Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases.

BACKGROUND: Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. PATIENTS AND METHODS: This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). RESULTS: Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. CONCLUSION: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. CLINICAL TRIAL REGISTRATION: NCT01921335.

Long-term results of en bloc transplantation of pediatric kidneys into adults using a vicryl mesh envelope technique.

En bloc transplantation of pediatric kidneys into adults is a suitable measure to help correct the shortage of available kidneys. This practice, however, is not widespread because of the high incidence of vascular complications. Our institution has previously described a vicryl mesh technique for en bloc kidneys, with an attempt to reduce the incidence of vascular complications. The purpose of this study was to evaluate the long-term results of recipients with en bloc kidneys stabilized with this technique. The charts of 644 adult renal transplants performed between July 1987 and July 1999 were reviewed. During this period, 14 adult patients have received 14 pairs of en bloc pediatric kidneys using the vicryl mesh technique. All patients received OKT3 as an induction immunosuppression with cyclosporine started 10-14 d after the transplant. The median donor age was 24 months (range 14-84 months), and the median recipient age was 49 yr (range 23-68 yr). The mean recipient weight was 79 kg (range 60-114 kg). The mean cold ischemia time was 14.2 hr. None of the patients developed vascular or urological complications. Delayed graft function and moderate acute rejection occurred in one patient each. At a mean follow-up of 51 months (range 7-96 months), all 14 patients maintained excellent renal function with a mean creatinine of 1.01 mg/dL. Renal measurements pre-operatively and at follow-up ultrasound examinations were available in 9 patients, and the mean length of the kidneys had grown approximately 5.0 cm. These data demonstrate that minimal vascular and immunological complication rates can be achieved with pediatric en bloc kidneys using the vicryl mesh envelope technique.

Cyclosporine challenge test revisited: does it predict outcome after solitary pancreas transplantation?

BACKGROUND: The selection of patients for solitary pancreas transplantation (PTA) requires identification of individuals who will not develop acute renal dysfunction in response to immunosuppressants. A cyclosporine challenge test (CCT) was developed to predict post-PTA kidney dysfunction secondary to calcineurin inhibitor immunosuppressants. We now report on the long-term follow-up of patients who received a PTA after undergoing a CCT. METHODS: Twelve potential PTA recipients were administered cyclosporine A (CsA) for 6 wk. Creatinine clearance (CrCl) was measured at 2, 4, and 6 wk. Those who did not fail the CCT received PTA. Baseline and post-transplant CrCl were retrospectively evaluated in the original cohort and in a group of matched patients who received PTA without a CCT. RESULTS: Of the original 12 recipients evaluated with the CCT, 6 received PTA. CrCl was followed for a mean of 45.8 months. Of the 4 who remained alive, 2 went on to develop renal failure (CrCl < 30 mL/min) at 18 and 65 months post-transplant. The baseline CrCl was higher in PTA recipients who had not been selected to be studied with CCT than those that were (117 +/- 32 vs 78 +/- 13 mL/min). By 12 months post-PTA, the CrCl was no longer different between the groups selected to be screened with CCT and those that were not. CONCLUSIONS: CCT may help predict risk for short-term changes in renal function (< 18 months) in response to CsA. CCT may be most helpful in candidates for PTA with borderline renal insufficiency (60-80 mL/min).

Pseudoaneurysm of the Y-graft/iliac artery anastomosis following pancreas transplantation: a case report and review of the literature.

Transplant-related aneurysms are an unusual complication following pancreas transplantation. We present a case of a pseudoaneurysm developing in a recipient 6 months after bladder-drained pancreas transplantation. The pseudoaneurysm was incidentally found during ultrasonographic evaluation in preparation for a pancreas biopsy. Angiography demonstrated that the origin of the pseudoaneurysm was located near the base of the Y-graft/iliac artery anastomosis. Surgical repair was performed using standard vascular techniques. The patient subsequently recovered without loss of graft exocrine or endocrine function. Review of the literature revealed that aneurysms of various types associated with pancreas transplantation have a high incidence of graft loss and contribute significantly to patient morbidity. However, with prompt diagnostic and surgical management, non-infected pseudoaneurysms can be repaired without loss of pancreatic function.

