Neoadjuvant versus definitive radiochemotherapy of locoregionally advanced oesophageal cancer-who benefits?

PURPOSE: For years, there have been discussions on whether neoadjuvant radiochemotherapy followed by surgery (nRCT-S) is superior to definitive radiochemotherapy (dRCT) as the standard of care for locoregionally advanced oesophageal cancer (OC). This retrospective study aimed to evaluate our patient cohort regarding differences in survival and recurrence between nRCT­S and dRCT. METHODS: Data from 68 patients with dRCT and 33 patients with nRCT­S treated from 2010 to 2018 were analysed. Comorbidities were recorded using the Charlson Comorbidity Index (CCI). Recurrence patterns were recorded as in-field or out-field. Kaplan-Meier analyses were used to compare survival data (overall survival [OS], progression-free survival [PFS], and locoregional control [LRC]). RESULTS: Patients with nRCT­S showed significantly lower CCI values than those with dRCT (p = 0.001). The median follow-up was 47 months. The median OS times were 31 months for nRCT­S and 12 months for dRCT (p = 0.009), the median PFS times were 11 and 9 months, respectively (p = 0.057), and the median LRC times were not reached and 23 months, respectively (p = 0.037). The only further factor with a significant impact on OS was the CCI (p = 0.016). In subgroup analyses for comorbidities regarding differences in OS, the superiority of the nRCT­S remained almost significant for CCI values 2-6 (p = 0.061). CONCLUSION: Our study showed significantly longer OS and LRC for patients with nRCT­S than for those with dRCT. Due to different comorbidities in the groups, it can be deduced from the subgroup analysis that patients with few comorbidities seem to especially profit from nRCT­S.

Impact of perioperative blood transfusions on postoperative renal function and survival after resection of colorectal liver metastases.

BACKGROUND AND AIMS: Recent studies focusing on thoracic surgery suggest postoperative kidney injury depending on the amount of perioperative blood transfusions. Data investigating similar effects after resection of colorectal liver metastases (CRLM) are not available. Aim of this study was therefore to evaluate the influence of perioperative blood transfusions on postoperative renal function and survival after resection of CRLM. METHODS: Seven hundred twenty-seven cases of liver resection for CRLM were retrospectively analyzed. Renal function was measured via estimated glomerular filtration rate (eGFR) and a postoperative decline of ≥ 10% was considered substantial. Potential influences on postoperative kidney function were assessed using univariable and multivariable logistic regression analyses. Cox-regression analyses were performed to estimate the impact on overall survival (OS). RESULTS: Preoperative impaired kidney function (p = 0.001, OR 2.477) and transfusion of > 2 units of packed red blood cells (PRBC) (p = 0.046; OR 1.638) were independently associated with an increased risk for ≥ 10% loss of renal function. Neither a pre-existing renal impairment, nor the additional loss of renal function were associated with reduced survival. Chemotherapies in the context of primary colorectal cancer treatment (p = 0.002), age > 70 years at liver resection (p = 0.005), number (p = 0.001), and size of metastases > 50 mm (p = 0.018), duration of resection > 120 min (p = 0.006) and transfusions of > 2 units of PRBC (p = 0.039) showed a negative independent influence on OS. CONCLUSION: The results demonstrate a negative impact of perioperative blood transfusions on the postoperative renal function and OS. Hence, efforts to reduce blood transfusions should be intensified.

Simultaneous heart-kidney transplantation results in respectable long-term outcome but a high rate of early kidney graft loss in high-risk recipients - a European single center analysis.

