Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members.

The epidermal growth factor receptor (EGFR) is a central regulator of proliferation and progression in human cancers. Five EGFR inhibitors, two monoclonal antibodies and three TKIs, have recently gained FDA approval in oncology (cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). These strategies of EGFR inhibition demonstrate major tumor regressions in approximately 10-20% of advanced cancer patients. However, many tumors eventually manifest acquired resistance to treatment. In this study we established and characterized a model to study molecular mechanisms of acquired resistance to the EGFR monoclonal antibody cetuximab. Using high-throughput screening we examined the activity of 42 receptor tyrosine kinases in resistant tumor cells following chronic exposure to cetuximab. Cells developing acquired resistance to cetuximab exhibited increased steady-state EGFR expression secondary to alterations in trafficking and degradation. In addition, cetuximab-resistant cells manifested strong activation of HER2, HER3 and cMET. EGFR upregulation promoted increased dimerization with HER2 and HER3 leading to their transactivation. Blockade of EGFR and HER2 led to loss of HER3 and PI(3)K/Akt activity. These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization/degradation and subsequent EGFR-dependent activation of HER3. Taken together these findings suggest a rationale for the clinical evaluation of combinatorial anti-HER targeting approaches in tumors manifesting acquired resistance to cetuximab.

Successful outpatient treatment of renal vein thrombosis by low-molecular weight heparins in 3 patients with nephrotic syndrome.

Renal vein thrombosis (RV Thromb) is a serious complication ofnephrotic syndrome. Anticoagulation is usually recommended as the treatment of choice. This study reports 3 nephrotic patients diagnosed to have RVThromb combined with thromboembolic events. Low-molecular weight heparin (LMWHep) was given subcutaneously every 12 hours following the diagnosis of RVTromb, which continued at the outpatient clinic after an average of 11 in-hospital days. The patients visited the nephrology outpatient clinic every other week and underwent magnetic resonance image (MRI) studies at 6-week intervals for follow-up of patency of the involved renal vein. LMWHep was discontinued when MRI showed this patency. The average outpatient treatment period was 74 days. There was no recurrent RVThromb in the follow-up course of 6 months after discontinuation of LMWHep. Kidney function was preserved, as indicated by image studies and serial renal function tests. LMWHep produced a more predictable anti-coagulant effect, a superior bioavailability, a longer half-life and a dose-independent effect than unfractionated heparin and coumadin. These benefits made the outpatient treatment of RVThromb possible. Our report recommends outpatient treatment of RVThromb by LMWHep because it is feasible, effective and safe.

Hyperhomocysteinaemia and vascular access thrombosis among chronic hemodialysis patients in Taiwan: a retrospective study.

Vascular access thrombosis (VAT) is an important cause of morbidity for chronic haemodialysis (HD) patients. Some risk factors for VAT have been well-defined for chronic HD patients from western countries. However, only a few such factors have been confirmed for Taiwanese patients. This study attempted to determine the association between hyperhomocysteinaemia and the incidence of VAT for chronic HD patients in Taiwan. We retrospectively enrolled a total of 196 patients into this study during 2003. The patients were separated into VAT (n = 142) and control (n = 54) group. The participants of the VAT group were identified as those having one or more VAT, and the participants of the control group were those with no VAT in the past. The mean follow-up period was 48 months. The mean serum homocysteine levels were 29.5 +/- 9.6 and 29.1 +/- 9.5 micromol/l for the VAT (n = 142) and the control (n = 54) group, respectively. There was no significant difference in the level of homocysteine between the VAT and the control group (p = 0.70). Female chronic HD patients had significantly greater mean total homocysteine levels than male (30.89 micromol/l, 95% CI 28.84-32.94 vs. 28.06 micromol/l, 95% CI 26.32-29.82, respectively, p = 0.038). That synthetic graft was a significant risk factor for VAT was determined using multivariate logistic regression analysis. There was no association between serum total homocysteine levels and the incidence of VAT in chronic HD patients in Taiwan.

Incidental primary hyperparathyroidism in a hypercalcaemic woman with tuberculous peritonitis.

We report on a 51-year-old woman with initial hypercalcaemia and unknown ascites. In spite of unyielding laparoscopy, laparotomy showed findings compatible with tuberculous peritonitis (TBP). Unexpectedly, a series of examinations eventually revealed the concurrence of hyperparathyroidism due to a parathyroid adenoma. Anti-tuberculous regimen was given and was uneventful. However, hypercalcaemia was not decreased but sustained at a high level even after anti-tuberculous therapy for 3 months. Parathyroidectomy was performed with subsequent normalisation of hypercalcaemia. The aetiology of hypercalcaemia in a patient with an explored disease able to cause this electrolyte abnormality such as TBP may be a coexistent occult parathyroid adenoma.