Reproductive hormones after pancreas transplantation.

BACKGROUND: Reproductive hormone function after pancreas transplantation (PTX) is unknown as it has not been studied. METHODS: We prospectively studied PTX recipients to determine changes in reproductive hormones after PTX. Testosterone or estradiol, leutinizing hormone, follicle stimulating hormone, and prolactin were determined before and 1 year after PTX in 23 patients (10 women, 13 men) followed for more than 1 year after PTX. Of these, 11 received simultaneous kidney-PTX; 8 PTX only; and 4, PTX after kidney. Average age was 38.4+/-1.6 years and average duration of diabetes was 24.5+/-1.3 years. Nine (four women, five men) patients had been on dialysis pre-PTX. Sixteen of 23 patients were treated with cyclosporine and seven with FK-506 along with prednisone and azathioprine post-PTX. RESULTS: Mean testosterone in men was normal pre- and post-PTX. Two men had secondary hypogonadism pre-PTX with resolution in one and persistence in the other post-PTX. Five of the ten women had evidence of hypogonadism pre-PTX: three had primary hypogonadism and two had secondary hypogonadism. Post-PTX, 7 of 10 women had abnormal reproductive hormones: 4 had primary hypogonadism, 2 had secondary hypogonadism, and 1 developed hyperestrogenemia with elevated estradiol (482 pg/ml) and leutinizing hormone (41 IU/liter). Mean prednisone dose and cyclosporine trough level were higher in the women than the men (P<0.05). No cases of secondary hypogonadism that developed or resolved post-PTX were related to changes in prolactin, renal function, or hyperglycemia. CONCLUSIONS: Women are more likely than men to have reproductive hormone abnormalities pre- and post-PTX and the causes may be multiple.

Clopidogrel-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in a kidney/pancreas transplant recipient.

BACKGROUND: We present a case report of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) developing in a kidney/pancreas transplant recipient after the initiation of treatment with clopidogrel for symptomatic coronary artery disease. METHODS: A 35-year-old male kidney/pancreas recipient developed unstable angina 5 years after transplantation. The patient was treated with clopidogrel as adjunct therapy. A TTP/HUS condition developed, was diagnosed early, and successfully reversed with the implementation of plasmapheresis and cessation of clopidogrel and cyclosporine A. RESULTS: The patient continues taking cyclosporine A with good renal function 6 months after the incident, and successfully underwent coronary artery by-pass grafting 3 months after the event. DISCUSSION: This case demonstrates that early identification and treatment can reverse the TTP/HUS process associated with thienopyridine-derived agents. We strongly recommend that drugs of the thienopyridine class be used cautiously in transplant recipients, especially those taking calcineurin-inhibitors.

Double renal transplants from marginal donors: 2-year results.

PURPOSE: Marginal cadaveric renal transplant donors represent a potential source for expansion of the donor pool but these kidneys have generally demonstrated significantly poorer survival compared to those from conventional donors. A strategy to provide sufficient renal mass for adequate nephron dosing and subsequent improved survival is the use of both kidneys for a single recipient. We present our 2-year experience with double renal transplants from marginal donors. MATERIALS AND METHODS: During an 8-year period 28 patients received double renal transplants (group 1) and 31 received a single transplant (group 2) from marginal donors. Donors were older than 55 years, or had diabetes mellitus, hypertension, greater than 15% glomerulosclerosis on biopsy, increasing creatinine or intrinsic renal parenchymal disease. RESULTS: Both groups were of similar age and the number of rejection episodes per year was similar but followup time differed (22.4+/-14.6 months for group 1 versus 43.7+/-20.5 for group 2). Male-to-female ratio, cold ischemia time, terminal creatinine and pre-transplant biopsy rates were similar for donors in both groups. Average donor age was younger in group 1 (48.9+/-15.8 versus 57.5+/-8.2 years, p = 0.01), and incidence of intrinsic renal disease and increasing donor creatinine was greater (12 versus 2, p = 0.002 and 4 versus 0, p = 0.04, respectively). Incidence of primary nonfunction (1 group 1 versus 5 group 2 patients) and delayed graft function (6 versus 7) was similar. The 1 and 2-year graft survival rates of 96% and 96%, respectively, for group 1 were significantly higher than those for group 2 (77% and 73%, p = 0.02). CONCLUSIONS: Our experience to date with double kidney transplants from marginal donors demonstrates acceptable 1 and 2-year survival rates significantly superior to the outcome using only 1 marginal kidney. This finding has important implications in the decision to use marginal donors in regard to cost-effectiveness and patient survival compared to the alternative of continued hemodialysis until an ideal donor organ becomes available.

