Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells.

Neovascularization is essential for growth and spread of primary and metastatic tumors. We have identified a novel cytokine, endothelial-monocyte activating polypeptide (EMAP) II, that potently inhibits tumor growth, and appears to have antiangiogenic activity. Mice implanted with Matrigel showed an intense local angiogenic response, which EMAP II blocked by 76% (P < 0.001). Neovascularization of the mouse cornea was similarly prevented by EMAP II (P < 0.003). Intraperitoneally administered EMAP II suppressed the growth of primary Lewis lung carcinomas, with a reduction in tumor volume of 65% versus controls (P < 0.003). Tumors from human breast carcinoma-derived MDA-MB 468 cells were suppressed by >80% in EMAP II-treated animals (P < 0.005). In a lung metastasis model, EMAP II blocked outgrowth of Lewis lung carcinoma macrometastases; total surface metastases were diminished by 65%, and of the 35% metastases present, approximately 80% were inhibited with maximum diameter <2 mm (P < 0.002 vs. controls). In growing capillary endothelial cultures, EMAP II induced apoptosis in a time- and dose-dependent manner, whereas other cell types were unaffected. These data suggest that EMAP II is a tumor-suppressive mediator with antiangiogenic properties allowing it to target growing endothelium and limit establishment of neovasculature.

The impact of immediate breast reconstruction after mastectomy on time to first adjuvant treatment in women with breast cancer in a community setting.

BACKGROUND: The impact of immediate breast reconstruction on the time to first adjuvant therapy is controversial. METHODS: Retrospective study design comparing time to first treatment in women undergoing mastectomy with and without immediate reconstruction in a community cancer center. RESULTS: Seventy-six cases fit inclusion criteria of which 44 (58%) underwent mastectomy with immediate reconstruction. Women undergoing immediate reconstruction were younger, had more bilateral mastectomies and had fewer prior breast procedures. The median time to first adjuvant therapy was longer in the immediate reconstruction group [80.5days (36-343) versus 53.5 days (18-96), p = 0.003]. Fifteen of 44 patients had the start of adjuvant treatment over 90 days after resection, 14 of whom (93%) had immediate reconstruction versus 1 (7%) who did not (p = 0.01). CONCLUSION: In this study immediate breast reconstruction was associated with a longer time to first adjuvant treatment, with adjuvant therapies being more likely delayed over 90 days.

A positive crosstalk between CXCR4 and CXCR2 promotes gastric cancer metastasis.

The molecular mechanism underlying gastric cancer (GC) invasion and metastasis is still poorly understood. In this study, we tried to investigate the roles of CXCR4 and CXCR2 signalings in gastric cancer metastasis. A highly invasive gastric cancer cell model was established. Chemokines receptors were profiled to search for the accountable ones. Then the underlying molecular mechanism was investigated using both in vitro and in vivo techniques, and the clinical relevance of CXCR4 and CXCR2 expression was studied in gastric cancer samples. CXCR4 and CXCR2 were highly expressed in a high invasive gastric cancer cell model and in gastric cancer tissues. Overexpression of CXCR4 and CXCR2 was associated with more advanced tumor stage and poorer survival for GC patients. CXCR4 and CXCR2 expression strongly correlated with each other in the way that CXCR2 expression changed accordingly with the activity of CXCR4 signaling and CXCR4 expression also changed in agreement with CXCR2 activity. Further studies demonstrated CXCR4 and CXCR2 can both activated NF-κB and STAT3 signaling, while NF-κBp65 can then transcriptionally activate CXCR4 and STAT3 can activate CXCR2 expression. This crosstalk between CXCR4 and CXCR2 contributed to EMT, migration and invasion of gastric cancer. Finally, Co-inhibition of CXCR4 and CXCR2 is more effective in reducing gastric cancer metastasis. Our results demonstrated that CXCR4 and CXCR2 cross-activate each other to promote the metastasis of gastric cancer.

Enhanced antimetastatic activity of lymphokine-activated killer cells purified and expanded by their adherence to plastic.

