Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study.

BACKGROUND: Evaluation of peritoneal metastases by computed tomography (CT) scans is challenging and has been reported to be inaccurate. METHODS: A multi-institutional prospective observational registry study of patients with peritoneal carcinomatosis from colorectal cancer was conducted and a subset analysis was performed to examine peritoneal cancer index (PCI) based on CT and intraoperative exploration. RESULTS: Fifty-two patients (mean age 52.6 ± 12.4 years) from 16 institutions were included in this study. Inaccuracies of CT-based assessment of lesion sizes were observed in the RUQ (P = 0.004), LLQ (P < 0.0005), RLQ (P = 0.003), distal jejunum (P = 0.004), and distal ileum (P < 0.0005). When CT-PCI was classified based on the extent of carcinomatosis, 17 cases (33%) were underestimations, of which, 11 cases (21%) were upstaged from low to moderate, 4 cases (8%) were upstaged from low to severe, and 2 cases (4%) were upstaged from moderate to severe. Relevant clinical discordance where an upstage occurred to severe carcinomatosis constituted a true inaccuracy and was observed in six cases (12%). CONCLUSIONS: The actual clinical impact of inaccuracies of CT-PCI was modest. CT-PCI will remain as a mandatory imaging tool and may be supplemented with other tools including positron emission tomography scan or diagnostic laparoscopy, in the patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Operative acute small bowel obstruction: admitting service impacts outcome.

Early surgical intervention in acute small bowel obstruction (SBO) has long been recognized as an important factor in preventing morbidity and mortality. Factors associated with surgically managed acute SBO were analyzed for delay in intervention and impact on outcome. A retrospective review of all patients evaluated for SBO on the surgical teaching service of the Greenville Hospital System from July 1, 1997 to June 30, 2000 was performed. Data were collected on patient demographics, admission information (date, admitting service, physical examination, and laboratory values), comorbidity, diagnostic studies, surgery date, operative findings, postoperative complications, operative mortality, and discharge date. Analysis of the data revealed 157 cases of presumed SBO of which 61 were managed nonoperatively and 96 required surgery. Acute SBO was diagnosed in 65 patients who constitute the basis for this review. Of these 65 patients 43 (66%) were admitted to the surgical service, 25 (38%) required small bowel resection, and 17 (26%) developed morbidity and/or mortality. When analyzed for morbidity and mortality the only characteristics that were statistically significant were the admitting service (P = 0.003) and length of stay (P = 0.003). On further analysis of admitting service and patient outcomes several factors were significant when we compared medical service admissions to surgical service admissions. These included days from admission to surgery (P = 0.003), length of stay (P = 0.019), morbidity (P = 0.004), mortality (P = 0.005), and combined morbidity and mortality (P = 0.003). Mortality of patients admitted to the medical service was 27 per cent compared with 2 per cent for the surgical service. There were no differences in morbidity and mortality when analyzed by the need for small bowel resection, patient age, etiology of obstruction, or presence of comorbidities. None of the factors studied were useful in predicting the need for small bowel resection. Our findings agree with those of previous investigators with regard to 1) lack of association between the preoperative evaluation and the need for small bowel resection and 2) the association between delay in diagnosis and increased morbidity and mortality. In addition we have found that one of the primary causes of delay in treatment for SBO was admission to the medical service. This delay led to significantly higher mortality in these patients. We recommend early surgical evaluation for any patient admitted with SBO as a differential diagnosis.

Structural analysis of cDNA encoding thymidylate synthase in hepatic metastases of human colorectal tumors.

The enzyme thymidylate synthase (TS) is an important target of 5-fluorouracil (FUra) that is utilized for the treatment of disseminated colorectal cancer. One determinant of clinical response to FUra-based therapy is TS expression. with high levels of expression being predictive of poor response. In the present investigation the levels of immunoreactive TS were analyzed in human colon metastases in the liver (n=l1). The levels of TS ranged from 0.30 to 4.60 pmol TS/g tissue. A good correlation was observed between the levels of immunoreactive TS and TS mRNA (n=6, r=0.69). Of the 11 metastases analyzed, 5 exhibited relatively high levels of TS expression. Two metastases with high TS expression were obtained from patients who received adjuvant therapy with FUra. In 4 metastases with relatively high levels of TS expression, TS gene copy number was analyzed. No evidence for amplification of TS gene sequences was observed. The basis for the high levels of TS expression was examined by structural analysis of TS cDNA. No nucleotide sequence differences were detected in the coding regions of the TS genes from the metastases. Mutations were detected at positions 961 and/or 1031 in the 3'-untranslated regions of the TS gene from the metastases; mutations at these sites were also detected in DNA isolated from normal colon mucosa (n=4) and primary colorectal tumors (n=4). No correlation was observed between TS expression and the nucleotide alterations at these positions. Polymorphism was observed in the 5'-untranslated regions of the TS gene in hepatic metastases (n=6). A general trend was observed between the structure of the 5'-untranslated region of the gene and TS expression.