Acute renal failure after cadaveric related liver transplantation.

Acute renal failure (ARF) is a frequent medical complication after liver transplantation (LT). We analyzed cadaveric related liver transplant recipients who had developed ARF early in the postoperative course. Between January 1982 and August 2003, a total of 67 patients underwent cadaveric related LT. Their mean age was 28.64 years at LT. The 67 recipients had the following indications: biliary atresia (n = 17), Wilson's disease (n = 15), hepatitis B-related liver cirrhosis (n = 14), hepatitis C-related liver cirrhosis (n = 4), primary biliary cirrhosis (n = 4), hepatitis B-related liver cirrhosis with hepatoma (n = 3), hepatitis C-related liver cirrhosis with hepatoma (n = 2), Budd-Chiari syndrome (n = 2), neonatal hepatitis (n = 1), choledochus cyst (n = 1), autoimmune cirrhosis (n = 1), neuroendocrine tumor (n = 1), and hemangioendothelioma (n = 1). Forty-nine patients received cyclosporine (CsA), azathioprine, and steroids and 18, a combination with tacrolimus (FK506). Eight (11.94%) patients developed ARF at a mean time of 17.25 days after LT. The mean peak serum creatinine was 2.24 mg%. Four of these patients had a diagnosis of hepatitis B-related liver cirrhosis; two, hepatitis C-related liver cirrhosis; one, primary biliary cirrhosis; and one, hepatitis B-related liver cirrhosis with hepatoma. The ARF etiology was multifactorial for the majority of patients. Eight ARF patients had a history of liver cirrhosis, which may be a risk factor for intraoperative ARF. ARF treatment included fluid replacement, decreased or altered immunosuppressive agents, avoiding exposure to nephrotoxic drugs, and adjusting antibiotic dosages. The majority of patients returned to normal renal function at 1 to 3 weeks after the diagnosis of ARF. No patient required dialysis and/or experienced a mortality. We conclude that the incidence of ARF is relatively low and with good outcomes. ARF etiology was multifactorial for the majority of patients, but eight patients had a history of liver cirrhosis, which may be a risk factor for intraoperative ARF. We suggest that in the early postoperative period of LT cases diagnosis and treatment of ARF are important.

Successful treatment of crescentic glomerulonephritis associated with adult-onset Henoch-Schoenlein purpura by double-filtration plasmapheresis.

Henoch-Schoenlein purpura (HSP) crescentic glomerulonephritis with acute renal failure in adults is extremely rare. The condition carries a grave renal outcome if it is not appropriately managed. Oral corticosteroids, intravenous methylprednisolone pulse therapy and plasmapheresis with concomitant plasma replacement have been used alone or in various combinations to treat patients with HSP nephritis, yet the effects are uncertain. We describe a 33-year-old man with oliguric acute renal failure in the setting of HSP crescentic glomerulonephritis that is refractory to intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days) with maintained oral prednisolone (1 mg/kg/day) and oral cyclophosphamide (2 mg/kg/day) for 3 weeks, resulting in successful recovery of renal function after 9 sessions of simple double-filtration plasmapheresis treatment without concomitant plasma replacement. There was no recurrence of vasculitic events within 18 months. In this case, we emphasize that simple double-filtration plasmapheresis without concomitant plasma replacement is an effective and safe modality therapy for adult patients with HSP crescentic glomerulonephritis and acute renal failure, especially when conventional therapy has failed.

Tuberculous peritonitis in uremic patients.

AIMS: To identify clinical features and treatment response of tuberculous peritonitis (TBP) in a uremic population, a retrospective case-control study was performed. MATERIALS AND METHODS: Thirteen uremic patients with TBP (Group I: 62.7 +/- 6.8 years, male 54%) collected between January 1986 and January 2002 were compared with another two age- and sex-matched controls: 19 non-azotemic patients with TBP (Group II: 62.9 +/- 7.3 years, male 47%) and 30 uremic patients without TBP (Group III: 61.1 +/- 8.7 years, male 47%). Clinical information and data of ascites and blood examinations were evaluated. RESULTS: Significant differences between Groups I and II were found in comorbidity, hypertension, anorexia, percentages of neutrophil and lymphocyte from blood and ascites, and serum calcium (sCa), phosphorus and albumin-adjusted calcium (sAACa). However, no significant differences in duration of symptoms, coexistent pulmonary tuberculosis (p = 0.061), duration or complications of therapy and mortality (p = 0.13) were detected. Significant differences between Groups I and III were found in peripheral white cell counts and percentages of neutrophil and lymphocyte as well as in serum creatinine (sCr), albumin, sCa, sAACa and intact parathyroid hormone (iPTH). CONCLUSIONS: Non-specific symptoms make the diagnosis of TBP in a uremic population difficult. However, neutrophil predominance in blood and ascites, hypoalbuminemia, relatively lower sCr and hypercalcemia with suppressed serum iPTH were found to be characteristic. In TBP uremic patients, therapy complications were not common and there was a tendency for higher mortality, largely due to septic shock.