We have recently reported a simple and reproducible technique for the purification and rapid expansion of homogeneous populations of large granular lymphocytes expressing a natural killer cell phenotype and high levels of broad antitumor cytotoxic activity [lymphokine-activated killer (LAK) activity]. This technique exploits the observation that, in the presence of recombinant interleukin 2 (rIL-2), large granular lymphocytes/natural killer cells become adherent to plastic surfaces, actively proliferate, and acquire high levels of LAK activity. Because of their adherent properties these cells have been termed adherent LAK or A-LAK cells. The present studies investigate the antimetastatic effects of A-LAK cells in a syngeneic rat model of experimental pulmonary and hepatic metastases. For pulmonary metastases, F344 rats received i.v. injections with a natural killer-resistant mammary adenocarcinoma, MADB106, and, for hepatic metastases, animals received an intrasplenic injection of MADB106 tumor cells followed by surgical splenectomy. Three days later, the animals were treated with A-LAK cells alone, A-LAK cells plus rIL-2, or rIL-2 alone. These treatments were compared to immunotherapy using standard cultures of LAK cells (unfractionated spleen cells) and rIL-2. The results indicate that the administration of unfractionated LAK cells plus interleukin 2 (IL-2) was effective in reducing established lung or liver metastases in this rat model. However, the results also indicate that purified populations of A-LAK cells in combination with rIL-2 demonstrate dramatic and superior antimetastatic effects when compared to LAK cells cultured under standard conditions. The antimetastatic effects of standard LAK cells or A-LAK cells plus IL-2 translated into significant survival benefits compared to animals receiving no therapy or IL-2 therapy alone. Survival after therapy with A-LAK cells plus IL-2 was significantly prolonged compared to treatment with standard LAK cells. These data suggest that purified populations of LAK cells (derived from natural killer cells) may prove superior for adoptive immunotherapy in the clinical setting.

Inferior vena cava filters in cancer patients: indications and outcome.

PURPOSE: Our experience with inferior vena cava (IVC) filter placement to prevent pulmonary emboli (PE) in cancer patients with deep vein thromboses (DVT) was reviewed to identify indications, patient characteristics, complications, and long-term outcome. METHODS: Charts of 182 patients with cancer were retrospectively analyzed. All patients had received an IVC filter in our institution between January 1980 and April 1992. RESULTS: Of 182 patients, 103 were men and 79 were women. Median age was 59 years (range, 15 to 88). Eight patients (4%) had stage I disease, 22 patients (12%) stage II, 37 patients (20%) stage III, and 115 patients (63%) stage IV. A DVT was diagnosed in 97 patients (53%), a PE in 46 patients (25%), and a combination in 39 patients (21%). Indications for IVC filter placement were DVT or PE in the presence of contraindications to anticoagulation therapy (perioperative, n = 58; CNS metastases, n = 20; thrombocytopenia, n = 7; bleeding, n = 61; others, n = 24; total, N = 170) or anticoagulation failure (recurrent PE, n = 6; recurrent DVT; n = 6; total N = 12). Filter placement complications (n = 6, 3%) included malposition (n = 3), migration (n = 1), arrhythmia (n = 1), and wound infection (n = 1), but no deaths. After filter placement, four patients developed a recurrent PE, and 11 patients developed a recurrent DVT. No significant postthrombotic complications were observed. CONCLUSION: IVC filter placement patients with advanced cancer and thrombotic complications is safe, well tolerated, and can offer effective therapy/prophylaxis with a low incidence of treatment failure.

Phytohemagglutinin-L (PHA-L) lectin surface binding of N-linked beta 1-6 carbohydrate and its relationship to activated mutant ras in human pancreatic cancer cell lines.

