The characteristics of KTR with post-transplant malignancy (excluding NMSC) were compared to those without post-transplant malignancy. Univariate and multivariate logistic regression analyses were conducted to identify the risk predictors of post-transplant cancers. Graft survival and dialysis free survival and death with functioning graft were assessed using Kaplan-Mayer analysis and Cox-regression. RESULTS We analysed the records of 962 KTR (mean age = 47 ± 15 years), followed-up over a median period of 16 years. About 365 (38%) were women, and 783(81%) were Caucasian. 268(32%) had a pre-emptive transplant and 277(29%) had a live donor transplant. Post-transplant malignancy was diagnosed in 84(9%) KTR. KTR with post-transplant cancers were likely to be older (53 ± 14 versus 47 ± 15 years; P = 0.004), on long-term steroid maintenance therapy (64% versus 47%; P = 0.004) and have a history of post-transplant DNA virus infection (40% versus 29%; P = 0.029). Conversely, those with cancers are less likely to be on mycophenolic acid (MPA) therapy (65% versus 78%; P = 0.023). The most common cancers diagnosed were genitourinary cancers (27%) followed by gastrointestinal (24%) and haematological cancers (24%). Respiratory, neurological and others accounted for 10%, 2.4% and 11% of the diagnosed cancers. In multivariate logistic regression analysis, increasing risk of post-transplant cancer was associated with older age at transplantation [OR: 1.81 (1.3–2.5; P &amp;lt; 0.001)], male gender [OR 2.3 (1.3–8.3; P = 0.01)], corticosteroid maintenance [OR 2.3 (1.1–5.2: P = 0.03)], Tobacco smoking [OR: 3.33 (1.2–8.9: P = 0.01)], higher Baseline estimated glomerular filtration rate (eGFR), [OR: 1.2 (1.0–1.4; P = 0.02)], and post-transplant DNA-virus infection [OR: 2.3 (1.0–5.1; P = 0.02)] (Figure 1). There was no difference in the death censored graft survival between the cancer group and the no-cancer group (log-rank, P = 0.51). However, those with cancers had a significantly worse dialysis free survival (log-rank; P = 0.04) and significantly higher death with functioning graft (log-rank; P = 0.02). In the multivariate Cox regression, adjusted for several confounders, dialysis free survival did not differ significantly between the cancer and non-cancer groups (adjusted hazard ratio; aHR: 1.6; P = 0.10). However, age (aHR: 1.16; P = 0.01), male gender (aHR: 1.6; P = 0.01), cardiovascular disease (CVD) (HR: 1.6; P = 0.01) and acute rejection (aHR: 1.7; P = 0.02) were predictors of lower dialysis free survival. CONCLUSION Post-transplant cancers occurred in 9% of our cohort during a median follow-up of 16years. Genitourinary cancers were the most commonly occurring cancers. Older age, male gender, corticosteroid maintenance, smoking and DNA virus infections were the risk factors of malignancy. There was no significant difference in dialysis free survival between the cancer group and the no cancer groups. Lower dialysis free survival was predicted by age, gender, CVD and a history of acute rejection.

De-novo malignancies after liver transplantation: Experience of a high-volume center

De-novo malignancies after liver transplantation: Experience of a high-volume center

De Novo Malignancies after Kidney Transplantation.

Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries. The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease. More importantly, effective screening and treatment strategies are limited in this high-risk population. In this review, we begin with a patient's journey that maps the experience of living with a kidney transplant and understand the patient's knowledge, education, and experience of cancer in the context of transplantation. The epidemiology and burden of cancer in recipients of kidney transplants, along with the up-to-date screening and treatment strategies, are discussed. We also focus on the current understanding of optimal care for recipients of kidney transplants who are living with cancer from the patients' perspectives.

Spectrum of Denovo Malignancies and their Predictors after Liver Transplantation

Introduction: De-novo malignancy (DNM) has become an important cause of death after long term survival following liver transplantation (LT). We share our experience of identifying and managing post-transplant patients with DNM and analysis of possible risk factors.

De Novo Malignancy After Liver Transplantation: Risk Assessment, Prevention, and Management-Guidelines From the ILTS-SETH Consensus Conference.

De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society-Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk factors, management, and survival after DNMs. Recommendations for screening and surveillance for specific tumors, as well as immunosuppression and cancer-specific management in patients with DNM, are summarized.