A rapid, novel strategy to induce tumor cell-specific cytotoxic T lymphocyte responses using instant dentritomas.

The generation of fused cells between dendritic cells (DC) and tumor cells is a very effective approach for tumor antigen presentation in cancer immunotherapy. However, the application of this approach in clinical studies is limited by the need for established tumor cell lines and the time-consuming procedures for selecting and expanding the fused cells. In the current study, the authors report a rapid, novel approach to produce fused cells between DCs and primary tumor cells from patients with malignant melanoma. Peripheral blood DCs and a primary tumor cell culture were generated from the same patients, labeled with fluorescent green and red dyes, respectively, and fused. The fused cells were isolated by fluorescence-activated cell sorting. Because the fused cells do not need to be expanded, these cell hybrids have been named instant dendritomas. Fluorescence-activated cell sorting analysis showed that instant dendritomas express the key molecules for antigen presentation (HLA-A, B, C; HLA-DR; CD80; and CD86). In vitro studies have shown that instant dendritomas effectively activated autologous CD8+ T lymphocytes to proliferate and secret interferon-gamma. More importantly, the activated CD8+ T lymphocytes effectively lysed the patients' primary tumor cells. This approach represents a practical clinical strategy for cancer immunotherapy.

In vitro studies of a prolactin antagonist, hPRL-G129R in human breast cancer cells.

Human prolactin (hPRL) has been shown to be one of the important survival/growth factors that promotes the proliferation of breast cancer cells in an autocrine/paracrine manner. In our recent studies, we demonstrated that a hPRL antagonist with a single amino acid substitution mutation (hPRL-G129R) was able to inhibit breast cancer cell proliferation via induction of apoptosis (1). In this study three independent yet related experiments were carried out regarding the effects of hPRL-G129R in breast cancer cells. We investigated the possible mechanism(s) of hPRL-G129R induced apoptosis in breast cancer cells. It is well documented that transforming growth factors (TGF) in conjunction with hormones such as estrogen and PRL play a major role in modulating the proliferation and apoptosis of mammary cells. We first investigated the relationships between hPRL/hPRL-G129R and TGFs. We show that hPRL is able to down-regulate TGF beta 1 (apoptotic factor) secretion and up-regulate TGF alpha (survival factor) secretion in a dose-dependent manner in T-47D cells. More importantly the hPRL antagonist up-regulates TGF beta 1 and down-regulates TGF alpha secretion. When hPRL-G129R was applied together with hPRL, it blocked the effects of hPRL. Secondly, we tested the possible involvement of caspases in hPRL-G129R induced apoptosis. We have shown that caspase-3 is activated by hPRL-G129R at a concentration of 250 ng/ml in T-47D breast cancer cells. Thirdly, we explored the additive effects of an anti-neoplastic drug, cisplatin, with the hPRL-G129R in T47D breast cancer cells. We show that cisplatin and hPRL-G129R when applied together resulted in about 40% growth inhibition in T-47D cells.

Inhibition of oncogene STAT3 phosphorylation by a prolactin antagonist, hPRL-G129R, in T-47D human breast cancer cells.

We have previously demonstrated that a hPRL antagonist (hPRL-G129R) was able to inhibit PRL induced breast cancer cell proliferation through induction of apoptosis. In the present study, we test the hypothesis that the inhibitory effect of hPRL-G129R in breast cancer cells occurs, at least in part, through the inhibition of oncogene STAT3 activation. We first demonstrated that STAT5 and STAT3 could be activated by either hGH or hPRL in T-47D breast cancer cells. Although the patterns of STAT5 activation by hGH and hPRL are similar, we observed a nearly 10-fold greater efficacy of hPRL in STAT3 activation as compared to that of hGH. More importantly, we have demonstrated that activation of STAT3 by hPRL could be inhibited by hPRL-G129R. Since T-47D cells coexpress GHR and PRLR, an attempt was made to dissect the molecular events mediated through hGHR or hPRLR using mouse L-cells expressing a single population of receptors (hGHR or hPRLR). To our surprise, only STAT5, not STAT3 phosphorylation was observed in these L-cells. In conclusion, our results suggest that: a) STAT3 is preferably activated through hPRLR in T-47D cells; b) hPRL-G129R is effective in inhibiting STAT3 phosphorylation; and c) the mechanism of STAT3 activation is different from that of STAT5.