Alterations of the N-linked carbohydrate core structure of cell surface glycoproteins (beta 1-6 branching) can be detected by phytohemagglutinin (PHA-L) lectin binding and has been linked to tumor progression and K-ras activation in colon cancer. The purpose of this study was to determine the prevalence of this carbohydrate alteration and its relationship to K-ras activation in pancreatic cancer. Nine human pancreatic cancer cell lines and 4 colon lines as controls were grown under standard tissue culture conditions. K-ras genome analysis was performed by polymerase chain reaction amplification and sequencing. The proportion of cellular p21-ras bound to GTP (ras-GTP level) was determined using immunoprecipitation of 32P-labeled cell lysates followed by thin layer chromatography and phosphoimaging analysis. Lectin blot analysis was performed on crude membrane preparations. Sensitivity to lectins was assessed with cell culture thymidine incorporation. Of 9 pancreatic cancer lines tested, 3 had wild type K-ras, 2 had heterozygous and 4 had homozygous mutations in codon 12 of K-ras. These genotypes correlated strongly with the level of ras-GTP measured. K-ras mutants had increased levels of ras-GTP compared to wild-type cell lines. PHA-L binding to cell membranes correlated positively with ras-GTP levels in 7 out of 9 cell lines. PHA-L toxicity was greatest in cells with positive PHA-L reactivity on Western blotting. A positive correlation between the presence of K-ras mutation, increased ras-GTP level, and increased cell surface beta 1-6 N-linked carbohydrate exists in pancreatic cancer cell lines.

Amyloid goiter and arthritides after kidney transplantation in a patient with systemic amyloidosis and Muckle-Wells syndrome.

A case of hereditary AA amyloidosis with Muckle-Wells syndrome is described. After a successful kidney transplantation for chronic renal failure due to renal amyloid deposits at age 21, the patient, a white female now 26 years of age, developed a large amyloid goiter as a manifestation of the systemic amyloidosis and recurrent monarthritides. Both observations are novel for this disease. Subtotal thyroidectomy and oral colchicine administration, known to be effective in preventing complications of familial Mediterranean fever, another hereditary type of AA amyloidosis, proved highly effective in the management of this unusual case.

An orthotopic in vivo model of human pancreatic cancer.

BACKGROUND: Pancreatic cancer is a highly lethal disease that frequently presents in advanced stages. For most patients, treatment with great clinical efficacy does not exist. Relevant in vivo models to test novel therapies are highly desirable. METHODS: The human pancreatic ductal adenocarcinoma cell line Panc-1 was injected intraperitoneally into SCID mice. The pattern of the resulting peripancreatic as well as metastatic disease was examined. Survival experiments after chemotherapy with gemcitabine or doxorubicin, and after immunotherapy with p53-specific cytotoxic T lymphocytes were performed. RESULTS: All animals developed isolated pancreatic tumor implants within 48 hours after injection. After the formation of invasive pancreatic tumor nodules, peripancreatic and portal adenopathy developed, causing biliary obstruction. All tumor-bearing animals died of disease within 5 to 12 weeks. Survival after gemcitabine treatment and after p53-CTL injection was significantly prolonged, with some animals remaining tumor-free. Doxorubicin treatment did not yield extended survival, but led to significant toxicity. CONCLUSION: Intraperitoneal injection of Panc-1 cells into SCID mice produces a quasi-orthotopic tumor development model that shares many characteristics with human pancreatic cancer. The ease of cell injection, avoidance of cumbersome surgical intervention with its resulting mortality, and the reliable development of obstructive jaundice as a dependent comorbid factor render this a useful model for in vivo testing of novel therapeutic approaches to pancreatic cancer. Our initial therapeutic studies demonstrate that in vitro antitumor efficacy against Panc-1 cancer cells does not necessarily predict the in vivo response, highlighting the preclinical experimental value of this model.

Tension pneumoperitoneum after heart-lung transplantation.

Tension pneumoperitoneum is a medical emergency. We report 2 cases in which tension pneumoperitoneum occurred after heart-lung transplantation and was related to positive-pressure ventilation and a transdiaphragmatic passage of omentum used to wrap the airway anastomosis. Management in these patients was targeted toward decompression of intraperitoneal air with percutaneous needle or tube placement without exploratory laparotomy, and tube thoracostomy for the concomitant pneumothorax.

Factors predicting hospitalization after operative treatment for gastric carcinoma in patients older than 70 years.