Lipids increase after solitary pancreas transplantation.

OBJECTIVE: The aims of this study were to determine 1) changes in lipids after solitary pancreas transplantation (SPTX) in patients with type 1 diabetes and 2) factors that influence those changes. RESEARCH DESIGN AND METHODS: Lipids were evaluated prospectively in 24 patients who underwent SPTX. Three were excluded because of early graft failure. The remaining patients (n = 21; 13 men, 8 women) were studied for changes in lipids over time (pre-SPTX, 0-2, 3-6, 7-12, and > 12 months). Glycohemoglobin, serum creatinine, BMI, and medications were also analyzed for their effects on lipid changes. RESULTS: Cholesterol, HDL, and LDL decreased in the immediate postoperative period (0-2 months), whereas triglycerides (TGs) increased (P < 0.05). At 3-6 months, cholesterol, HDL, and TG were higher than before the SPTX, whereas LDL returned to pre-SPTX levels. After 12 months, HDL and TG remained higher than their pre-SPTX levels (P < 0.05). During the study, systolic and diastolic blood pressure increased, renal function decreased, glyco-hemoglobin improved, and weight was unchanged. Changes in cholesterol/HDL ratio, HDL, and TG correlated with changes in prednisone dose (P < 0.05), and changes in TG correlated with changes in creatinine (P < 0.05). The same pattern of lipids occurred in patients prescribed or not prescribed hypolipidemic agents. CONCLUSIONS: Lipids do not improve within the 1st year after SPTX, despite improved glycemic control and blood pressure control, and renal function is worse. These results are in contrast to those reported for combined kidney-pancreas transplantation, where lipids, blood pressure, and renal function improved immediately after transplant. Further studies are needed to determine whether lipids continue to change with time after SPTX. The impact of these changes after SPTX on overall cardiovascular risk is unknown.

Posttransplant nonfunction of canine islets in PVG rats deficient in complement component C6.

BACKGROUND: Discordant islet xenografts are immediately nonfunctional in nonimmunosuppressed recipients other than the mouse, a process called primary nonfunction. Although at present it is unknown whether complement is involved, complement might participate in the induction of primary nonfunction through a number of mechanisms. We investigated the potential role of the membrane attack complex of complement in primary nonfunction of transplanted xenoislets. METHODS: Canine islets were transplanted into both nonimmunosuppressed and immunosuppressed normocomplementemic and C6-deficient (C6D) PVG rats. Cyclosporine, rapamycin, deoxyspergualin, and mycophenolate mofetil were used for immunosuppression from day -3 to cessation of islet cell function. Serum glucose was measured at 6 hr after transplant and daily thereafter. Xenograft tissue sections were obtained at various times after transplant and stained for inflammatory cells and insulin. RESULTS: Canine islets grafted in nonimmunosuppressed C6D rats and normocomplementemic rats underwent primary nonfunction in all animals. The incidence of primary nonfunction in animals receiving a four-drug immunosuppressive regimen was 33% in the normocomplementemic rats but only 10% in the C6D rats. The mean functional islet survival time was 1.57+/-0.33 days in the normocomplementemic group and 2.70+/-0.67 days in the C6D group (P=0.38). The islet xenografts showed little difference in degree and composition of cell infiltration between normocomplementemic and C6D rats. CONCLUSION: The membrane attack complex does not appear to play a major role in primary nonfunction of canine islet xenografts in nonimmunosuppressed PVG rats. However, there was a lower incidence of primary nonfunction and a longer posttransplant survival time in immunosuppressed C6D rats, suggesting the membrane attack complex may play a minor role in recipients that are heavily immunosuppressed.