Minimal change nephrotic syndrome associated with malignant thymoma: case report and literature review.

We report on a patient with nephrotic syndrome with myasthenia gravis and malignant thymoma status post thymectomy and radiotherapy. This 44-year-old woman underwent a thymectomy and localized radiotherapy for invasive thymoma in 1991. She also took azathioprine and pyridostigmine regularly for the control of her symptoms of myasthenia gravis following thymectomy. Neither evidence of recurrence of myasthenia gravis, nor enlargement of residual thymoma was noted following treatment in 1991. Unfortunately, this patient developed a pronounced nephrotic syndrome in 1999, a renal biopsy revealing a minimal-change glomerulonephritis as being present. The patient entered remission subsequent to steroid and cyclosporin therapy, whereas many previously-reported cases of a similar nature either died or remained with a persistent proteinuria. Herein, we review the literature pertaining to examples of nephrotic syndrome for those patients diagnosed with malignant thymoma, and discuss the possible mechanisms for this association, and emphasize the need for the aggressive treatment of the condition, recommending the early use of steroids and cyclosporins.

Improvement of sexual function in male patients after parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: Clinically, the severity of uremia is known to be inversely proportional to sexual desire and activity in patients with chronic renal failure. We studied sexual function and sex hormones in male patients with symptomatic hyperparathyroidism before and 3 months after parathyroidectomy. STUDY DESIGN: From October 1998 to December 2000, 20 male patients with symptomatic secondary hyperparathyroidism were enrolled in this study. They underwent total parathyridectomy and autotransplantation of 90 mg of tissue to the subcutaneous tissue of the forearm or thigh. They all had regular sexual partners and were sexually active. Preoperatively, hemoglobin, hematocrit, calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone (iPTH), prolactin, testosterone, leutenizing hormone (LH), and follicle stimulation hormone (FSH) were checked routinely. Three months after operation those data were checked again. Sexual function was evaluated with the International Index of Erectile Function (IIEF). Monthly frequency of attempted sexual intercourse, satisfaction of attempted intercourse, and enjoyment of intercourse were individually analyzed preoperatively and 3 months postoperatively. RESULTS: Hemoglobin, hematocrit, testosterone, and LH were noted to have not significantly changed 3 months after surgery. Serum levels of calcium, phosphorus, alkaline phosphatase, FSH, and iPTH were significantly reduced, as were the levels of prolactin. But preoperative and postoperative FSH levels were within normal limits, and 70% of the postoperative alkaline phosphatase levels were above normal. Sexual function increased significantly 3 months after parathyroidectomy, as did monthly frequency of attempted intercourse, satisfaction of attempted intercourse, and enjoyment of intercourse. CONCLUSIONS: Sexual function of male patients with symptomatic hyperparathyroidism can possibly be improved by parathyroidectomy and autotransplantation. Decreases in the levels of prolactin, calcium, phosphorus, and iPTH are also noticed after parathyroidectomy.

Acute renal failure caused by rifampicin re-exposure with 10-year of interval.

A 53-year-old woman was treated for recurrent pulmonary tuberculosis with reintroduction of rifampicin after a medication-free interval of 10 years. After taking the first dose, she developed severe hemolytic anemia and oliguric acute renal failure and required temporary hemodialysis. The fulminant clinical course was compatible with rifampicin-induced acute renal failure. The renal function of this patient completely recovered after discontinuation of rifampicin and temporary hemodialysis. Since renal biopsy and anti-rifampicin antibodies cannot offer a definite diagnosis of rifampicin-induced acute renal failure, we must emphasize the importance of a clinical diagnosis of rifampicin-induced acute renal failure and complete history taking. Re-exposure is a critical factor. In this case, the rifampicin-free interval was as long as 10 years. Because of the feasible prognosis, reintroduction of rifampicin for recurrent pulmonary tuberculosis should not be abandoned, but the infrequent and life-threatening side effects should be kept in mind.