BACKGROUND: Variable reports exist about the early and long-term outcome after operative treatment for gastric carcinoma in the elderly. This study was designed to describe perioperative morbidity and factors influencing the length of hospitalization in patients older than 70 years of age in a tertiary care cancer center. METHODS: Patient information for a 10-year period, between July 1985 and July 1995, was obtained through a prospective database and chart review. Complications and length of stay were tabulated. Patient-, disease-, and treatment-related factors and their influence on outcome were compared by univariate and multivariate analysis using nonparametric product-limit models. RESULTS: Of 385 patients aged 71 years or older with gastric adenocarcinoma, 310 underwent resection. Postoperative complications occurred in 47.1 percent. Infectious complications predominated, most frequently involving intra-abdominal and pulmonary sites. Perioperative mortality was 7.1 percent. The median postoperative length of stay was 13 days (95 percent confidence interval 12 to 14 days; 25th percentile, 10 days; 75th percentile, 20 days). Factors independently predicting an increased duration of stay were presence of any complications, the type of resection, site of the primary carcinoma, and presence of postoperative infection. Complications added 30.4 percent of total patient days, or an average of 11.5 hospital days per patient with a complication. Although patients with postoperative complications had inferior overall and disease-specific survival, this was not an independent prognostic variable. Compared with patients younger than 70 years of age, elderly patients had a significantly increased hospital stay. CONCLUSIONS: The single most important factor leading to increased length of hospitalization is the occurrence of any complication. Although complicated by higher morbidity and mortality, the resection of gastric carcinoma in elderly patients can be performed relatively safely and leads to survival that is comparable to younger patients. The findings support careful patient selection and optimal preparation of elderly patients undergoing resection for gastric carcinoma.

The impact of splenectomy on outcomes after resection of pancreatic adenocarcinoma.

BACKGROUND: Splenectomy at the time of resection of esophageal, gastric, or colon cancer has been correlated with inferior longterm survival. No such effect has yet been demonstrated for pancreatic cancer. STUDY DESIGN: Patients undergoing resection of pancreatic adenocarcinoma with curative intent at Memorial Sloan-Kettering Cancer Center between October 1983 and October 1995 were identified from a prospective clinical database. The impact of splenectomy on hospital stay and survival was calculated with univariate and multivariate nonparametric methods. RESULTS: Of 332 patients undergoing pancreatectomy, 326 with confirmed local or regional disease only formed the study cohort. Of these, 37 underwent concomitant splenectomy (11.4%). Splenectomy was significantly correlated with distal or total pancreatectomy, primary location in tail or body, portal vein invasion or resection, a larger maximal tumor diameter, and an operative blood loss of greater than 2,000 mL. Death or need for reoperation was not affected by splenectomy. Patients undergoing splenectomy had a higher median transfusion requirement (3 versus 1; p = 0.002). The median postoperative length of stay was 15 days regardless of splenectomy. At a median followup of 16.3 months (36.4 months for surviving patients), the median actuarial survival was 12.2 months with splenectomy versus 17.8 months without splenectomy (p<0.005). On multivariate analysis, splenectomy emerged as an independent factor predictive of decreased postoperative survival (p = 0.02), in addition to pathologic lymph node status (p = 0.0002), tumor diameter (p = 0.0004), and tumor differentiation (p = 0.007). Tumor location within the pancreas and the type of pancreatectomy were not independent prognostic factors influencing survival. CONCLUSIONS: After pancreatectomy for pancreatic cancer, splenectomy has no significant measurable impact on postoperative recovery, but has a negative influence on longterm survival independent of disease-related factors. Unless required because of tumor proximity or invasion, splenectomy should be avoided in the operative treatment of exocrine pancreatic cancer at any location.

Esthetic reconstruction after mastectomy for inflammatory breast cancer: is it worthwhile?

