Robotic and laparoscopic liver resection-comparative experiences at a high-volume German academic center.

PURPOSE: Minimally invasive liver surgery (MILS) is a feasible and safe procedure for benign and malignant tumors. There has been an ongoing debate on whether conventional laparoscopic liver resection (LLR) or robotic liver resection (RLR) is superior and if one approach should be favored over the other. We started using LLR in 2010, and introduced RLR in 2013. In the present paper, we report on our experiences with these two techniques as early adopters in Germany. METHODS: The data of patients who underwent MILS between 2010 and 2020 were collected prospectively in the Magdeburg Registry for Minimally Invasive Liver Surgery (MD-MILS). A retrospective analysis was performed regarding patient demographics, tumor characteristics, and perioperative parameters. RESULTS: We identified 155 patients fulfilling the inclusion criteria. Of these, 111 (71.6%) underwent LLR and 44 (29.4%) received RLR. After excluding cystic lesions, 113 cases were used for the analysis of perioperative parameters. Resected specimens were significantly bigger in the RLR vs. the LLR group (405 g vs. 169 g, p = 0.002); in addition, the tumor diameter was significantly larger in the RLR vs. the LLR group (5.6 cm vs. 3.7 cm, p = 0.001). Hence, the amount of major liver resections (three or more segments) was significantly higher in the RLR vs. the LLR group (39.0% vs. 16.7%, p = 0.005). The mean operative time was significantly longer in the RLR vs. the LLR group (331 min vs. 181 min, p = 0.0001). The postoperative hospital stay was significantly longer in the RLR vs. the LLR group (13.4 vs. LLR 8.7 days, p = 0.03). The R0 resection rate for solid tumors was higher in the RLR vs. the LLR group but without statistical significance (93.8% vs. 87.9%, p = 0.48). The postoperative morbidity ≥ Clavien-Dindo grade 3 was 5.6% in the LLR vs. 17.1% in the RLR group (p = 0.1). No patient died in the RLR but two patients (2.8%) died in the LLR group, 30 and 90 days after surgery (p = 0.53). CONCLUSION: Minimally invasive liver surgery is safe and feasible. Robotic and laparoscopic liver surgery shows similar and adequate perioperative oncological results for selected patients. RLR might be advantageous for more advanced and technically challenging procedures.

Trans-stomal single-port laparoscopic Hartmann's reversal is an efficacious and efficient procedure: a case-controlled study.

BACKGROUND: Hartman's reversal remains challenging and is associated with a widely variable success rate. In a previous study, we reported that laparoscopy may lower the mortality and morbidity rates of the procedure. The aim of the current study was to assess the operative results of single-port laparoscopic Hartmann's reversal (SP-HR) as compared to the more standard, multi-port laparoscopic variant (MP-HR). METHODS: We performed a retrospective, non-randomized, case-controlled study of 44 consecutive patients who had SP-HR (Group A) compared to 44 patients who had MP-HR (Group B). The study was conducted in a high-volume colorectal unit in a 1200-bed university affiliated hospital, The Poissy-Saint Germain Medical Complex, France. RESULTS: Preoperative patients' characteristics (sex, body mass index, American Society of Anesthesiologists status, prior surgery, comorbidities, colonic disease) were comparable in both groups. The conversion rate was 13.6% and 4.5% in Group A and in Group B, respectively (p = 0.084) and consisted of placement of any additional ports. Conversion to open surgery did not occur in any patient in either group (p = 1). Mean operative time was shorter in Group A than in in Group B, (105 vs. 155 min; p = 0.0133). The mortality rate was 2.2% in Group A and 0% in Group B (p = 0.3145). The overall morbidity rate was 11.4% in Group A and 18.2% in Group B (p = 0.5344). The median length of hospital stay was significantly shorter in Group than in Group B (4.8 vs. 6.8 days; p = 0.0102). CONCLUSIONS: The SP-HR technique was found to be safe and efficient. It compares favorably with MP-HR. Moreover, indirect cost savings could be induced by the reduction in the length of hospital stay.