BACKGROUND: In spite of renal graft shortage and increasing waiting times for transplant candidates, simultaneous heart and kidney transplantation (HKTx) is an increasingly performed procedure established for patients with combined end-stage cardiac and renal failure. Although data on renal graft outcome in this setting is limited, reports on reduced graft survival in comparison to solitary kidney transplantation (KTx) have led to an ongoing discussion of adequate organ utilization. METHODS: This retrospective study was conducted to evaluate prognostic factors and outcomes of 27 patients undergoing HKTx in comparison to a matched cohort of 27 patients undergoing solitary KTx between September 1987 and October 2019 in one of Europe's largest transplant centers. RESULTS: Median follow-up was 100.33 (0.46-362.09) months. Despite lower five-year kidney graft survival (62.6% versus 92.1%; 111.73 versus 183.08 months; p = 0.189), graft function and patient survival (138.90 versus 192.71 months; p = 0.128) were not significantly inferior after HKTx in general. However, in case of prior cardiac surgery requiring sternotomy we observed significantly reduced early graft and patient survival (57.00 and 94.09 months, respectively) when compared to patients undergoing solitary KTx (183.08 and 192.71 months; p < 0.001, respectively) or HKTx without prior cardiac surgery (203.22 and 203.22 months; p = 0.016 and p = 0.019, respectively), most probably explained by the significantly increased rate of primary nonfunction (33.3%) and in-hospital mortality (25.0%). CONCLUSIONS: Our data demonstrates the increased rate of early kidney graft loss and thus significantly inferior graft survival in high-risk patients undergoing HKTx. Thus, we advocate for a "kidney-after-heart" program in such patients to ensure responsible and reasonable utilization of scarce resources in times of ongoing organ shortage crisis.

Liver-first strategy for a combined lung and liver transplant in patients with cystic fibrosis.

OBJECTIVES: A combined lung and liver transplant in patients with cystic fibrosis (CF) is an uncommon procedure. The goal of this study was to compare long-term outcomes between patients with CF who underwent either a combined lung-liver or a lung-only transplant. METHODS: This is a retrospective single-centre study of patients with CF who underwent a lung transplant between January 2005 and May 2020. Since 2006, our preference for a combined lung-liver transplant was to transplant the liver first and then the lung. Outcomes were compared using the Kaplan-Meier analysis and the log-rank test. Median follow-up was 53 (23-97) months. RESULTS: During the study period, among 357 patients with CF who underwent a lung transplant, 14 (4%) required a lung-liver transplant whereas 343 (96%) had a lung-only transplant. Lung cold ischaemic time was longer in the lung-liver transplant group, but no patient in this group showed primary graft dysfunction at 72 h after the transplant. Prevalence of anti-human leucocyte antigen donor-specific antibodies was 7.1% vs 13.7% in the lung-liver versus the lung-only transplant group (P = 0.42). At 5 years, lung graft survival (78% vs 69%) and freedom from chronic lung allograft dysfunction (79% vs 62%) did not differ between the lung-liver versus the lung-only groups (P = 0.45 and P = 0.55, respectively). Freedom from lung biopsy-confirmed rejection was significantly higher in patients undergoing a lung-liver transplant (91% vs 50%; P = 0.027). CONCLUSIONS: A lung-liver transplant did not impair lung graft function. The lower prevalence of donor-specific antibodies and the better freedom from lung biopsy-confirmed rejection suggest tolerogenic effects of the liver graft.

Multivisceral resection for adenocarcinoma of the pancreatic body and tail-a retrospective single-center analysis.

BACKGROUND: Adenocarcinoma of the pancreatic body and tail is associated with a dismal prognosis. As patients frequently present themselves with locally advanced tumors, extended surgery including multivisceral resection is often necessary in order to achieve tumor-free resection margins. The aim of this study was to identify prognostic factors for postoperative morbidity and mortality and to evaluate the influence of multivisceral resections on patient outcome. METHODS: This is a retrospective analysis of 94 patients undergoing resection of adenocarcinoma located in the pancreatic body and/or tail between April 1995 and December 2016 at our institution. Uni- and multivariable Cox regression analysis was conducted to identify independent prognostic factors for postoperative survival. RESULTS: Multivisceral resections, including partial resections of the liver, the large and small intestines, the stomach, the left kidney and adrenal gland, and major vessels, were carried out in 47 patients (50.0%). The median postoperative follow-up time was 12.90 (0.16-220.92) months. Median Kaplan-Meier survival after resection was 12.78 months with 1-, 3-, and 5-year survival rates of 53.2%, 15.8%, and 9.0%. Multivariable Cox regression identified coeliac trunk resection (p = 0.027), portal vein resection (p = 0.010), intraoperative blood transfusions (p = 0.005), and lymph node ratio in percentage (p = 0.001) as independent risk factors for survival. Although postoperative complications requiring surgical revision were observed more frequently after multivisceral resections (14.9 versus 2.1%; p = 0.029), postoperative survival was not significantly inferior when compared to patients undergoing standard distal or subtotal pancreatectomy (12.35 versus 13.87 months; p = 0.377). CONCLUSIONS: Our data indicates that multivisceral resection in cases of locally advanced pancreatic carcinoma of the body and/or tail is justified, as it is not associated with increased mortality and can even facilitate long-term survival, albeit with an increase in postoperative morbidity. Simultaneous resections of major vessels, however, should be considered carefully, as they are associated with inferior survival.