BACKGROUND: Because inflammatory breast cancer (IBC) has been viewed as a malignancy with a poor likelihood of longterm survival, few women have been offered esthetic reconstruction after mastectomy for IBC. Recent advances in multimodality therapy have improved the outcomes for women with this disease. The purpose of this review was to assess the results of esthetic breast reconstruction in the population with IBC. STUDY DESIGN: Review of medical records at the City of Hope National Medical Center for the 10-year period ending in May 1997, revealed 23 women who underwent elective esthetic breast reconstruction after mastectomy for IBC. The records of these patients were reviewed retrospectively. Patients requiring reconstruction for large surgical chest wall defects were not included in the review. RESULTS: Treatment for IBC included mastectomy in all patients, chemotherapy in 22, and chest wall radiation therapy in 14. Immediate reconstruction was performed at the time of mastectomy (n = 14) or was delayed (n = 9). The types of reconstruction included transverse rectus abdominis musculocutaneous flap (n = 18), latissimus dorsi flap (n = 2), or prosthetic mammary implant reconstruction (n = 3). Seven women chose to undergo additional reconstruction procedures (ie, nipple reconstruction) after their initial reconstruction. With a median followup of 44 months for survivors, 16 patients developed recurrence after reconstruction. Of these, 6 were local recurrences and 10 were distant failures. Seven patients are currently alive with no evidence of disease, 4 are currently alive with disease, and 12 have died as a result of breast cancer. The median disease-free survival after reconstruction was 19 months. The median overall survival after reconstruction for all patients was 22 months. The only negative predictor of survival was a positive surgical margin at mastectomy. CONCLUSIONS: The significant emotional and esthetic benefits of breast reconstruction should be available to women with IBC. In light of the improving prognosis of IBC with current aggressive multimodality treatment, reconstructive procedures should be offered as part of comprehensive therapy.

Ethnic survival differences after gastrectomy for gastric cancer are better explained by factors specific for disease location and individual patient comorbidity.

INTRODUCTION: Different outcomes after resection of gastric cancer between various ethnic patient groups have been described. It remains unclear whether disparity of treatment forms, disease-related variables, or individual patients accounts for this effect. METHODS: In the 10 years between 1989 and 1999, 75 patients with gastric adenocarcinoma underwent gastrectomy at a single institution, with constant surgical standards during this time period, including complete (R0) resection attempt and extended lymphadenectomy. Ethnicity, disease characteristics, and treatment variables were analysed for their impact on survival. RESULTS: There were 40 males and 35 females, with a median age of 67 years (range 31-97). The gastrectomy extent was total (n=25), proximal (n=18), subtotal (n=17), distal (n=14), and segmental (n=1). The mean lymph-node count was 25+/-17 (SD). There was one post-operative death, and an overall complication rate of 27%; the median hospital stay was 11 days. Overall actuarial 5-year survival was 33% (95% CI: 19-47); potentially curable disease (stage 1A-IIIB) led to a median survival of 49 months. Asian (n=18) and Hispanic patients (n=20) had significantly better survival than Caucasian (n=31) or other patients (n=6) (P=0.01). Ethnicity was linked to the location of the primary tumour ( P=0.002), the gastrectomy extent (P=0.003), and the patient's prior abdominal operation (P=0.01) or tobacco history (P=0.03), but not to resection extent parameters (such as number of lymph nodes retrieved) or differences in pathologic characteristics. When controlling for differences of disease site, stage, R status, and patient comorbidity, ethnicity did not retain an independent prognostic impact on survival. CONCLUSIONS: Obvious survival differences after gastrectomy for gastric adenocarcinoma favouring Asian and Hispanic patients in this experience can be explained by different disease patterns (distal location), the related need for fewer extensive procedures (such as total gastrectomy), and diminished patient risks (tobacco, prior operations, non-cancer deaths). Our therapeutic approach remains an aggressive gastrectomy/lymphadenectomy combination for potentially curable gastric cancer, irrespective of ethnic patient factors.

Soft tissue masses of the chest wall and axilla: has metastatic melanoma been considered?

Isolated axillary and chest wall soft tissue masses are an uncommon presentation of metastatic cancer. The authors present three patients in whom malignant melanomas metastatic to these sites had been misdiagnosed, leading to inappropriate oncologic treatment planning in all three cases. The presumed diagnoses, even after fine-needle aspiration or trucut biopsies, were soft-tissue sarcoma (n = 2) and undifferentiated breast cancer (n = 1). The combination of taking a thorough history and performing proper immunohistochemical analysis of the biopsy material would have suggested the presence of malignant melanoma in all cases. As the disease appeared locoregionally limited in all patients, radical surgical resection with extended lymphadenectomy was performed without significant dysfunction of the upper extremity. One patient agreed to postoperative immunotherapy with interferon-alpha. Two patients are currently alive 17 and 14 months after operation. One patient was found to have systemic recurrence at 5 months, one experienced two isolated local recurrences in a prior operative site that were amenable to reresection and presently has no evidence of disease 12 months after resection, and one patient remains free of disease at 14 months. Clinical presentation, suggested diagnostic workup, and therapeutic implications are discussed to avoid misdiagnoses in this setting of possible clinical presentations of metastatic melanoma.

