Karen T. Brown

Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family--oncogenic activation of v-kit involves deletion of extracellular domain and C terminus.

The protein kinase domains of v‐kit, the oncogene of the acute transforming feline retrovirus HZ4‐FeSV (HZ4‐feline sarcoma virus), CSF‐1R (macrophage colony stimulating factor receptor) and PDGFR (platelet derived growth factor receptor) display extensive homology. Because of the close structural relationship of v‐kit, CSF‐1R and PDGFR we predicted that c‐kit would encode a protein kinase transmembrane receptor (Besmer et al., 1986a; Yarden et al., 1986). We have now determined the primary structure of murine c‐kit from a DNA clone isolated from a brain cDNA library. The nucleotide sequence of the c‐kit cDNA predicts a 975 amino acid protein product with a calculated mol. wt of 109.001 kd. It contains an N‐terminal signal peptide, a transmembrane domain (residues 519‐543) and in the C‐terminal half the v‐kit homologous sequences (residues 558‐925). c‐kit therefore contains the features which are characteristic of a transmembrane receptor kinase. Comparison of c‐kit, CSF‐1R and PDGFR revealed a unique structural relationship of these receptor kinases suggesting a common evolutionary origin. The outer cellular domain of c‐kit was shown to be related to the immunoglobulin superfamily. The sites of expression of c‐kit in normal tissue predict a function in the brain and in hematopoietic cells. N‐terminal sequences which include the extracellular domain and the transmembrane domain as well as 50 amino acids from the C‐terminus of c‐kit are deleted in v‐kit. These structural alterations are likely determinants of the oncogenic activation of v‐kit.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic neuroendocrine metastases: does intervention alter outcomes?

BACKGROUND In most instances, advanced neuroendocrine tumors follow an indolent course. Hepatic metastases are common, and although they can cause significant pain, incapacitating endocrinopathy, and even death, they are usually asymptomatic. The appropriate timing and efficacy of interventions, such as hepatic artery embolization (HAE) and operation, remain controversial. STUDY DESIGN The records of 85 selected patients referred for treatment of hepatic neuroendocrine tumor metastases between 1992 and 1998 were reviewed from a prospective database. A multidisciplinary group of surgeons, radiologists, and oncologists managed all patients. Overall survival among this cohort is reported and prognostic variables, which may be predictive of survival, are analyzed. RESULTS There were 37 men and 48 women, with a median age of 52 years. There were 41 carcinoid tumors, 26 nonfunctional islet cell tumors, and 18 functional islet cell tumors. Thirty-eight patients had extrahepatic metastases, and in 84% of patients, the liver metastases were bilobar. Eighteen patients were treated with medical therapy or best supportive care, 33 patients underwent HAE, and 34 patients underwent hepatic resection. Both the HAE-related mortality and the 30-day operative mortality rates were 6%. By univariate analysis, earlier resection of the primary tumor, curative intent of treatment, and initial surgical treatment were associated with prolonged survival (p < 0.05). On multivariate analysis, only curative intent to treat remained significant (p < 0.04). Patients with bilobar or more than 75% liver involvement by tumor were least likely to benefit from surgical resection. One-, 3-, and 5-year survival rates for the entire group were 83%, 61%, and 53%, respectively. The 1-, 3-, and 5-year survivals for patients treated with medical therapy, HAE, and operation were 76%, 39%, and not available; 94%, 83%, and 50%; and 94%, 83%, and 76%, respectively. CONCLUSIONS Hepatic metastases from neuroendocrine tumors are best managed with a multidisciplinary approach. Both HAE and surgical resection provide excellent palliation of hormonal and pain symptoms. In select patients, surgical resection of hepatic metastases may prolong survival, but is rarely curative.

c-kit protein, a transmembrane kinase: identification in tissues and characterization.