Prediction of survival after left-sided pancreatic resection for adenocarcinoma: Introduction of a new prognostic score.

BACKGROUND: Due to the clinically unapparent course the entity of left-sided pancreatic adenocarcinoma is often diagnosed at advanced stages, resulting in small numbers of patients qualifying for pancreatectomy. This study strives to develop a prognostic model for survival after left-sided pancreatic resection. METHODS: A total of 54 patients were analyzed. Pre- and intra-operative predictive factors for 18-month mortality were identified with multivariable binary logistic regression analysis and compiled into a prognostic model. The applicability was evaluated by assessment of the area under the receiver operating characteristic curve (AUROC). The model was internally validated applying a randomized backwards bootstrapping analysis. RESULTS: The 18-month mortality rate was 74.1% (n = 40). Mean survival was 19.1 months. A prognostic model for 18-month mortality after left sided-pancreatectomy showed an AUROC >0.800: 18-month mortality risk in% = Exp(Y) / (1 + Exp(Y)) with y= -0.927 + (1.724, if CA 19-9 elevated, otherwise 0) + (1.212 × number of intra-operative transfused packed red blood cells) + (2.771, if prior abdominal surgery, otherwise 0) - (3.612, if gastric resection, otherwise 0) This model was internally validated in 40 randomized backwards bootstrapping steps with AUROCs ranging from 0.757 to 0.971. CONCLUSIONS: The 18-month mortality risk for patients after left-sided pancreatectomy for adenocarcinoma of the pancreatic body can be assessed with the number of intra-operatively transfused packed red blood cells, elevated CA 19-9 levels, additional gastric resection and prior abdominal surgeries in the patient's history.

The liver-first approach for combined lung and liver transplantation.

OBJECTIVES: Combined lung and liver transplantation (Lu-LTx) is an established therapy for patients with cystic fibrosis. The initial sequence has primarily been lung first. We changed the sequence to 'liver first' in 2006. The aim of this study is to present outcomes of this procedure. METHODS: The records of combined lung and liver transplant patients treated at our institution between April 1999 and November 2016 were reviewed retrospectively. RESULTS: A total of 27 patients received a combined Lu-LTx at our institute. Seventeen patients underwent Lu-LTx beginning with the lung transplantation. In this group, 5 patients had cystic fibrosis (lung first). The other 10 patients received the liver transplant first (liver first). All patients in this group had cystic fibrosis as underlying disease. The lung-first group showed a trend towards longer stays in the intensive care unit (ICU) and in the hospital [median 17 days in the ICU, interquartile range (IQR) 3-47 and 55 in-hospital days, IQR 29-108] than the liver-first group (median 6 days in the ICU, IQR 4-19 and 33 in-hospital days, IQR 26-63). The 90-day, 1- and 5-year survival rates were 80%, 60% and 20% in the lung-first group vs 90%, 79% and 79% in the liver-first group. CONCLUSIONS: We present the largest series of patients following combined Lu-LTx according to the liver-first approach. The liver-first sequence results in favourable outcomes in our cohort of combined lung and liver transplants.

Differential impact of belatacept and cyclosporine A on central aortic blood pressure and arterial stiffness after renal transplantation.

