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.

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.

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.

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.

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.

Outcome of palliative operations for malignant bowel obstruction in patients with peritoneal carcinomatosis from nongynecological cancer.

BACKGROUND: Malignant bowel obstruction (MBO) secondary to peritoneal carcinomatosis carries a grave prognosis. We evaluated clinicopathologic factors that predict outcomes after palliative operations for MBO. METHODS: Data on patients undergoing laparotomy for palliation of gastrointestinal MBO at City of Hope between 1995 and 2000 were retrospectively collected. Successful palliation was defined as the ability to tolerate solid food (TSF). RESULTS: Sixty-three patients underwent operative treatment. In 20 patients, MBO was the first presentation of disease; for others, the median disease-free interval was 15 months. The complication rate was 44%, and postoperative mortality was 15%. The median length of stay was 12 days. Twenty-nine patients (45%) were discharged from the hospital on a regular diet; 22 (76%) continued to eat until their last follow-up. Median survival was 90 days. Univariate factors for longer survival were TSF on discharge, colorectal primary, and nonmetastatic status at first diagnosis. Patients with ascites and whose cancer first presented with MBO had an inferior survival. Noncolorectal primary remained a multivariate predictor for decreased survival. TSF was predicted by the absence of ascites, an obstruction not involving the small bowel, and a preoperative albumin of >3.0 mg/dl. Multiple logistic regression analysis yielded presence of ascites and small-bowel obstruction as predictors of inability to TSF. CONCLUSIONS: Only one third of patients with MBO from peritoneal carcinomatosis will have prolonged postoperative palliation with significant, but acceptable, treatment-related morbidity. TSF at discharge is a useful predictor of continued palliation for most patients. Patients with colorectal cancer may have superior survival outcome and better palliation; others are at risk for poor outcomes, especially in the presence of ascites and MBO of small bowel. In these patients, highly selective use of laparotomy is recommended.

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.

Transcutaneously tunneled central venous lines in cancer patients: an analysis of device-related morbidity factors based on prospective data collection.

BACKGROUND: Long-term transcutaneous tunneled central venous catheters are frequently placed in cancer patients, accounting for significant costs and morbidity. Factors influencing outcome, though, are poorly studied. METHODS: Between June 1991 and June 1993, 923 central venous tunneled catheters were placed in 791 patients at Memorial Sloan-Kettering Cancer Center. Placement-, device-, and patient-related parameters were charted prospectively (median follow-up: 120 days) and correlated to device-specific outcome events. RESULTS: Median patient age was 28.5 years (range: 0.025 - 84.5). Disease distribution included hematologic malignancies (64.7%), solid tumors (30.4%), and others (4.9%). Primary indications for line access included chemotherapy (72.8%), bone marrow transplantation (18.7%), total parenteral nutrition (6.4%), and drug administration (2.1%). There were 11 insertion complications (1.2%), including insertion failure (n = 6), hemorrhage (n = 4), and malposition (n = 1). Subsequent to placement, a proven or suspected device-specific complication occurred in 540 lines (58.5%). Per 10,000 catheter days, there were 17.6 infection episodes, 8.1 thrombotic complications, 6.9 instances of catheter breakage, 3.5 accidental or inadvertent cases of displacement, and 0.6 device leaks. Reasons for line removal or other termination of follow-up were patient's death (32.1%), treatment end (28%), infection (19.6%), suspected infection (6.3%), displacement (6.8%), thrombosis (3.1%), leak (1%), and others (3.1%). Median device-specific duration was 365 days, compared with a median complication-free device-specific duration of 167 days (P < 0.0001), reflecting a highly significant device salvage rate after complications. Catheter tip position emerged as the dominant independent prognostic factor for reduced device-specific duration or complication-free device-specific duration. CONCLUSIONS: Transcutaneous tunneled central venous lines can be placed safely, with a considerable incidence of subsequent device-specific complications, but a high salvage rate. Factors determining outcome are related to device placement, as well as the patient's disease status. In this study, patients alive 90 days after catheter placement had a 37% chance for a device complication, with a 20% chance for device loss. Future analyses of intermediate-term intravenous access should employ the measurement of device-specific outcome as a reference parameter to assess clinical results.

A carcinoembryonic antigen-secreting adenocarcinoma arising within a retrorectal tailgut cyst: clinicopathological considerations.

Retrorectal tailgut cysts (TGC) develop from postanal fetal gut remnants. They have specific radiological and histopathological features that distinguish them from dermoid cysts, enteric duplication cysts, and teratomas. We report a patient with a carcinoembryonic antigen-producing adenocarcinoma arising within a TGC who underwent resection through a combined anterior laparotomy/posterior pelvic approach. Despite complete resection and delayed but complete functional recovery, diffusely metastatic disease was encountered 6 months after resection. Diagnostic, therapeutic, histopathological, and oncological implications of this illustrative case are discussed. It seems possible to use carcinoembryonic antigen measurements for treatment planning and for assessing treatment response for this rare disease. The described outcome also suggests that TGC can develop malignant degeneration and should be resected at the time of diagnosis.