NOTES total mesorectal excision (TME) for patients with rectal neoplasia: a preliminary experience.

BACKGROUND: Natural orifice transluminal endoscopic surgery (NOTES) and single-incision laparoscopy are emerging, minimally invasive techniques. Total mesorectal excision (TME), the gold standard treatment for patients with resectable distal rectal tumors, is usually performed in an "up-to-down" approach, either laparoscopically or via open techniques. A transanal, "down-to-up" TME has already been reported. Our NOTES variant of TME (NOTESTME) is based on a transperineal approach without any form of abdominal assistance. The aim was to reduce further the invasiveness of the procedure while optimizing the anatomical definition of the distal mesorectum. This approach may lead to reduced postoperative pain, decreased hernia formation and improved cosmesis when compared to standard laparoscopy. METHODS: NOTESTME was attempted in 16 patients with distal rectal neoplasia (i.e., distal edge of the tumor lower than the pouch of Douglas, between 0 and 12 cm from the dentate line). Additional inclusion criteria consisted of an ASA status ≤III and the absence of previous abdominal surgery. RESULTS: NOTESTME was completed in all patients. Additional abdominal, single-incision laparoscopic assistance was required in 6 (38 %) patients. Mean operative time was 265 min (range 155-440 min). The morbidity rate was 18.8 % (two small bowel obstructions and one pelvic abscess), requiring re-operation in each case. No leaks occurred, and the mortality rate at 30 and 90 days was 0 %. Resection margins were negative in all patients. A median of 17 nodes (range 12-81) was retrieved per specimen. Mean length of hospital stay was 10 days (range 4-29 days). Patients were followed for an average of 7 months (range 3-23 months). CONCLUSION: NOTESTME was feasible and safe in this series of patients with mid- or low rectal tumors. The short-term mortality and morbidity rates are acceptable, with no apparent compromise in the oncological quality of the resection. Larger, randomized controlled trials with long-term follow-up are warranted.

Minimally invasive pancreatic surgery of the entire gland: initial experience.

Many pancreatic cancer surgeons have been slow to adopt minimally invasive pancreatic surgery (MIPS) due a lack of formalized minimally invasive training and the perceived difficulty in dissecting pancreatic tumors and tissue away from the superior mesenteric vessels and consequent concerns for adequacy of oncologic margins and lymph node retrieval. A review of the first 29 MIPS procedures for malignant and premalignant tumors of the pancreas with the aid of a sterilizeable robotically-controlled camera holder was undertaken. As opposed to other robots currently available, this device allows for hand-assistance by the operating surgeon. Fourteen minimally invasive distal pancreatectomies (MIDP) (10 laparoscopic, 3 hand-assisted, 1 converted to open), 13 MIPDs (6 laparoscopic, 5 hand-assisted, 2 converted to open), and 2 laparoscopic central pancreatectomies have been performed. Seventeen (59%) of these patients were treated for cancer. Of these, 11 underwent a MIPD and 6 a MIDP. There were postoperative complications in seven patients (24%) at 30 days. Thirty and 90 day mortality was 3%. A sterilizeable robotically-controlled laparoscope holder that enables the operating surgeon to remain in contact with the patient and have the option of a hand-assisted approach may be particularly helpful for minimally invasive approaches to malignant and premalignant pancreatic tumors.

Liver resection for cystic lesions: a 15-year experience.