Critical care of patients with cancer. Surgical considerations.

Surgical evaluation of and therapy for the critically ill cancer patient continue to present significant challenges despite, or perhaps in part because of, an ongoing technologic refinement of therapeutic modalities within a modern ICU.

Advanced age does not contribute to increased risks or poor outcome after major abdominal operations.

Elderly patients are still frequently denied major operations out of concerns over increased morbidity. The impact of advanced age on morbidity, mortality, and late outcomes after major gastric and pancreatic resections was studied by retrospective review with Chi square and regression analysis. Between July 1987 and June 2000, 179 patients underwent a major gastrectomy or pancreatectomy procedure at the City of Hope Cancer Center. There were 96 males and 83 females with a median age of 64 years (range 17-97) and elderly subsets more than 70 (n = 53) and more than 80 (n = 18) years of age. Diagnoses included gastric cancer (n = 83, 46%), pancreatic or periampullary cancer (n = 78, 44%), and benign pancreatic (n = 11, 6%) or gastric (n = 7, 4%) conditions. Age >70 years was correlated with more complex underlying medical conditions (P = 0.001) and gastrectomy for cancer (P = 0.01). None of four in-hospital deaths or 11 90-day lethal events occurred in patients >70 years of age (P = 0.005). Overall complications (35% vs 49%) and major complications (25% vs 37%) were less frequent in the older patient group [P = not significant (NS)]. Median intensive care unit stay (3 vs 2 days) and hospital stay (12 vs 12.5 days) were similar (P = NS). Pancreatoduodenectomy, gastrectomy for "benign" indications, and splenectomy--but not age--were significant prognostic variables for increased complications and longer hospital stay (at P < 0.05). At a median follow-up of 13 months (20 for survivors) the median survival after resection for gastric cancer (30 vs 16 months) or pancreatic/periampullary cancer (30 vs 23 months) was not inferior in elderly patients (P = NS). Five-year disease-free survival was superior in gastric cancer patients >70 years (59% vs 26%, P = 0.03) but not for pancreatic cancer. Advanced age under current clinical selection criteria does not impose increased hazards beyond disease- and procedure-related risk factors for patients undergoing gastrectomy or pancreatectomy; no patient should be denied these operations on the basis of age criteria alone.

A mortality-free decade of pancreatoduodenectomy: is quality independent of quantity?

Pancreatoduodenectomy (PD) for periampullary cancer is a procedure of high morbidity and poor long-term survival. Superior clinical outcome has been described in high-volume institutions or for surgeons with a high case load. All patients undergoing pancreatectomy at the City of Hope National Medical Center (Duarte, CA) between 1987 and 1998 were analyzed retrospectively for postoperative outcome, and correlating or predictive clinicopathological factors were identified. Fifty-four patients underwent pancreatectomy [PD, n = 43; pylorus-preserving PD, n = 8; total pancreatectomy, n = 3]. There were 26 males and 28 females, with a median age of 63 years (range, 19-86). Fifty patients had a malignant diagnosis, and four patients had a benign diagnosis. Nine surgical oncologists performed an average of six pancreatectomies (range, 2-8). There was no perioperative death. Postoperative complications occurred in 30 patients, and infections predominated (n = 17). The median hospital stay was 16.5 days. The median postoperative actuarial survival by cancer site was 56 months (ampullary/ bile duct), 32.5 months (duodenal), 22.5 months (pancreatic), and 23.2 months (others). In this 11-year single institutional experience, PD and total pancreatectomy have been performed without lethal complication. In the setting of an exclusive oncology practice, operative mortality rates and survival outcome can be generated that compare favorably to large center experiences. Quality of outcome after pancreatectomy can be independent of quantity.

The importance of splenectomy for the adoptive immunotherapy of cancer.