Successful islet autotransplantation in humans: functional insulin secretory reserve as an estimate of surviving islet cell mass.

Islet autotransplantation for treatment of chronic painful pancreatitis in nondiabetic patients reliably establishes normoglycemia and phasic insulin secretion and can achieve prolonged insulin independence. Whether functional transplanted beta-cell reserve is normal after intrahepatic islet transplantation is not known, nor is it known whether conventional measures of insulin secretion accurately reflect the functional beta-cell mass. To determine insulin secretory reserve after islet transplant, we performed studies of glucose potentiation of arginine-induced insulin secretion (GPAIS) in eight recipients of intrahepatic islet autotransplants. All eight subjects (and matched, healthy controls) were studied cross-sectionally 49 +/- 12 months posttransplant, and four subjects were studied pre- and posttransplant. Subjects had received a mean +/- SE of 479,000 +/- 79,000 islets, and all were insulin independent and normoglycemic at the time of study. Acute insulin responses to arginine, glucose, and GPAIS were significantly reduced after islet transplantation in both study groups. Importantly, the magnitudes of these three responses were highly correlated to the mass of islets transplanted (response to glucose: r = 0.84, P < 0.01; response to arginine: r = 0.69, P < 0.05; response to GPAIS = 0.81, P < 0.01). Data from hemipancreatectomized and normal control subjects generally agreed with the regression lines. These findings demonstrate that despite normoglycemia and insulin independence, recipients of intrahepatic islet transplantation have significantly reduced functional beta-secretory reserve and that after islet transplantation, functional beta-cell mass can be estimated by measurements of glucose and arginine-induced insulin responses. Thus, these measurements can be used to estimate the mass and functional capacity of islets surviving intrahepatic transplantation in humans.

Lymphomas in solid organ transplantation.

BACKGROUND: The purpose of this investigation was to identify and characterize abdominal lymphomas as they occur in a large solid-organ-transplant population. METHODS: A large transplant population was isolated, and all patients developing an abdominal lymphoma were identified. These patients were further characterized after review of their medical records and radiologic examinations. RESULTS: Twenty-eight (1%) of 2925 patients developed lymphoma following transplantation. Of these 28 patients, 14 developed abdominal manifestations of disease. Examples of the wide variety of abdominal manifestations of posttransplant lymphoma are presented. Most of these patients had positive titers for Epstein-Barr virus and were treated with cyclosporin as a part of their immunotherapy. The majority of patients died secondary to this aggressive disease process. CONCLUSION: The development of lymphoma following solid organ transplantation is more common than in the general population. One-half of the patients in our study population developed abdominal manifestations of this disease.

Fatal disseminated intravascular coagulation after autologous islet transplantation.

Autologous islet transplantation after pancreatectomy has been used in the surgical management of patients with intractable pain secondary to chronic pancreatitis. Total or near total pancreatectomy invariably leads to exogenous insulin dependence in these patients unless they undergo islet transplantation. Transplantation of autologous islet cells harvested from the patient's pancreas into the liver through portal vein infusion has led to long-term euglycemia in 30% to 50% of patients. We report the development of disseminated intravascular coagulation and fatal hemorrhagic shock in a 36-year-old woman after total pancreatectomy and autologous islet transplantation through retrograde infusion into the splenic vein. We report the clinical and pathological findings and discuss the possible pathophysiological mechanisms involved in the development of disseminated intravascular coagulation after this procedure.