The proto-oncogene c-kit encodes a transmembrane kinase which is related to the receptors for colony-stimulating factor type 1 and platelet-derived growth factor, as well as to the immunoglobulin superfamily. Antibodies specific for the kinase domain of the P80 gag-kit protein of the Hardy-Zuckerman 4 feline sarcoma virus were prepared. These kit-specific antibodies were used to identify and characterize the c-kit protein in cat brain tissue. The c-kit protein product displays an autophosphorylating activity in immune complex kinase assays, and, in turn, this activity was used to identify the c-kit protein in different tissues. In cat brain, a single 145-kilodalton (kDa) glycoprotein was detected. Its N-linked carbohydrates were found to be sensitive to digestion with the endoglycosidases (neuraminidase, endoglycosidase F, and endoglycosidase H), indicating hybrid and/or complex and high-mannose structures. A partial purification of the c-kit protein was achieved by wheat germ agglutinin affinity chromatography, and the autophosphorylating activity of the partially purified c-kit protein was characterized and found to be specific for tyrosine. The kit antibodies cross-react with the murine c-kit protein product, and variant c-kit proteins in different mouse tissues were identified, with sizes of about 145 kDa (brain), 160 kDa (spleen), and 150 kDa (testis).

Combined Portal Vein Embolization and Neoadjuvant Chemotherapy As a Treatment Strategy for Resectable Hepatic Colorectal Metastases

Objectives:The objectives of this study are 1) to determine whether the future liver remnant will grow after portal vein embolization (PVE) in patients with colon cancer on concurrent chemotherapy and 2) to determine whether recovery after extended hepatectomy is improved after PVE. Purpose:Neoadjuvant chemotherapy followed by hepatic resection is an increasingly used therapeutic strategy for curative treatment for colorectal metastases. However, such chemotherapy may result in steatosis, liver damage, and compromised liver regeneration and recovery. This study aims to determine whether PVE can be used during neoadjuvant therapy to enhance growth of future residual liver and to improve postoperative recovery. Methods:From September 1999 to September 2004, 100 patients with colorectal metastases to the liver were subjected to PVE as preparation for extended hepatic resection, 43 of whom were embolized during neoadjuvant chemotherapy. Liver growth was examined by computed tomography volumetric analysis. Clinical outcomes of the 71 patients subsequently resected were compared with 100 consecutive patients subjected to extended resection without PVE (controls). Results:After a median wait of 30 ± 2 days after PVE, patients on neoadjuvant chemotherapy experienced a median contralateral (nonembolized) liver growth of 22% ± 3% compared with 26% ± 3% for those without chemotherapy (P = NS). The number of patients with <5% growth was also similar: 4 of 43 versus 6 of 57 (P = NS). Comparison of patients resected after PVE to a simultaneous cohort of 100 consecutive patients subjected to extended resection without prior PVE demonstrated a lower fresh frozen plasma requirement (P = 0.01), a lower peak bilirubin (P = 0.002), and a shorter length of stay (P = 0.03). Mortality was similar (0% vs. 2%). Conclusions:Liver growth occurs after PVE even when cytotoxic chemotherapy is administered. No major complications occurred with PVE. Patients requiring major hepatic resection should be considered for PVE during neoadjuvant chemotherapy to improve subsequent recovery after resection.

Management and Outcomes of Postpancreatectomy Fistula, Leak, and Abscess: Results of 908 Patients Resected at a Single Institution Between 2000 and 2005