Adoptive immunotherapy (AIT) of cancer using lymphocytes cultured in vitro in interleukin-2 (LAK cells) has gained much attention due to the high level of broad anti-tumor activity both in vitro and in vivo. A major hypothesis has suggested that if unfractionated lymphoid cells grown in IL-2 can mediate significant anti-tumor effects then purified LAK effector cells should yield even higher activity. Furthermore, devising new techniques to achieve optimal expansion of the purified LAK effector cells would further improve this form of immunotherapy. In this report we present data on a new method for purifying and expanding LAK effector cells obtained from the peripheral blood and spleen. The results indicate that as a source of LAK cells, the spleen is superior both quantitatively ani qualitatively when compared to peripheral blood and should be seriously considered as the source of cells for AIT of cancer.

Preoperative platelet count predicts survival after resection of periampullary adenocarcinoma.

BACKGROUND/AIMS: Thrombocytosis or thrombocytopenia have been shown to act as negative predictors of outcome for various solid tumors. No such effect is known for periampullary cancer. The preoperative peripheral blood platelet count impacts on outcome after resection of pancreatic and other periampullary adenocarcinomas. METHODOLOGY: Clinicopathologic information, treatment aspects, and outcome parameters of patients undergoing pancreatectomy at City of Hope Cancer Center were retrospectively collected and tabulated. The impact of the preoperative platelet count on postoperative recovery, disease-free survival, and overall survival was analyzed. RESULTS: Between 1988 and 1998, 65 patients underwent partial or total pancreatectomy at City of Hope Cancer Center, 49 of whom had a diagnosis of pancreatic or periampullary adenocarcinoma. There were 26 females and 23 males, with a median age of 64 years (range: 24-86). Median preoperative platelet count was 308 (x10(9)/L; range: 104 to 547). Diagnoses were pancreatic (n = 28), duodenal (n = 12), and bile duct/ampullary cancer (n = 9). Procedures included pancreatoduodenectomy (n = 42), distal pancreatectomy (n = 4), and total pancreatectomy (n = 3). Six patients underwent a splenectomy. A lower preoperative platelet count was correlated to a shortened prothrombin time (P = 0.02), and a positive resection margin (P = 0.01), but not operative blood loss or transfusion requirements. Postoperative complications and hospital stay were not affected by the platelet count. Preoperative platelets of < 300 were associated with a decreased median overall survival (13 vs. 33 months, P = 0.02) and disease-free survival (11 vs. 29 months, P = 0.02), at a median follow-up of 14 months (18 for survivors). On multivariate analysis, the platelet count remained a significant predictor of survival in addition to grade, perineural invasion, the primary tumor size, and the surgeon. CONCLUSIONS: Based on these retrospective data, a lower preoperative platelet count correlates with inferior, a higher count with superior survival outcome after resection of periampullary cancer. The mechanism is unclear, but may relate to general factors (bone-marrow suppression or hypersplenism for low platelets, systemic antitumor mediators for high platelets) or platelet-specific effects (platelet influence on tumor angiogenesis or metastatic efficiency). The preoperative thrombocyte count should be considered a parameter with potential clinical significance in prospective clinical studies of periampullary neoplasms.

Pancreatic neuroendocrine tumors: signal pathways and targeted therapies.

Pancreatic neuroendocrine tumors (PNETs) are rare but are well understood to cover a broad spectrum of clinical presentation, tumor biology and prognosis. More than 60% of PNETs are diagnosed at advanced disease stage and are ineligible for surgical resection. Prior to 2011, streptozocin was the only approved agent for unresectable advanced PNETs. In recent years, breakthroughs in signal pathway research have led to the identification of new therapeutic targets and agents directed at the molecular level. In 2011, two new targeted therapeutic agents, sunitinib and everolimus, were approved by the Food and Drug Administration (FDA). Sunitinib is an inhibitor of multiple tyrosine kinases, and everolimus is an inhibitor of the mammalian target of rapamycin (mTOR) pathway. This review discusses the major signaling pathways that are frequently mutated or deregulated in PNETs, and the implications of molecular alterations for PNET therapy. Biologic therapy through targeting relevant pathways represents a promising approach in the therapy of advanced and unresectable PNETs.