AIM: The aim pf this paper was to review the management strategies in patients who had hepatic resection for cystic lesions. If symptomatic, a simple liver cyst (SC) is best treated by unroofing. A hydatid cyst (HC) is treated by simple cystectomy or pericystectomy. Many procedures have been described for the management of complex non-HCS including aspiration, sclerosing therapy, drainage, unroofing, and resection. METHODS: A retrospective review of patients who had liver resection for cystic lesions between January 1, 1992, and December 31, 2006. The study was carried out at a University Hospital and a General Community Hospital affiliated with a University program. Management strategies were detailed, including clinical, biological, and imaging features. Operative morbidity and mortality as well as long-term outcome were also assessed. A comparison between preoperative and postoperative diagnoses was performed. RESULTS: Thirty-three patients (24 women and 9 men) underwent 39 liver resections, including 14 left lateral resections, 12 right hemi-hepatectomies, 7 left hemi-hepatectomies and 6 segmentectomies or wedge resections. The final diagnosis included hydatid cyst in 10 patients (30%), cystadenoma in 6 (18%), simple cysts in 6 (18%), Caroli's disease in 4 (12%), cystadenocarcinoma in 3 (9%) and miscellaneous in the 4 remaining (12%). There was no mortality and the postoperative morbidity rate was 15%. Long-term follow-up revealed that, besides patients with malignancies whose outcome was dismal, overall prognosis was positive with efficacious symptom control. CONCLUSION; Accurate preoperative diagnosis of liver cystic lesions may be difficult. However, liver resection for such lesions is a safe procedure that provides long-term symptomatic control in benign disease and may be curative in cases of underlying malignancy. Even if nearly 50% of liver cystic lesions treated by resection were either symptomatic SC or HC, we recommend en-bloc liver resection for all liver cystic lesions that are not clearly parasitic or simple cysts.

Laparoscopic versus open gastrectomy for adenocarcinoma: a prospective comparative analysis.

AIM: Laparoscopic gastrectomy (LG) is still not a widely accepted option for the treatment of invasive gastric cancer. This study was conducted to evaluate the results of LG for gastric adenocarcinoma in two French surgical departments. METHODS: Between 2001 and 2007, 51 patients underwent LG for gastric cancer. The results were compared to those of 79 patients who had open gastrectomy (OG) during the same study period. RESULTS: Mean age was 61 years (31-81) and 66 years (27-88) in the LG group and in the OG group, respectively. The sex ratio was 21 women to 30 men and 25 women for 54 men in the LG group and the OG group, respectively. The mean operative duration was 260 minutes (90-420) and 200 (120-360) the LG group and the OG group, respectively (P=0.11). Estimated operative blood loss was 150 ml (50-870) and 240 (120-955) in the LG group and the OG group, respectively (P=0.07). The mean number of harvested lymph nodes was 19 (8-51) in the LG group and 22 (3-101) in the OG group, respectively (P=0.76). The overall mortality rate was 0% and 2.5% in the LG group and the OG group, respectively (P=0.49). The overall abdominal morbidity rate was 12% and 16.4% in the LG group and the OG group, respectively (P=0.42). The mean duration of hospital stay was 8.0 days (5-23) and 11.5 days (5-31) in the LG group and the OG group, respectively (P=0.023). Survival analysis at 1, 2, and 3 years showed no significant difference between the two groups. CONCLUSION: LG for cancer is feasible and safe in patients with invasive gastric cancer. However, randomized controlled trials are necessary to accurately define the role of laparoscopy in the treatment of gastric cancer.

Endovascular treatment of arterial bleeding in patients with pancreatitis.

PURPOSE: To assess the technical and clinical success of endovascular treatment of arterial bleeding in pancreatitis. MATERIALS AND METHODS: From 1992 to 2005, 28 patients with pancreatitis underwent endovascular treatment of associated arterial lesions. Fifteen patients were affected by acute pancreatitis and 13 by chronic pancreatitis. The diagnosis was obtained according to medical history and clinical and laboratory evidence of disease. Arterial involvement was diagnosed by non-invasive imaging and angiography. After treatment, all patients underwent CT scanning at a minimum of 15, 30 and 90 days. We evaluated the feasibility of embolization and patients' survival at 90 days. RESULTS: Transcatheter embolization was feasible in 26/28 patients (93%). In 2 patients with acute pancreatitis, selective catheterization failed so we could not proceed with the angiographic approach. After treatment, there were 3/26 rebleeds (11.5%), all of whom died within the first week. At 90 days' follow-up, 21/26 patients (81%) were alive. Two of 26 patients (8%) suffered splenic complications. Among the 13 patients with acute pancreatitis, 8 (61.5%) were alive after 90 days. All 13 patients with chronic pancreatitis were alive after 90 days. CONCLUSIONS: Comparing our results with the surgical literature, we found that embolization is less invasive and, at least, as successful as surgery. Thus, it should be considered the first choice in pancreatitis arterial complications.