Calcineurin inhibitors (CNI) are potent vasoconstrictors and induce an acceleration of arteriosclerosis, thus contributing to the cardiovascular risk after renal transplantation. The study compares the impact of belatacept and cyclosporine A (CsA) on arterial stiffness and central aortic blood pressure. We performed a case-control study in 46 patients (23 on belatacept and 23 on CsA) matched for age, body mass index, time after transplantation, and time on dialysis prior to transplantation. Pulse wave analysis (SphygmoCor, AtCor(®) ) was used to assess central aortic blood pressure, aortic augmentation pressure, and pulse wave velocity (PWV) as a marker of arterial stiffness. Assessment of vascular function was performed after a minimum of 20 months and a median follow-up of 81 months post-transplant. Peripheral systolic and diastolic blood pressure did not significantly differ in the two groups (p > 0.05 each). The central aortic augmentation pressure was higher in the CsA group (12.7 mmHg vs. 7.3 mmHg, p = 0.048). PWV as a measure of arterial stiffness did not differ in the two groups. Thus, belatacept is not associated with a significant difference in arterial stiffness compared to CsA after a median of 81 months post-transplant. It is associated, however, with a lower aortic augmentation pressure, a strong independent cardiovascular risk factor.

Ten years experience with belatacept-based immunosuppression after kidney transplantation.

BACKGROUND: Belatacept was approved for prevention of acute rejection in adult kidney transplantation in 2011 based on two randomized, controlled, multicenter phase 3 studies. Long-term experience over 10 years with belatacept-based immunosuppression after kidney transplantation has not been reported before. PATIENTS AND METHODS: Analyzed were 20 patients who had been included into a randomized multicenter phase 2 study by our institution between March 2001 and November 2002. For 10-year follow-up, three different groups could be analyzed: 1) patients with primary calcineurin inhibitor-based (CNI-based) immunosuppression (n = 5), 2) patients with early switch from a belatacept-based to a CNI-based regimen within the first 14 months (n = 8) and 3) patients with completely CNI-free belatacept immunosuppression (n = 7). RESULTS: Fifteen patients received primary belatacept-based immunosuppression and five patients primary cyclosporine A (CyA). Five patients are still on belatacept. Kidney function measured by serum creatinine levels worsened in the CNI group and the belatacept to CNI switch group during long-term follow-up whereas all patients receiving belatacept throughout follow-up showed stable creatinine values. Acute rejections occurred predominantly in the first 12 months after transplantation and were responsible for four of seven switches from belatacept- to CNI-based immunosuppression within the first 14 months. Five of the 20 patients died. CONCLUSIONS: Belatacept is effective and safe in renal transplant patients and was not associated with graft loss due to chronic allograft nephropathy. Belatacept was well tolerated in all patients and caused less nephrotoxic side effects and was well accepted in most patients.

Effects of mycophenolate mofetil introduction in liver transplant patients: results from an observational, non-interventional, multicenter study (LOBSTER).

The benefits of calcineurin inhibitor (CNI)-sparing regimens on renal function following liver transplantation (LT) have been demonstrated in clinical studies. This observational study assessed the real-life effects of mycophenolate mofetil (MMF) introduction in LT patients. Four hundred and ninety-seven patients in whom MMF was introduced according to local standards or clinical considerations were entered. Patients were grouped by time between transplantation and start of MMF (start of study): Group A (n = 263): ≤6 d; Group B (n = 64): >6 d to ≤1 month; Group C (n = 74): >1 month to ≤1 yr; and Group D (n = 96): >1 yr. CNI sparing occurred in all groups, particularly in Groups C and D. Mean MMF doses at 12 months were 1202.7, 1363.5, 1504.7, and 1578.1 mg/d, respectively, in Groups A-D. At introduction of MMF, median glomerular filtration rate was 73.3, 81.7, 62.7, and 53.7 mL/min/1.73 m(2) in Groups A-D. At 12 months, this decreased to 66 mL/min/1.73 m(2) in Groups A and B, remained stable in Group C, and increased in Group D (64.8 mL/min/1.73 m(2) ). Serious adverse drug reactions were lowest in Group D. In conclusion, MMF with a subsequent decrease in CNI was well tolerated and improved renal function even years after transplantation. A more forceful MMF dosing strategy with greater CNI sparing may further improve renal function.

Indications for and outcomes after combined lung and liver transplantation: a single-center experience on 13 consecutive cases.