Enhanced transgene expression and effective in vivo antitumor immune responses initiated by dendritic progenitors transfected with a nonviral T7 vector expressing a model tumor antigen.

Genetic education of dendritic cells (DCs) with tumor-associated antigens is an encouraging development in DC-mediated tumor immunotherapy. In this study, to increase the transgene expression by DCs using nonviral vectors, a cytoplasmic T7 vector (T7T7/T7Luc) was used to transfect bone marrow-derived DCs with the firefly luciferase gene as a reporter and as a model tumor antigen. As a result, the luciferase activity of T7T7/T7Luc-transfected DCs was more than four times greater than that of DCs transfected with pCMVLuc, a commonly used nonviral vector. Furthermore, the luciferase activity was increased three times more when dendritic progenitor cells rather than mature DCs were transfected. In vivo tumor studies showed that T7T7/T7Luc-transfected DCs, which express high levels of luciferase (model tumor antigen), stimulated a stronger immune response than did pCMVLuc-transfected DCs, which express relatively low levels of luciferase, as indicated by the cytotoxic T lymphocyte assay. T7T7/T7Luc transfected DCs, when injected into recipient mice, evoked an antigen-specific immune response that can effectively eradicate implanted metastasis and prevent new tumor development by murine melanoma cells genetically modified to express luciferase. Therefore, the T7 system is a powerful nonviral vector that can be used to genetically educate DCs with tumor-associated antigens for tumor immunotherapy.

A human prolactin antagonist, hPRL-G129R, inhibits breast cancer cell proliferation through induction of apoptosis.

Human breast cancer is the predominant malignancy and the leading cause of cancer death in women from Western societies. The cause of breast cancer is still unknown. Recently, the association between human prolactin (hPRL) activity and breast cancer has been reemphasized. Biologically active hPRL has been found to be produced locally by breast cancer cells that contain high levels of PRL receptor. A high incidence of mammary tumor growth has also been found in transgenic mice overexpressing lactogenic hormones. More importantly, it has been demonstrated that the receptors for sex steroids and PRL are coexpressed and cross-regulated. In this study, we report that we have designed and produced a hPRL antagonist, hPRL-G129R. By using cell proliferation assays, we have demonstrated that: (a) hPRL and E2 exhibited an additive stimulatory effect on human breast cancer cell (T-47D) proliferation; (b) hPRL-G129R possessed an inhibitory effect on T-47D cell proliferation; and (c) when antiestrogen (4-OH-tamoxifen) and anti-PRL (hPRL-G129R) agents were added together, an additive inhibitory effect was observed. We further investigated the mechanism of the inhibitory effects of hPRL-G129R in four hPRLR positive breast cancer cell lines. We report that hPRL-G129R is able to induce apoptosis in all four cell lines in a dose-dependent manner as determined by the Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The apoptosis is induced within 2 h of treatment at a dose as low as 50 ng/ml. We hope that the hPRL antagonist could be used to improve the outcome of human breast cancer therapy in the near future.

Laparoscopic cholecystectomy in pregnancy.

Laparoscopic cholecystectomy has been performed in the United States since 1989 and currently is the procedure of choice for the management of symptomatic cholelithiasis. Its utility in the pregnant patient has been controversial. Concerns have been expressed for a number of potential problems, including trocar injury to uterus and fetus, effect of pneumoperitoneum on both mother and fetus, induction of preterm labor, teratogenic effects on the fetus, and long-term effects on fetal and neonatal development. We describe the Greenville Hospital System experience with laparoscopic cholecystectomy in pregnancy. From 1992 to 1996, eight laparoscopic cholecystectomies were performed in pregnant females, one during the first trimester and seven during the second trimester. Mean maternal age was 23.8 years (range, 18-31). All procedures were performed for recurrent and intractable symptoms with the average length of symptoms 3.5 weeks (range, 2-4 weeks). Two patients were diagnosed preoperatively with gallstone pancreatitis, two had acute cholecystitis, and four patients were felt to have hyperemesis gravidarum before their diagnosis of gallstones. All procedures were performed under general endotracheal anesthesia with CO2 insufflation pressures of 12 mm Hg. Postoperatively, all patients had uneventful recoveries with complete resolution of their symptoms and were discharged home in an average of 3 days (range, 1-7 days). No postoperative complications to mother or fetus were documented. Eight patients have delivered full-term healthy fetuses with no documented neonatal morbidity or mortality. Long-term follow-up of the infants at a mean of 23 months (range, 2.5-47 months) reveals that all eight infants have progressed to normal healthy children. Our experience and the current world literature demonstrate that laparoscopic cholecystectomy in pregnancy can be performed safely and effectively for symptomatic cholelithiasis, especially when symptoms are recurrent and persistent and may endanger fetal and maternal livelihood. The diagnosis of symptomatic cholelithiasis should be considered in the pregnant patient with recurrent episodes of nausea and vomiting.