Review of the clinical, histological, and molecular aspects of pancreatic endocrine neoplasms.

Pancreatic endocrine neoplasms (PENs) are rare tumors, and little is known about their genetic and chromosomal alterations. Elucidation of the molecular events involved in PEN carcinogenesis has been hindered by the fact that PENs have been considered a single disease entity. The emergence of novel molecular characterization strategies has, however, made it apparent that these lesions exhibit diverse molecular fingerprints, which will facilitate the precise delineation of PEN prognosis, histopathology, and carcinogenesis.

BAG-1: a novel biomarker predicting long-term survival in early-stage breast cancer.

PURPOSE: Among women with early-stage breast cancer treated with lumpectomy and radiation therapy, 30% to 40% will develop metastatic disease, which is often fatal. A need exists therefore for biomarkers that distinguish patients at high risk of relapse. We performed a retrospective correlative analysis of BAG-1 protein expression in breast tumors derived from a cohort of early-stage breast cancer patients. PATIENTS AND METHODS: Archival paraffin blocks from 122 women with stages I to II breast cancer treated with lumpectomy and radiation therapy (median follow-up, 12.1 years) were analyzed by immunohistochemical methods using monoclonal antibodies recognizing BAG-1 and other biomarkers, including Bcl-2, estrogen receptor, progesterone receptor, p53, and HER2/Neu. Immunostaining data were correlated with distant metastasis-free survival (DMFS) and overall survival (OS). RESULTS: Cytosolic immunostaining for BAG-1 was upregulated in 79 (65%) of 122 invasive breast cancers (P <.001) compared with normal breast. Elevated BAG-1 was significantly associated with longer DMFS and OS, overall (stages 1 and II) and in node-negative (stage I only) patients, on the basis of univariate and multivariate analyses (DMFS, P =.005; OS, P =.01, in multivariate analysis of all patients; DMFS, P =.005; OS, P =.001, in multivariate analysis of node-negative patients). All other biomarkers failed to reach statistical significance in multivariate analysis. Clinical stage was an independent predictor of OS (P =.04) and DMFS (P =.02). CONCLUSION: These findings provide preliminary evidence that BAG-1 represents a potential marker of improved survival in early-stage breast cancer patients, independent of the status of axillary lymph nodes.

Cyclin D1 expression and early breast cancer recurrence following lumpectomy and radiation.

PURPOSE: The purpose of this study was to determine the prognostic significance of cyclin D1 (cycD1) levels in ipsilateral breast tumor recurrence (IBTR) following lumpectomy and radiation therapy. METHODS AND MATERIALS: A total of 98 patients (49 patients with IBTR and 49 matched cases without IBTR) selected from our conservatively treated breast cancer population served as the patient population for the current study. All patients were treated with lumpectomy followed by radiation therapy to the intact breast to a total median dose of 64 Gy. The patients were followed in our clinic with a median follow-up of 13 years. Immunohistochemical analysis of cycD1 in these 98 early-stage breast cancer patients was performed using a polyclonal antibody generated against the human cycD1 protein. All clinical, pathologic, and molecular variables were entered into a computerized data base for statistical analysis. RESULTS: Low levels of immunohistochemically detected cycD1 protein correlated with IBTR (p = 0.001), but there was no association between cycD1 protein levels and metastatic disease, axillary lymph node involvement, distant disease-free survival (DDFS), and overall survival (OS). Subgroup analysis revealed that for early breast tumor relapses (within 4 years of initial breast tumor diagnosis), low levels of cycD1 were associated with IBTR (p = 0.004), but cycD1 expression was not prognostic for IBTR from breast cancer patients with late relapses (p = NS). CONCLUSION: These studies provide in vivo evidence for the prognostic and biologic significance of cycD1 expression in determining response to radiation therapy in breast cancer patients.

Elevated frequency and functional activity of a specific germ-line p53 intron mutation in familial breast cancer.

