The effect of preoperative nutritional status on postoperative complications and overall survival in patients undergoing pelvic exenteration: A multi-disciplinary, multi-institutional cohort study.

INTRODUCTION: Optimization of preoperative nutritional status has been recommended and associated with improved outcomes for other oncologic procedures, but has not been studied in patients undergoing pelvic exenteration. METHODS: A retrospective chart review of 199 patients was conducted. Overall survival (OS) was calculated using the Kaplan-Meier method and multivariate analysis was performed with Cox proportional hazards. RESULTS: 199 patients underwent PE with 61 (31%), 78 (40%) and 58 (29%) patients having colorectal, gynecologic and urologic histological diagnoses, respectively. Median OS following PE was 25 months. Preoperative serum albumin <3.5 g/dL was associated with worsened OS (HR 1.661; 95% CI 1.052-2.624) as well as increased incidence of any postoperative complication (85.9% vs 72.3%, p = 0.034), but was not associated with 90-day mortality (11.3% vs 7.9%, p = 0.457). CONCLUSION: Poor preoperative nutritional status is associated with increased complications and decreased OS. Surgeons should maximize preoperative nutritional status to improve perioperative outcomes and long-term survival.

Influence of tumor size on outcomes following pelvic exenteration.

OBJECTIVE: Pelvic exenteration (PE) is often the only curative option for locally advanced or recurrent pelvic malignancies. Despite radical surgery, recurrence risk and morbidity remain high. In this study, we sought to determine tumor size effect on perioperative outcomes and subsequent survival in patients undergoing PE. METHODS: Retrospective chart review was performed for female patients who underwent PE at two comprehensive cancer centers from 2000 to 2015. Demographics, complications and outcomes were recorded. Statistical analyses were performed using chi-square, student's t-test, logistic regression, non-parametric tests, log-rank test, and Cox proportional hazards. RESULTS: Of 151 women who underwent PE, 144 had available pathologic tumor size. Gynecologic oncology, surgical oncology, and urology performed 84, 29, and 31 exenterations, respectively. Tumor dimensions ranged from 0 to 25.5cm. Perioperative complications, 30-day mortality, reoperation, and readmission rates were not associated with tumor size. Obesity and prior radiation increased risk for major perioperative complication while anterior exenterations decreased risk. Larger tumors were more likely to undergo total pelvic exenteration (OR 1.14; 95%CI 1.03-1.27), have positive margins (OR 1.11; 95%CI 1.02-1.22), and recur (65%, 42% and 20% for tumors >4cm, ≤4cm and no residual tumor respectively, p=0.016). Tumor size >4cm and positive margins were associated with worse overall survival amongst gynecologic oncology patients. CONCLUSION: Tumor size was not associated with perioperative morbidity. Larger tumors were associated with positive margins, more extensive resection, and worse survival in gynecologic oncology patients. Larger studies are needed to further understand tumor size impact on PE outcomes within specific tumor types.

Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection.

HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c(+) and CD1c(neg)) and plasmacytoid DCs in untreated HIV-1-infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c(+) mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percentage of CD83(+)CD1c(+) mDCs negatively correlated with frequencies of interferon-γ-producing colon CD4(+) and CD8(+) T cells. CD40 expression on CD1c(+) mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and Prevotella stercorea but negatively associated with a number of low prevalence mucosal species, including Rumminococcus bromii. CD1c(+) mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that, during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation.

Localization of the sentinel node in breast cancer: identical results with same-day and day-before isotope injection.