BACKGROUND Anastomotic fistula, leak, and abscess are common complications of pancreatectomy. The goal of this study was to describe our current management and outcomes of clinically significant postpancreatectomy fistula, leak, and abscess. STUDY DESIGN Review of a prospectively maintained database identified 908 patients who underwent pancreatectomy between January 2000 and August 2005. Complication data were prospectively entered into a validated postoperative complication database. Patients were included if they were identified as having a clinically significant (>/=grade 2) pancreatic fistula, leak, or abscess. Multivariate analyses were performed to identify factors predictive of prolonged drainage (> 30 days). RESULTS Clinically significant postoperative fistula, leak, or abscess occurred in 158 of 908 resected patients (17%) and included 63 culture-positive pancreatic fistulas, 29 noninfected pancreatic fistulas, 42 abscesses, and 24 other collections (biliary fistula, culture-negative collection). Surgical drains were placed at the time of initial resection in 88 of these 158 patients (56%). Adequate drainage was obtained by prolonged use of surgical drains in 16 patients (16 of 88 [18%]). Reoperation was required in 26 of the 158 patients (16%). ICU admission was required in 22%. Within this group of 158 patients the mortality rate was 5% (8 of 158; 90 days). At the time of discharge a home health aide was required in 56% of patients, 8% were discharged to a rehabilitation facility, and readmission was required in 50% of patients. Mean drainage time was 38 days (range 3 to 228). Predictors of prolonged drainage included drain output > 200 mL during the first 48 hours (odds ratio = 2.88; p = 0.02) and distal (versus proximal) pancreatectomy (odds ratio = 4.29; p = 0.01). CONCLUSIONS Although mortality after pancreatectomy has decreased to approximately 2%, the morbidity associated with pancreatic fistula, leak, and abscess remains substantial.

Particle Embolization of Hepatic Neuroendocrine Metastases for Control of Pain and Hormonal Symptoms

PURPOSE To evaluate treatment outcome with respect to the indication for treatment in patients with neuroendocrine tumors metastatic to the liver undergoing hepatic artery embolization with polyvinyl alcohol (PVA) particles. MATERIALS AND METHODS Charts and radiographs were reviewed of 35 patients undergoing 63 separate sessions of embolotherapy between January 1993 and July 1997. Patient demographics, tumor type, indication for embolization, and complications were recorded. Symptomatic and morphologic responses to therapy were noted, as well as duration of response. RESULTS Fourteen men and 21 women underwent embolization of 21 carcinoid and 14 islet cell tumors metastatic to the liver. These patients underwent 63 separate episodes of embolotherapy. Of 48 episodes that could be evaluated, response to treatment was noted following 46 episodes (96%). The duration of response was longest in patients treated for hormonal symptoms with (17.5 months) or without (16 months) pain, and was shortest (6.2 months) when the indication was pain alone. Complications occurred after 11 of the 63 embolizations (17%), including four (6%) deaths. Cumulative 5-year survival following embolotherapy was 54%. CONCLUSION Hepatic artery embolization with PVA particles is beneficial for patients with neuroendocrine tumors metastatic to the liver and may be used for control of pain as well as hormonal symptoms. This therapy should be used cautiously when more than 75% of the hepatic parenchyma is replaced by tumor.

Germline BRCA1 185delAG mutations in Jewish women with breast cancer

BACKGROUND We aimed to find out the proportion of breast cancers in Ashkenazi Jewish women attributable to the frameshift mutation at position 185 involving the deletion of adenine and guanine (185delAG) in the breast cancer gene BRCA1. METHODS We studied 107 Ashkenazi Jewish women with breast cancer seen at medical oncology and genetic counseling clinics in New York over a three and a half year period beginning in 1992. 80 of the women were diagnosed before age 42 years; the other 27 were diagnosed between 42 and 50 years and had a positive family history. Genomic DNA testing by PCR amplification was done to identify any 185delAG mutations of the BRCA1 gene. FINDINGS Of the 80 women diagnosed before the age of 42 years, 16 (20%, 95% CI 11.2-28.8) were heterozygous for the mutation. All 16 women had at least one first-degree or second-degree relative with breast or ovarian cancer. Of 27 probands diagnosed with breast cancer between the ages of 42 and 50 years who had at least one first-degree relative affected with breast or ovarian cancer, 8 (30%, 95% CI 12-47) had 185delAG mutations. INTERPRETATION These data suggest that screening for the 185delAG mutation may be useful in genetic counselling of these women where options for detection and prevention of possible cancers can be discussed.