Previous studies have determined that the frequency of germ-line p53 mutations in familial breast cancer patients is 1% or less, but these reports have not investigated the importance of polymorphic intron base changes in the p53 gene. Therefore, we investigated the frequency of both exon and intron germ-line p53 base changes in 42 breast cancer patients with a strong family history of breast cancer. The mean age of presentation of these patients was 44.0 years (range, 29-69), and 12 of 42 (29%) were of known Ashkenazi ancestry. Purified DNA obtained from the 42 index cases was screened for germ-line p53 mutations in exons 2-11 and surrounding introns using a combination of intron based primers for PCR-single strand conformation polymorphism analysis, direct sequencing, and microarray sequencing using the Affymetrix p53 gene chip methodology. Morphological analysis of apoptosis and cell survival determination were performed on EBV-immortalized lymphoblastoid cell lines from two patients with the p53 intron 6 mutation. A germ-line mutation in the p53 gene at nucleotide 13964 with a G to C base change (13964GC) was identified in 3 of 42 (7.1%) hereditary breast cancer patients. Two patients were heterozygous for this mutation, and one patient had a homozygous mutation. In comparison, 0 of 171 (0%) of sporadic breast cancer patients had the p53 13964GC mutation (P = 0.0003). We found that 0 of 42 (0%) of these hereditary breast cancer patients had other germ-line p53 mutation in exons 2-11. However, pedigree analysis demonstrated that all three patients had strong family histories of multiple types of cancers consistent with Li-Fraumeni syndrome but with late age of onset. Comprehensive BRCA1 and BRCA2 nucleotide analysis from patients with the p53 13964GC mutation revealed no concomitant deleterious BRCA1 or BRCA2 mutations, although they were found in the other hereditary breast cancer patients. Functional analysis of two immortalized lymphoblastoid cell lines derived from patients with the p53 13964GC mutation demonstrated prolonged in vitro survival in response to cisplatinum treatment and showed decreased chemotherapy-induced apoptosis. Immunohistochemical analysis of breast tumors from these patients revealed high levels of mutant p53 protein, suggesting a functional mutation in the p53 gene. In summary, we have identified a single p53 intron mutation in familial breast cancer patients that is present at elevated frequency and has functional activity.

Mutant p53 protein overexpression in women with ipsilateral breast tumor recurrence following lumpectomy and radiation therapy.

BACKGROUND: The p53 tumor suppressor gene encodes a nuclear phosphoprotein that is thought to be important to cell cycle regulation and DNA repair and that also may regulate induction of apoptosis by ionizing radiation. Somatic p53 gene mutations occur in 30-50% of breast carcinomas and are associated with poor prognosis. Mutations in the p53 gene result in prolonged stability of the protein that can be detected by immunohistochemical techniques. In a matched case-control study of breast carcinoma patients with ipsilateral breast tumor recurrence (IBTR) following lumpectomy and radiation therapy, the authors investigated the frequency and prognostic significance of somatic p53 mutations as well as the clinical characteristics of patients with these mutations. METHODS: Between 1973 and 1995, there were 121 breast carcinoma patients with IBTR following lumpectomy and radiation therapy, and the authors identified 47 patients in whom the paraffin embedded tissue blocks from the primary breast tumors were available for further molecular analysis. Forty-seven control breast carcinoma patients from the breast carcinoma data base were individually matched to the index cases who did not have IBTR for age, treatment date, follow-up, histology, margin status, radiation dose, and adjuvant treatment. Immunohistochemistry using a monoclonal antibody to mutant p53 protein was used to determine mutant p53 protein overexpression in breast tumors and appropriately scored. RESULTS: A total of 12 of 47 tumor specimens (26%) from index patients with breast tumor relapses demonstrated mutant p53 protein overexpression, whereas only 4 of 47 specimens from controls (9%) demonstrated high mutant p53 immunoreactivity (P = 0.02). The authors found that 9 of 23 patients (39%) with early breast tumor recurrences (recurrences within 4 years of diagnosis) had overexpression of mutant p53 protein, whereas only 1 of 23 control cases (4%) had high mutant p53 protein immunoreactivity (P = 0.003). In contrast, index cases from patients with late breast tumor relapses (more than 4 years after diagnosis), which are more likely to represent de novo breast tumors, and control cases from the breast carcinoma data base without IBTR had similar levels of mutant p53 protein overexpression (P = not significant). The 10-year distant disease free survival for patients with mutant p53 protein was 48%, compared with 67% for breast carcinoma patients without detection of mutant p53 protein (P = 0. 08). The authors found that 13 of 14 primary breast tumors (93%) with mutant p53 protein overexpression were estrogen receptor negative (P = 0.01) and 11 of 14 (79%) were progesterone receptor negative (P = not significant). CONCLUSIONS: In a matched case-control study, overexpression of mutant p53 protein has prognostic significance with respect to IBTR following lumpectomy and radiation therapy. Breast tumors with p53 mutations are generally estrogen receptor negative and are associated with compromised distant disease free survival.

BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations.

PURPOSE: Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (ipsilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treatment with LRT with respect to IBTR has not been determined. In this study, we estimate the frequency of BRCA1/2 mutations in a study of breast cancer patients with IBTR treated with LRT. PATIENTS AND METHODS: Between 1973 and 1994, there were 52 breast cancer patients treated with LRT who developed an IBTR within the prior irradiated breast and who were willing to participate in the current study. From our database, we also identified 52 control breast cancer patients treated with LRT without IBTR. The control patients were individually matched to the index cases with respect to multiple clinical and pathologic parameters. Lymphocyte DNA specimens from all 52 locally recurrent patients and 15 of the matched control patients under age 40 were used as templates for polymerase chain reaction amplification and dye-primer sequencing of exons 2 to 24 of BRCA1, exons 2 to 27 of BRCA2, and flanking intron sequences. RESULTS: After LRT, eight (15%) of 52 breast cancer patients had IBTR with deleterious BRCA1/2 mutations. By age, there were six (40%) of 15 patients with IBTR under age 40 with BRCA1/2 mutations, one (9.0%) of 11 between ages 40 and 49, and one (3.8%) of 26 older than age 49. In comparison to the six (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mutations, only one (6.6%) of 15 matched control patients without IBTR and had a BRCA1/2 mutation (P =.03). The median time to IBTR for patients with BRCA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P =.03). By clinical and histologic criteria, these relapses represented second primary tumors developing in the conservatively treated breast. All patients with BRCA1/2 mutations and IBTR underwent successful surgical salvage mastectomy at the time of IBTR and remain alive without evidence of local or systemic progression of disease. CONCLUSION: In this study, we found an elevated frequency of deleterious BRCA1/2 mutations in breast cancer patients treated with LRT who developed late IBTR. The relatively long time to IBTR, as well as the histologic and clinical criteria, suggests that these recurrent cancers actually represent new primary breast cancers. Early onset breast cancer patients experiencing IBTR have a disproportionately high frequency of deleterious BRCA1/2 mutations. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast-conserving therapy.

Expression of a functional antibody fragment in the gut of Rhodnius prolixus via transgenic bacterial symbiont Rhodococcus rhodnii.

Expression within insects of foreign antiparasitic gene products via microbial symbionts could be used to prevent transmission of vector-borne pathogens to vertebrate hosts. Genetically transformed symbiotic bacteria Rhodococcus rhodnii expressed functional antibody fragments (rDB3 encoding murine V(H)/K which binds progesterone) that were exported into the gut lumen of the triatomine bug Rhodnius prolixus (Hemiptera: Reduviidae), a vector of Chagas disease. Transgenic symbionts were maintained in successive nymphal instars and adults of Rhodnius prolixus despite competition with native untransformed Rhodococcus rhodnii. This is the first description of a functional mammalian antibody fragment expressed in an insect. Our system is a model for constructing paratransgenic insects (insects carrying transformed symbionts) with compromised ability to transmit pathogens.

Human insulin receptor and insulin signaling proteins in hepatic disease.