Carcinoma of the ampulla of Vater: a community hospital experience.

Carcinoma of the ampulla of Vater is an uncommon malignancy often treated at tertiary referral centers. Most published series are derived from these centers and show resectability rated of 80 to 90 percent, with overall 5 year survival rates of 25 to 60 per cent. Twenty cases of ampullary carcinoma treated in a community hospital setting were reviewed. The mean age at diagnosis was 69 years (range, 49-89), and 65 per cent of the patients were female. The most common presenting symptoms were jaundice (85%) and abdominal pain (50%). Stages at diagnosis included stage II, 12 patients; stage III, 5 patients; and stage IV, 3 patients. Nine patients underwent curative resections (resectability rate, 45%), of which five were pylorus-preserving pancreaticoduodenectomies and four were standard pancreaticoduodenectomies. There were no operative mortalities. Overall survival was 23 per cent, while survival in the resected patients was 60 per cent at 2 years. The majority of the patients not resected were felt to be poor candidates for major surgery either because of significant comorbid disease or advanced age. Three patients presented with advanced disease, and two patients died within 7 days of presentation. This review demonstrated a significantly lower resectability rate for carcinoma of the ampulla of Vater, with comparable survival rates. Differences from published studies at tertiary referral centers reflect a selection bias of patients referred to these centers.

Curative resection for stage I rectal cancer: natural history, prognostic factors, and recurrence patterns.

Our goal was to evaluate the recurrence patterns and outcomes of a large group of patients with stage I rectal adenocarcinoma treated at a single institution with uniform surgical and pathological techniques. Medical records of 71 patients who had undergone potentially curative surgery were reviewed to determine clinical and histologically significant prognostic factors that could affect survival and recurrence patterns. The median follow-up for all patients was 81 months. Twenty patients had T1N0M0 cancers and 51 patients had T2N0M0 cancers. The median number of lymph nodes examined per surgical specimen was 32. There were no recurrences in the 20 patients with T1 lesions. All 7 recurrences (10%) occurred in patients with T2 lesions. Only 2 of these recurrences were local. In the T2 group, the 5- and 10-year disease-free survivals were 88% and 83%, respectively. The 5- and 10-year disease-free survival for all state I lesions was 91% and 88%, respectively. The overall recurrence rate of 10% does not justify adjuvant therapy for stage I rectal adenocarcinoma. Although the subset of patients with T2N0M0 distal one-third rectal cancers may be at risk for recurrence, additional prognostic factors are needed to evaluate these patients before adjuvant therapy can be recommended.

Long-term follow-up of patients with Roux-en-Y gastrojejunostomy for gastric disease.

OBJECTIVE: A consecutive series of Roux-en-Y gastrojejunostomies with a mean follow-up of 11.9 years was reviewed to characterize the long-term results of patients having this operation to treat or prevent bile reflux gastritis. SUMMARY BACKGROUND: Development of postprandial abdominal discomfort, nausea, vomiting, or bezoar formation (Roux stasis syndrome) in the postoperative follow-up period has prompted questions about the role of Roux-en-Y gastrojejunostomy to treat or prevent bile reflux gastritis. METHODS: Long-term clinical follow-up (mean, 11.9 years) data for 24 patients was collected by reviewing medical records, interviewing patients directly through telephone contact, or both. All patients who had symptoms in the follow-up period were evaluated by upper gastrointestinal series, endoscopy, or both. A modified Visick scale was used for clinical ratings. RESULTS: Of the 22 evaluable patients, follow-up was complete in 20; the clinical condition that prompted surgery was corrected in 21 (95%). Roux-en-Y gastrojejunostomy was successful for treating or preventing bile reflux gastritis in all 22 patients. Despite this success, clinical failure (Visick scale III or IV) was documented in 8 patients (36%). Seven of the 8 patients had clinical failure within 6 months of operation, with the Roux stasis syndrome developing in 6 of them (27%). CONCLUSION: This consecutive series of Roux-en-Y gastrojejunostomies performed by one surgeon has the longest follow-up to date. Although the Roux-en-Y gastrojejunostomy is safe and often successful, the procedure appears to be limited by a substantial rate of clinical dissatisfaction. Surgeons should be cautious in using it to treat primary or remedial gastrointestinal disease.