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.

Acute postoperative dermatosis at the site of the electrocautery pad: sweet diagnosis of a burning issue.

Acute febrile neutrophilic dermatosis or Sweet's syndrome is a well-described acute condition with possible paraneoplastic and inflammatory associations. A case of a 49-year-old man with a prior history of Hodgkin's disease is described, who underwent a laparotomy for operative treatment of a small intestinal stricture and therapy-refractory gastroesophageal reflux. Incidentally, mild mesenteric lymphadenopathy was encountered, and a biopsy confirmed the presence of a new, unrelated low-grade follicular lymphoma. Two weeks postoperatively, the patient developed a tender erythematous plaque at the site of the Bovie electrocautery pad on the proximal thigh. Over the following week, the affected area extended in size, and became markedly edematous and infiltrated, with hemorrhagic surface studding. Multiple small plaques, some with annular arrays of pustules, were found on the opposite lower extremity, the lower back, and the arms. A skin biopsy suggested the presence of Sweet's syndrome, and corticosteroid treatment was initiated. All cutaneous manifestations disappeared within 48 h except for the presence of postinflammatory erythema. Acute neutrophilic dermatoses have not been previously described in this postoperative presentation. The differential diagnostic importance of this emergent entity and the potential for it being caused by surgical trauma are discussed.

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.

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.

Wheatgerm agglutinin-mediated toxicity in pancreatic cancer cells.

Lectin binding specificities for carbohydrate allow phenotypic and functional characterization of membrane-associated glycoproteins expressed on cancer cells. This analysis examined wheatgerm agglutinin binding to pancreatic cancer cells in vitro and the resulting toxicity. Membrane preparations of nine human pancreatic carcinoma cell lines were studied for lectin binding using wheatgerm agglutinin (WGA), concanavalin A (ConA) and phytohaemagglutinin-L (PHA-L) in a lectin blot analysis. Cell proliferation in vitro was measured by thymidine incorporation in the absence or presence of lectins at various concentrations. Sialic acid binding lectins or succinyl-WGA (succWGA) served as controls. WGA toxicity was tested after swainsonine or neuraminidase pretreatment. Binding and uptake of fluorescein-labelled lectins was studied under fluorescence microscopy. All pancreatic cell lines displayed high WGA membrane binding, primarily to sialic acid residues. Other lectins were bound with weak to moderate intensity only. Lectin toxicity corresponded to membrane binding intensity, and was profound in case of WGA (ID50 at 2.5-5 microg ml(-1)). WGA exposure induced chromatin condensation, nuclear fragmentation and DNA release consistent with apoptosis. Important steps for WGA toxicity included binding to sialic acid on swainsonine-sensitive carbohydrate and lectin internalization. There was rapid cellular uptake and subsequent nuclear relocalization of WGA. In contradistinction to the other lectins studied, WGA proved highly toxic to human pancreatic carcinoma cells in vitro. WGA binding to sialic acid residues of N-linked carbohydrate, cellular uptake and subsequent affinity to N-acetyl glucosamine appear to be necessary steps. Further analysis of this mechanism of profound toxicity may provide insight relevant to the treatment of pancreatic cancer.

Lymphoepithelial cyst of the pancreas. No evidence for Epstein-Barr virus-related pathogenesis.

Compared to pseudocyst formation after prior pancreatitis, true cysts of the pancreas are rare. Pancreatic cysts with irregular wall components or a mucinous content raise the suspicion for the presence of a cystic neoplasm, and surgical resection is recommended. A case of a patient with a history of prostate cancer is described in whom a cyst of the pancreatic tail was discovered incidentally. Based on the radiographic features, which did not support the presence of a serous cystadenoma, a spleen-preserving distal pancreatectomy was performed. Histologic features were characteristic for a lymphoepithelial cyst (LEC) of the pancreas, lined with thinned squamous epithelium surrounded by benign lymphoid tissue. Since LECs of the parotid gland, which are associated with acquired human immunodeficiency, are frequently related to Epstein-Barr virus (EBV) infection, EBV in situ hybridization was performed and did not reveal evidence for EBV. Twenty-eight instances of pancreatic LECs have been reported, primarily affecting adult males, without evidence of increased numbers of EBV-positive cells. The pathogenesis, differential diagnosis, and clinical implications of lymphoepithelial pancreatic cysts are discussed.