Implications of sonographic identification of duplex kidney in adults.

BACKGROUND: Duplication of the renal pelvis and ureter constitutes the most common anomalies of the upper urinary tract. Most patients are asymptomatic and don't need treatment. However, the associated anomaly and acquired renal disease may cause morbidity and mortality. The aim of this study was to investigate the prevalence of duplex kidney in sonographic examinations and the predictive capability of this method. An analysis of patients with urography-confirmed duplication anomaly was also performed. METHODS: During a period of 9 year (from 1988 to 1996), sonographic examination records of 19,287 patients were reviewed. Patients with a diagnosis of duplex kidney were enrolled. Their clinical characteristics and radiological images were recorded and evaluated. RESULTS: One hundred and sixty-three patients were found by sonography to have duplex kidney, for an prevalence of 0.85%. Urography studies were done on 64 (39.2%) patients, and 42 patients were proven to have duplex kidney. The positive predictive rate of sonography was 65.6%. Eighty percent of patients with duplex kidney had associated ureteral duplication. No associated anomalies were found. Four patients had urolithiasis, and 3 patients had recurrent urinary tract infection. One patient had coexisting uroepithelial malignancy, and 1 patient had refractory gross hematuria. CONCLUSIONS: Duplex kidney is an uncommon finding during adult sonographic examinations. The sensitivity and specificity of sonography in identifying this anomaly are controversial. An experienced hand with good knowledge of the anomaly and its sonographic signs is helpful in more accurately diagnosing this anomaly.

Risk factors for renal allograft survival in patients receiving cyclosporine immunosuppression.

BACKGROUND AND PURPOSE: Although cyclosporine (CsA) has been widely used in renal transplantation for more than 10 years, no large series of renal transplant patients has been studied in southern Taiwan. The purpose of this retrospective cohort study was to investigate the risk factors for graft survival in renal transplant recipients. METHODS: From August 1987 to January 1998, 101 primary cadaveric renal transplantations were performed. The minimum follow-up period was 1 year. CsA and prednisolone were initially used as immunosuppressive agents in all patients. Use of lower doses of CsA to reduce CsA trough level (50-99 ng/mL) in hepatitis B surface antigen (HBsAg)-positive recipients was attempted at 6 months after transplantation. RESULTS: Graft actuarial survival rates at 1, 5, and 10 years posttransplantation were 89%, 75%, and 57%, respectively. Acute rejection and increased recipient age were found to be significant risk factors (p < 0.05) affecting graft survival, with hazard ratios of 5.20 and 1.74, respectively, by multivariate analysis using a Cox proportional hazards model. Hepatitis B and/or hepatitis C infection had no influence on graft survival. CONCLUSIONS: In this series of cadaveric renal allograft patients, the risk factors affecting allograft survival were acute rejection and recipient age.

Low dose desferrioxamine can improve erythropoiesis in iron-overload hemodialysis patients without side effects.

OBJECTIVE: Multiple blood transfusions were often required to treat anemia in uremia patients before the era of recombinant human erythropoietin (r-HuEPO). Iron overload thus frequently occurred in chronic hemodialysis patients. Desferrioxamine (DFO) is an effective chelating agent, which can remove excessive iron and can enhance erythropoiesis. Large dose DFO treatment is a therapy associated with the development of severe complications. In this study, a low dose DFO regime was used to treat iron overloaded hemodialysis patients. The efficacy and side effects of this regiment were evaluated. MATERIALS AND METHODS: Eight iron overloaded chronic hemodialysis patients were enrolled in this study. All patients received DFO 500 mg intravenously twice-a-week for eight months. Serum aluminum, transferrin saturation (TFS) and r-HuEPO requirement were recorded before and after DFO treatment. Serum ferritin and hematocrit (Hct) were measured before, during, and after the DFO withdrawal period. All patients were evaluated and followed closely during treatment. RESULTS: Changes in aluminum, TFS and r-HuEPO dosage were unremarkable (p > 0.05). Hct increased significantly after eight months of DFO treatment (from 25.3% to 27.0%, p < 0.05). Ferritin level was reduced by 43.2% at the end of treatment and an evident decline of ferritin was achieved after four months of treatment (2102 ng/mL to 1166 ng/mL, p < 0.05). All patients tolerated the treatment well and no complications were found. CONCLUSION: Low dose DFO can chelate iron effectively in chronic hemodialysis patients. This treatment can enhance erythropoiesis without adverse effects.

Hyperglycemic hyperosmolar non-ketotic syndrome in hemodialysis patients.