Transcontinental shipping of pancreatic islets for autotransplantation after total pancreatectomy.

Islet autotransplantation prevents diabetes in some patients after total pancreatectomy. Pancreatectomy is done at most hospitals but islets are prepared at only a few centers. We report a case in which the pancreas was sent to a laboratory half a continent distant from the operative site, and islets were prepared and returned to the original hospital for autotransplantation 16 h after resection. At 10 months posttransplantation, the patient is normoglycemic and insulin independent, with an appropriate insulin secretion in response to glucose. Endocrine function can be retained after pancreatectomy even if the islets are isolated at a remote laboratory, and autotransplantation could be offered to patients without the need to travel. This outcome implies that the typical handling and processing of a pancreas destined to yield an islet allograft should not prevent the recovery of a sufficient number of viable beta cells to establish insulin independence in type 1 diabetic recipients.

Kidney transplantation: a brief review.

Since the first successful kidney transplant in 1954, results of these transplants have dramatically improved. Given refinements in surgical techniques and perioperative care, combined with superior immunosuppression, the procedure is now the treatment of choice for patients of all ages with ESRD. Acute rejection no longer represents a significant threat to graft loss, and the newer immunosuppressive drugs will likely diminish this problem further. Complications such as sepsis are fewer and more reliably managed with current therapies. Chronic rejection remains a major problem whose incidence has not been significantly altered. This along with a better understanding of the processes that may ultimately lead to graft tolerance will be the major challenges facing the field of renal transplantation as it enters the 21st century.

Pancreas transplantation: indications, clinical management, and outcomes.

Although many advances have been made, pancreas transplantation still poses several challenges to the surgeon, internist and patient. With success rates now above 80% and improving yearly, diabetic patients must make a major life-style decision when considering a pancreas transplant. The main concerns are will the benefits of insulin-independence off-set the risks of surgery and immunosuppression. For diabetics near dialysis and considering a kidney transplant, the decision may not be as difficult. However, for those patients who are failing insulin therapy (brittle control) and remain with good renal function, the options are limited. As the success of pancreas transplantation improves, the procedure may become routine at more centers and become accepted by more third-party carriers. However, as with other solid organs, the availability of pancreases is limited and the supply soon to be exhausted. Thus, further advances are required for the prevention and treatment of Type 1 diabetes. Hopefully, the new frontiers of the next century will allow physicians to identify and preventively treat those at risk for the development of diabetes. Thus, the population of patients suffering from the consequences of this dreadful disease will be greatly reduced. With new developments in immunosuppression and islet transplantation, diabetic patients of the future may be offered the option of a procedure with reduced risks, less morbidity, and improved long-term cure rates.

Excellence of the two-layer method (University of Wisconsin solution/perfluorochemical) in pancreas preservation before islet isolation.

BACKGROUND: In islet transplantation pancreatic preservation before islet isolation is an obstacle compromising islet yield and viability. We tested the feasibility of a two-layer method (University of Wisconsin solution [UW]/perfluorochemical) for pancreatic preservation before islet isolation. METHODS: Dog pancreases were processed into pure islets by the method of Ricordi preceded by five different preservations (groups 1-a and 1-b, the two-layer method for 3 and 24 hours; groups 2-a and 2-b, simple cold storage in UW for 3 and 24 hours; group 3, without preservation). Islet yields and functional success after autotransplantation into the liver were compared among the groups. RESULTS: Postpurification islet equivalents (IE)/gm pancreas and functional success rate were 5600 (mean), 83% in group 1-a; 4000, 56% in group 1-b; 4700, 33% in group 2-a; 1300, 0% in group 2-b; and 5000, 89% in group 3 (p < 0.05; 2b versus 1-a, 1-b, and 3), respectively. There was no statistical difference among groups 1-a, 1-b, and 3 in terms of islet yield and function (p > 0.2). CONCLUSIONS: The two-layer method is more effective than conventional simple cold storage in UW for pancreatic preservation before islet isolation. Clinical trials with the two-layer method are warranted.