BACKGROUND: Combined lung and liver transplantation (Lu-LTx) is a therapeutic option for selected patients with coexisting lung and liver disease. For several reasons, Lu-LTx is performed in few centers and information about the technical issues, posttransplant management and long-term outcomes associated with this procedure is limited. METHODS: We analyzed data from 13 consecutive patients who underwent combined Lu-LTx at Hannover Medical School (Hannover, Germany) between April 1999 and December 2003. The main indications were cystic fibrosis, alpha1-proteinase inhibitor deficiency and portopulmonary hypertension. All patients had advanced cirrhosis and severe pulmonary disease manifestation. RESULTS: Ten patients received a sequential double Lu-LTx, one patient received a single Lu-LTx, one received a double lung and split liver transplantation, and one received an en-bloc heart-lung and liver transplantation. Immunosuppression was based on cyclosporine in a triple/quadruple regimen. Postoperative surgical complications occurred in eight patients. There were two perioperative deaths; two patients died during the first year on day 67 and 354, respectively, and one patient died at month 53. The overall patient survival rates at 1, 3, and 5 years were 69%, 62%, and 49%, respectively. CONCLUSION: Combined Lu-LTx is a therapeutic option for highly selected patients with end-stage lung and liver disease with acceptable long-term outcome.

Resource use and treatment costs after kidney transplantation: impact of demographic factors, comorbidities, and complications.

BACKGROUND: Our goal was to quantify outcomes, resource use, and treatment costs for the first 2 years after renal transplantation in a "real-life" European setting and to assess the impact of preoperative risk factors and postoperative complications on treatment costs. METHODS: Inpatient and outpatient records of all patients who received a renal transplant at Medizinische Hochschule Hannover, Germany, between January 1998 and July 2000, were evaluated. Key clinical events were recorded. Direct costs were calculated for primary hospitalization, the remainder of year 1, and year 2 after transplantation. Cost of organ procurement, pretransplant care, and transplant surgery were excluded. Cost consequences for key clinical events were determined. RESULTS: Of 204 patients undergoing transplantation, 195 and 149 completed 1 year and 2 years of follow-up, respectively. The outcomes of years 1 and 2, respectively, were as follows: graft failure, 5.4%, 0.7%; acute rejection, 35.9%, 5.4%; cytomegalovirus (CMV) infection, 29.2%, 2.0%; and delayed graft function, 30.9%. Costs for primary hospitalization, the remainder of year 1, and year 2 averaged Euro 15,380, Euro 18,636, and Euro 14,484, respectively. Cost-driving events included graft failure Euro 36,228), acute rejection (Euro 9,638), delayed graft function (Euro7,359), and CMV infection (Euro 4,149). Graft failure and acute rejection for year 1 also added significantly to the costs for year 2. CONCLUSIONS: These results show that posttransplant clinical outcomes result in a significant increase in treatment costs. Because the economic impact of primary causes of chronic rejection (acute rejection and CMV) and delayed graft function is substantial, careful selection of the most appropriate immunosuppressive regimen is essential.

Expansion of the donor pool in liver transplantation: the Hannover experience 1996-2002.

In the past decade liver transplantation has become the standard therapy for terminal liver failure. An increasing organ shortage, specific regional allocation systems within the Eurotransplant area and the lack of an efficient system to identify donors have resulted in decreasing numbers of liver transplants. Approximately 20% of patients are dying on the waiting list, a list that has exploded in numbers and waiting time in the past 3 years. In particular children and small adults are put at a disadvantage since standard donors have standard size livers. Two options to solve this dilemma are the expanded use of split-liver and living-donor liver transplantation. The specific experiences applying these techniques at the Medizinische Hochschule Hannover are discussed and compared with the results given in the European Liver Transplant Registry. The retrospective analysis demonstrates a shift in the use of resources, with decreasing numbers of full-size cadaver liver transplants and an increase in split- and living-donor liver transplantation. Both techniques are limited to specific patient populations, a notion that has to be considered in the comparison of results and outcome. According to our experience the full-size cadaver liver is still the standard option, while other techniques require careful attention to the chosen recipient population, advanced surgical skills and, for living donors, as a sine qua non the prerequisite of nihil nocere.