BACKGROUND: Hyperglycemic hyperosmolar non-ketotic syndrome (HHNK) is an emergency complication of diabetes mellitus. The conventional treatment modality often includes massive fluid supplementation. In maintenance hemodialysis patients, dehydration via the renal route may not occur, and fluid management is rather complicated. In this study, we investigated the precipitating factors, treatment modalities, clinical course and prognosis of HHNK patients who received maintenance hemodialysis. METHODS: From January 1988 through August 1998, 16 diabetic patients who had developed HHNK were enrolled. Eight of them were end stage renal disease (ESRD) patients on maintenance hemodialysis, and another group included 8 acute renal failure (ARF) diabetes mellitus patients who received their first hemodialysis during the HHNK episode. We retrospectively reviewed their medical charts and recorded each patient's age, treatment modalities, especially fluid supplementation, predisposing factors, and biochemical data during the HHNK episode. Complications and the final outcome were also recorded. RESULTS: There were no significant differences in biochemical data and patients' ages between the two groups (p > 0.05). The major predisposing factor for the ARF patients was infection, but irregular use of or discontinuing oral hypoglycemic agents (OHA) or insulin was the major predisposing factor for the ESRD patients. Less fluid supplementation was given in the ESRD group as compared to the ARF group and no deaths occurred in the ESRD group of patients. However, 6 patients expired in the ARF group of patients. CONCLUSION: Regular medical care, early diagnosis and recognition, and easier management of fluid administration explain the rather smooth course and better prognosis in the ESRD group of patients.

Spontaneous bacterial peritonitis in adult patients with primary nephrotic syndrome.

BACKGROUND: Susceptibility to bacterial infection is a common problem in nephrotic patients. Spontaneous bacterial peritonitis, although characteristic of nephrotic children, is extremely rare in adults. METHODS: A retrospective review was performed on all adult patients with the discharge diagnoses of primary nephrotic syndrome and spontaneous bacterial peritonitis treated between 1986 and 1998 at Chang Gung Memorial Hospital in Kaohsiung, Taiwan. Ten patients were included in this study, 9 of them men and one woman. The average age was 30.5 years. RESULTS: All the patients had signs of active nephrosis and presented with diffuse abdominal pain, ascites, fever and/or chills. Thirty percent (3/10) of the causative pathogens were gram-positive bacteria and 60% (6/10) were gram-negative bacteria. One patient had sterile cultures. Seven patients recovered after antibiotic treatment for 1 to 2 weeks. Three patients died of septic shock. CONCLUSION: Therefore, to improve patient outcome, it is essential to establish a diagnosis early and to initiate broad-spectrum antimicrobial therapy even before culture results are available.

Acute goby poisoning in southern Taiwan.

Food poisoning due to ingestion of two fishes, Yongeichthys nebulosus and Sillago japonica, occurred in Kaohsiung, Taiwan, in February 1997. Two male persons (48 and 58 years old) were poisoned, with symptoms featured by dizziness, nausea, vomiting, numbness, and difficulty in respiration. All of the specimens of fish retained by the victims were combined and consisted of Yongeichthys nebulosus and Sillago japonica. These retained specimens were assayed for anatomical distribution of toxicity (as tetrodotoxin) and all specimens were found to be toxic. The highest toxicity of specimen was 7,650 mouse units (MU) in Y. nebulosus and 1,460 MU in S. japonica. However, the other specimens re-collected from that fish pier were also found to be highly toxic in Y. nebulosus, but nontoxic in S. japonica. Hence, Y. nebulosus was judged as the real causative fish in this food poisoning. The toxins were partially purified from the methanolic extracts of toxic fishes by ultrafiltration and Bio-Gel P-2 column chromatography. Cellulose acetate membrane electrophoresis and high performance liquid chromatography analyses demonstrated that tetrodotoxin was the causative agent of this food poisoning.

Renal tubular acidosis, hypokalemic paralysis, rhabdomyolysis, and acute renal failure--a rare presentation of Chinese herbal nephropathy.

We encountered a 66-year-old Chinese man presented with hypokalemic paralysis, rhabdomyolysis and acute renal failure after administration of mixed Chinese herbs. Proximal renal tubular acidosis and selective glucosuria were the main tubular dysfunctions. The renal failure recovered smoothly and rapidly after resuscitation and the tubular function abnormalities regained spontaneously after medicine withdrawal. It should be recognized that renal tubular acidosis with hypokalemic paralysis, rhabdomyolysis and subsequent acute renal failure may develop after taking Chinese mixed herbal medicine.