BACKGROUND: Although the technique of sentinel lymph node (SLN) biopsy in breast cancer is not fully standardized, an increasing number of centers map the SLN by using radioisotope supplemented by blue dye, and most have injected isotope on the day of surgery. Here we directly compare the results of same-day and day-before isotope injection in a large series of breast cancer patients having SLN biopsy with our mature technique. METHODS: Starting with our 961st SLN procedure for breast cancer, 1320 consecutive patients had SLN biopsy after the injection of unfiltered 99mTc-labeled sulfur colloid given as a single-site, low-volume (0.05 ml) intradermal injection: 933 on the day of surgery (1-day protocol) and 387 on the day before (2-day protocol). All had intraparenchymal injection of blue dye. RESULTS: The two groups were comparable in age, tumor location, histopathologic characteristics, and number of SLNs identified. LSG taken at 2 hours in the 2-day protocol was positive more often than LSG performed at 30 minutes in the 1-day protocol, and nonaxillary sites of lymphatic drainage were seen in <1% of each group. Absolute isotope counts and the ratio of SLN to axillary background counts were similar. Isotope localization of the SLN succeeded in a comparable fraction of patients, as did SLN identification overall. CONCLUSIONS: The results of SLN mapping with same-day and day-before injection of radioisotope are virtually identical. The logistical advantages of day-before injection do not compromise the success of the procedure.

Suppression of macrophage nitric oxide production by melanoma: mediation by a melanoma-derived product.

The tumour-bearing state is known to induce immune dysfunction that contributes to increased infectious complications and tumour progression. However, the mechanisms underlying this immunosuppression remain unclear. This study investigated in a murine model the effects of melanoma growth on nitric oxide (NO) production by peritoneal macrophages in vivo and in vitro. B16 and K1735 melanoma cells were inoculated subcutaneously into C57BL/6 and C3H/HeN mice, respectively. Stimulated NO production by elicited peritoneal macrophages was examined in control and melanoma- bearing mice. An in vitro system was established to assess the effects of co-culturing melanoma cells (B16 and K1735) or melanoma-conditioned medium with normal peritoneal macrophages on subsequent NO production. NO production was significantly suppressed in macrophages from melanoma-bearing mice. Co-culture of normal macrophages with melanoma cells in a transwell system or with melanoma-conditioned media in vitro reproduced the defects observed in vivo without affecting macrophage viability, pointing to a melanoma-derived product as the basis for the observed suppression of NO production. This inhibition required RNA and protein synthesis and was dose and time dependent. Using inhibition profiles and neutralizing antibodies, it was demonstrated that this melanoma inhibitory activity was distinct from known NO inhibitors. Preliminary characterization attributed this activity to a melanoma-secreted protein moiety.

The breast cancer patient with multiple sentinel nodes: when to stop?

BACKGROUND: During sentinel lymph node (SLN) biopsy for breast cancer, most authors report identifying a mean of 1 to 3 SLNs, but a range of 1 to 8 (or more) SLNs per patient. A significant minority of patients have 4 or more SLNs. Here we seek to determine the significance for the breast cancer patient of finding multiple SLNs, and whether there is an optimal threshold number of SLNs that should be removed. STUDY DESIGN: 1,561 patients who underwent successful SLN biopsy using blue dye and radioisotope in combination. Each SLN site was categorized prospectively by the operating surgeon as a dye success, an isotope success, or both. All SLNs containing counts at least four times greater than the postexcision axillary background were considered to be isotope successes. RESULTS: Fifteen percent of patients (241) had multiple (>3) SLNs. Ninety-eight percent of node-positive patients (440 of 449) were identified within the first three SLN sites examined. In 2% of all SLN positive patients (9 of 449) or 4% of patients with multiple SLN (9 of 241), a positive SLN was detected at site four or more. In eight patients the first positive SLN was found at sites four or more. Blue dye and isotope were equally effective in identifying metastases in patients with multiple SLNs. CONCLUSIONS: Fifteen percent of patients having SLN biopsy for breast cancer have multiple SLNs. Although 98% of positive SLNs were identified within the first three sites sampled, a small number of patients had their first positive SLN at sites 4 to 8. These data suggest that there is no absolute upper threshold for the number of SLNs that should be removed. Sampling a few additional SLNs probably adds little morbidity to the procedure, yet may significantly alter the treatment of some individuals. SLN biopsy should be continued until all blue and hot nodes are removed.

Metastatic liver tumors.