Insulin regulates hepatocellular metabolism and growth following insulin receptor (IR) autophosphorylation and activation of the intracellular adapter protein, insulin receptor substrate 1 (IRS-1). IRS-1 activates SH2 domain proteins such as Grb2, which may be vital to hepatocyte growth. To determine if these substances are abnormally expressed under pathophysiologic conditions, IR, IRS-1, Grb2 protein, and IR mRNA were studied in normal human liver (n = 10), cirrhotic liver (n = 10), and hepatocellular carcinoma (HCC) (n = 10) that had been procured during operative procedures. IR mRNA was quantified by S1-nuclease assay using a 195-bp digoxigenin-labeled IR DNA probe and normalized to the level of expression of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) gene. Protein concentrations were determined by immunoblot analysis following SDS-PAGE of liver homogenate samples. Labeled DNA and antibody-complexed protein were detected by chemiluminescent means and quantified by densitometric analysis (mean densitometric units +/- standard error). Similar levels of IR mRNA were observed in normal tissue, cirrhosis, and HCC. IR protein concentration was significantly greater in HCC than in normal liver (1.82 +/- 0.2 vs 1. 25 +/- 0.17; P < 0.05). IRS-1 was significantly increased in cirrhosis compared to normal liver (1.61 +/- 0.31 vs 0.86 +/- 0.21; P < 0.05). No differences were observed in Grb2 in the three tissue types. Insulin receptor overexpression, previously seen in other tumor types, may confer an insulin-mediated growth advantage in HCC if added receptors reflect functional high affinity binding sites. Although an altered mass of IRS-1 protein was not observed in HCC, an IRS-1 increase in cirrhosis may favor hepatic regeneration.

Expression of AP-2 transcription factors in human breast cancer correlates with the regulation of multiple growth factor signalling pathways.

The AP-2 transcription factors are required for normal growth and morphogenesis during mammalian development. Previous in vitro studies have also indicated that the AP-2 family of proteins may be involved in the etiology of human breast cancer. The AP-2 genes are expressed in many human breast cancer cell lines, and critical AP-2-binding sites are present in both the ERBB-2 (HER2/neu) and estrogen receptor promoters. We have now characterized immunological reagents that enable specific AP-2 family members, including AP-2alpha and AP-2gamma, to be detected in human breast cancer epithelium. Data obtained with these reagents demonstrate that whereas AP-2alpha and AP-2gamma are both present in benign breast epithelia, there is a significant up-regulation of AP-2gamma expression in breast cancer specimens (P = 0.01). There was also a significant correlation between the presence of the AP-2alpha protein and estrogen receptor expression (P = 0.018) and between specimens containing both AP-2alpha/AP-2gamma proteins and ERBB-2 expression (P = 0.003). Furthermore, we detected an association (P = 0.04) between the expression of AP-2gamma and the presence of an additional signal transduction molecule implicated in breast cancer, the insulin-like growth factor I receptor. Analysis of the proximal promoter of the insulin-like growth factor I receptor revealed a novel AP-2-binding site. Thus, AP-2 proteins may directly regulate the transcription of this growth factor receptor. Taken together, these data strongly support a role for the AP-2 gene family in the control of cell growth and differentiation in breast cancer.

Prognostic significance of colony-stimulating factor receptor expression in ipsilateral breast cancer recurrence.

The macrophage colony-stimulating factor receptor (CSF-1R), the product of the c-fms proto-oncogene, regulates normal proliferation and differentiation of macrophages and trophoblasts. Recent research found abnormal expression of CSF-1R in human carcinomas of the breast, endometrium, and ovary. Furthermore, activation of CSF-1R by its ligand has been shown to regulate invasiveness and anchorage-independent growth in breast carcinoma cells. To study the significance of CSF-1R expression in breast cancer, we designed a case-controlled immunohistochemical study. We chose 80 patients from a database of 1200 early stage I or II breast cancer patients treated with conservative surgery and radiation therapy. Expression of CSF-1R in the tumors of 40 patients who experienced an ipsilateral breast tumor recurrence (IBTR) as a primary site of relapse were compared with 40 patients who had not experienced an IBTR. The index and control patients were matched by age, clinical stage, nodal status, and follow-up. Paraffin-embedded sections were immunostained with antibodies directed toward CSF-1R. For the CSF-1R antibody, a total of 28 index cases (70%) demonstrated strong staining, whereas only 16 control cases (40%) demonstrated high immunoreactivity (P = 0.007). The CSF-1R antibody showed a positive correlation for local relapse, but no correlation was found between CSF-1R expression and distant metastasis. In summary, our findings provide evidence for the poor prognostic role of CSF-1R in IBTR.