Foremost Concepts in Mechanisms of De Novo Post-Liver Transplantation Malignancy

In liver transplant patients, solid tumors and post-transplant lymphoproliferative disorders (PTLD) have emerged as significant long-term mortality causes. Additionally, it is assumed that de novo malignancy (DNM) after liver transplantation (LT) is the second-leading cause of death after cardiovascular complications. Well-established risk factors for PTLD and solid tumors are calcineurin inhibitors (CNIs), tacrolimus (TAC), and cyclosporine, the cornerstones of all immunosuppressive (IS) therapies used after LT. The loss of immunocompetence facilitated by the host immune system due to prolonged IS therapy leads to cancer development, including in LT patients. Hindering DNA repair mechanisms, promoting tumor cell invasiveness, and hampering apoptosis are critical events in tumorigenesis and tumor growth in LT patients resulting from IS administration. This paper aims to overview the refined mechanisms of IS-induced tumorigenesis after LT and the loss of immunocompetence facilitated by the host immune system due to prolonged IS therapy. In addition, we also discuss in detail the mechanisms of action in different types of IS regimen used after LT, and their putative effect on DNM.

Early mortality in metastatic cancer: A SEER population data analysis.

e18789 Background: Overall survival from cancer has continuously improved over the last thirty years. This is due, in part, to advances in systemic treatment of some cancers resulting in clinically significant increases in long-term survival. Despite these improvements in long-term survival, many patients die quickly after a diagnosis of metastatic cancer, possibly being denied the opportunity to benefit from these recent advances in cancer treatment. To identify the scope and predictors of early mortality in de novo metastatic cancer, we analyzed population-based data, focusing on patients with early mortality. Methods: Using the Survival, Epidemiology and End Results (SEER) Database we analyzed adult patients who presented with de-novo metastatic solid malignancies diagnosed between 2008-2016. We defined early mortality as 1- and 2-month mortality. Factors associated with early mortality were analyzed including primary site of cancer and demographics. Correlations between categorical variables were analyzed with chi squared tests and survival data was derived from life tables using STATA I/C 12.1. Results: Of 519,553 patients identified, 273,976 (53%) were males, 411,041 (79%) were white, 213,325 (41%) had lung cancer, 65,679 (13%) colorectal cancer and 49,139 (10%) pancreatic cancer. One - and two - month cancer specific mortality was 12.4% and 22.5% respectively for the entire cohort. Mortality from cancer in the first two months after diagnosis decreased only marginally between 2008 and 2016 (23.4% and 21.6 %, respectively). Cancers with the highest 2-month cancer specific mortality rates were liver (39.5%), pancreatic (36.3%), lung (26.8%), gastroesophageal (23.7%), and urothelial (21.2%). Cancers with the lowest 2-month mortality rate were breast (10.4%) and prostate cancer (5%). Patients who presented with liver metastases had a clinically significant higher 2- month cancer specific mortality rate (29% vs. 18% p &lt; 0.001), brain metastases were associated with a milder increase in 2-month cancer specific mortality (25%vs 21% p &lt; 0.001) and bone metastases were not associated with a clinically significant difference in 2-month cancer specific mortality (22% vs 21%, p = 0.047). Other factors associated with early mortality included increasing age, low income, and living in a rural area. Conclusions: Over 21% of newly diagnosed metastatic cancer patients die within 2 months of their diagnosis, with little improvement over the last decade, rendering this an urgent unmet need in cancer care. Further research is urgently required to better identify the causative and treatable factors of early mortality in cancer patients.

Hepatocellular carcinoma and the risk of de novo malignancies after liver transplantation - a multicenter cohort study.

Patients with hepatocellular carcinoma (HCC) are at high risk of second primary malignancies. As HCC has become the leading indication of liver transplant (LT), the aim of this study was to investigate whether the presence of HCC before LT could influence the onset of de novo malignancies (DNM). A cohort study was conducted on 2653 LT recipients. Hazard ratios (HR) of DNM development for patients transplanted for HCC (HCC patients) were compared with those of patients without any previous malignancy (non-HCC patients). All models were adjusted for sex, age, calendar year at transplant, and liver disease etiology. Throughout 17903 person-years, 6.6% of HCC patients and 7.4% of non-HCC patients developed DNM (202 cases). The median time from LT to first DNM diagnosis was shorter for solid tumors in HCC patients (2.7 vs 4.5years for HCC and non-HCC patients, respectively, P<0.01). HCC patients were at a higher risk of bladder cancer and skin melanoma. There were no differences in cumulative DNM-specific mortality by HCC status. This study suggests that primary HCC could be a risk factor for DNM in LT recipients, allowing for risk stratification and screening individualization.