Transcatheter Arterial Embolization with Only Particles for the Treatment of Unresectable Hepatocellular Carcinoma

PURPOSE To determine the survival of patients with hepatocellular carcinoma (HCC) treated with a standardized method of transcatheter arterial embolization (TAE) with small embolic particles intended to impart terminal vessel blockade, and to evaluate prognostic factors that impact overall survival. MATERIALS AND METHODS A total of 322 patients with HCC who underwent 766 embolizations from January 1997 to December 2004 were retrospectively reviewed. Selective embolization of vessels feeding individual tumors was performed with small (50 microm) polyvinyl alcohol or spherical embolic particles (40-120 microm) intended to cause terminal vessel blockade. Repeat embolization was performed in cases of evidence of persistent viable tumor or development of new lesions. Patient, tumor, and treatment characteristics were prospectively recorded and tested for prognostic significance by univariate and multivariate analysis. RESULTS The median survival time was 21 months, with 1-, 2-, and 3-year overall survival rates of 66%, 46%, and 33%, respectively. In patients without extrahepatic disease or portal vein involvement by tumor, the overall 1-, 2-, and 3-year survival rates increased to 84%, 66%, and 51%, respectively. Okuda stage, extrahepatic disease, diffuse disease (> or =5 tumors), and tumor size were independent predictors of survival on multivariate analysis. There were 90 complications (11.9%) in 75 patients, including eight deaths (2.5%), within 30 days of embolization. CONCLUSIONS Hepatic arterial embolization with small particles to cause terminal vessel blockade is an effective treatment method for patients with unresectable HCC. These data support our hypothesis that particles alone may be the critical component of catheter-directed embolotherapy.

Particle Embolization for Hepatocellular Carcinoma

PURPOSE To evaluate the outcome of all patients undergoing particle embolization for hepatocellular carcinoma at a single institution from January 1, 1993, through December 31, 1995. MATERIALS AND METHODS The charts and radiographs of all patients undergoing particle embolization during the study period were reviewed. The following information was collected: patient demographics, Child class and Okuda stage, number of embolization treatment sessions, length of hospital stay, complications related to the embolization procedure, including postembolization syndrome, current patient status, and date of death. RESULTS Forty-six patients underwent 86 embolization sessions during the study period. Postembolization syndrome developed after 70 of the 86 sessions (81%); in four cases (4.6%) this required treatment that extended the patients hospital stay. Three other complications occurred (3.5%), including a splenic infarct and two episodes of transient hepatic failure, all treated supportively. There was one death within 30 days, but it was not directly attributable to embolotherapy. Follow-up was available for all of the patients who underwent treatment. Thirty-four patients were classified as Child class A, and 12 were classified as Child class B. Thirty patients were classified as Okuda stage I, 14 were classified as Okuda stage II, and two were classified as Okuda stage III. Overall actuarial survival was 50% at 1 year and 33% at 2 years. There was a statistically significant difference in survival between Okuda stage I and stage II patients, but not between Child class A and class B patients. CONCLUSION Particle embolization for hepatocellular carcinoma is well tolerated and demonstrates actuarial survival of 50% at 1 year and 33% at 2 years.

Fatal Pulmonary Complications after Arterial Embolization with 40–120-μm Tris-acryl Gelatin Microspheres

Hepatic arterial embolization is a recognized method of treating primary malignancies and some secondary hepatic malignancies. Particle embolization alone has been shown to be safe and effective and is routinely performed for hypervascular tumors. Tris-acryl gelatin microspheres have been widely acclaimed for their ease of delivery and uniform size, allowing for accurate targeting of particular end arteries. There have been three deaths at the authors institution related to respiratory compromise since the 40-120- micro m particles became available 31 months ago. These complications were never observed with larger tris-acryl gelatin microspheres or polyvinyl alcohol particles. This is an unusual and serious complication of which interventionalists performing embolotherapy need to be aware.