Effective treatment of stage I uterine papillary serous carcinoma with high dose-rate vaginal apex radiation (192Ir) and chemotherapy.

PURPOSE: Uterine papillary serous carcinoma (UPSC) is a morphologically distinct variant of endometrial carcinoma that is associated with a poor prognosis, high recurrence rate, frequent clinical understaging, and poor response to salvage treatment. We retrospectively analyzed local control, actuarial overall survival (OS), actuarial disease-free survival (DFS), salvage rate, and complications for patients with Federation International of Gynecology and Obstetrics (FIGO) (1988) Stage I UPSC. METHODS AND MATERIALS: This retrospective analysis describes 38 patients with FIGO Stage I UPSC who were treated with the combinations of radiation therapy, chemotherapy, total abdominal hysterectomy, and bilateral salpingo-oophorectomy (TAH/BSO), with or without a surgical staging procedure. Twenty of 38 patients were treated with a combination of low dose-rate (LDR) uterine/vaginal brachytherapy using 226Ra or 137Cs and conventional whole-abdomen radiation therapy (WART) or whole-pelvic radiation therapy (WPRT). Of 20 patients (10%) in this treatment group, 2 received cisplatin chemotherapy. Eighteen patients were treated with high dose-rate (HDR) vaginal apex brachytherapy using 192Ir with an afterloading device and cisplatin, doxorubicin, and cyclophosphamide (CAP) chemotherapy (5 of 18 patients). Only 6 of 20 UPSC patients treated with combination LDR uterine/vaginal brachytherapy and conventional external beam radiotherapy underwent complete surgical staging, consisting of TAH/BSO, pelvic/para-aortic lymph node sampling, omentectomy, and peritoneal fluid analysis, compared to 15 of 18 patients treated with HDR vaginal apex brachytherapy. RESULTS: The 5-year actuarial OS for patients with complete surgical staging and adjuvant radiation/chemotherapy treatment was 100% vs. 61% for patients without complete staging (p = 0.002). The 5-year actuarial OS for all Stage I UPSC patients treated with postoperative HDR vaginal apex brachytherapy and systemic chemotherapy was 94% (18 patients). The 5-year actuarial OS for Stage I UPSC patients treated with HDR vaginal apex brachytherapy and chemotherapy who underwent complete surgical staging was 100% (15 patients). The 5-year actuarial OS for the 20 Stage I UPSC patients treated with combinations of pre- and postoperative LDR brachytherapy and postop WART was 65%. None of the 6 surgically staged UPSC patients treated with LDR radiation and WART/WPRT developed recurrent disease. For patients with FIGO Stage IA, IB, and IC UPSC who underwent complete surgical staging, the 5-year actuarial DFS by depth of myometrial invasion was 100, 71, and 40%, respectively (p = 0.006). The overall salvage rate for local and distant recurrence was 0%. Complications following HDR vaginal apex brachytherapy included only Radiation Therapy Oncology Group (RTOG) grade 1 and 2 toxicity in 16% of patients. However, complications from patients treated with WART/WPRT, and/or LDR brachytherapy, included RTOG grade 3 and 4 toxicity in 15% of patients. CONCLUSION: Patients with UPSC should undergo complete surgical staging, and completely surgically staged FIGO Stage I UPSC patients can be effectively and safely treated with HDR vaginal apex brachytherapy and chemotherapy. Both OS and DFS of patients with UPSC are dependent on depth of myometrial invasion. The salvage rate for both local and distant UPSC recurrences is extremely poor. Complications from HDR vaginal apex brachytherapy were minimal.