The liver is a common site of metastasis from a variety of tumors. In many cases, liver resection for metastatic cancer provides the only chance for a cure and can be performed with less than 5% mortality and acceptable morbidity. The 5-year survival following liver resection for colorectal metastasis is reported in many large series to be 25% to 37%. The data regarding liver resection for other metastatic tumor types are less clear. However, resection for selected tumors, such as neuroendocrine and renal cell, can provide durable palliation and/or cure. We will review important prognostic factors used to guide the selection of patients for resection of metastatic disease and make recommendations for imaging studies and follow-up routines. The role of adjuvant regional and systemic chemotherapy for resectable metastatic disease is also discussed. Methods for ablating unresectable metastatic tumors may prove to be useful adjuncts to current therapies.

Extraskeletal osteosarcoma: analysis of outcome of a rare neoplasm.

Purpose. Extraskeletal osteosarcoma represents an unusual soft-tissue sarcoma that historically is reported to carry an exceptionally poor prognosis.The objectives of this study were to use a prospectively gathered sarcoma database to test the prevailing clinical bias and more accurately describe the natural history, characterize the prognostic features, estimate survival and evaluate treatment strategies for this unusual sarcoma.Patients and methods. From a large database of nearly 4000 sarcomas at a single institution, 15 patients with pathologically confirmed extraskeletal osteosarcoma were analysed.Results and discussion. Extraskeletal osteosarcoma usually occurs as a large, deep, high-grade lesion in the lower extremity of older patients. Overall and disease-specific survival at 5 years was 50%, with a median follow-up of 35 months (range 3- 200 months). Use of adjuvant chemotherapy or radiation therapy did not appear to influence survival, but an effect may have been missed by the relatively low numbers in each group.When matched to a comparable group of patients with stage III extremity sarcomas, there was no significant difference in overall or disease-specific survival between groups. Treatment for extraskeletal osteosarcoma should follow established guidelines for treatment of soft-tissue sarcomas, with the decision regarding adjuvant therapy to be based on individual risk factors.

Glucocorticoid blockade does not abrogate tumor-induced cachexia.

Cancer-induced cachexia is a common manifestation observed in patients with malignancies. Elevated levels of circulating glucocorticoids and interleukin-6 (IL-6) have been observed in cancer patients with cachexia and are implicated as major mediators in this process. The purpose of this study was to investigate the role of circulating glucocorticoid levels as primary mediators in cancer-induced cachexia. We evaluated whether inhibition of glucocorticoids with the receptor antagonist RU-486 could abrogate the detrimental wasting of muscle and adipose tissues seen in a well-characterized murine tumor-induced cachexia model. Mice (12/group) were randomized to control, tumor-bearing, control + vehicle, or tumor-bearing + glucocorticoid receptor antagonist groups. Circulating serum glucocorticoid and IL-6 levels were measured in addition to multiple body composition parameters, such as total body weight, lean body mass, and adipose content. The results of this study indicate a significant physiological alteration in the tumor-bearing host that causes severe and detrimental changes in body composition parameters. Regression analysis demonstrated a significant correlation between increased circulating glucocorticoid levels and alterations in body composition parameters. These observed defects were not abrogated with the administration of a glucocorticoid receptor antagonist. We therefore conclude that the untoward effects of tumor-induced cachexia are not mediated primarily by the peripheral effects of high circulating glucocorticoid levels but may involve a complex interaction with IL-6.

Preoperative oral supplement with immunonutrients in cancer patients.

BACKGROUND: Early postoperative enteral nutrition with immune-enhancing supplements has helped to restore immune function and reduce infectious complications in patients with cancer undergoing major gastrointestinal operations. The aim of this study was to evaluate the effectiveness of similar supplements (containing arginine and arginine plus omega-3 fatty acids) given preoperatively for 1 week before cancer surgery. METHODS: In this randomized, double-blinded study, patients scheduled to undergo elective resection of upper gastrointestinal tumors were given one of three different oral liquid supplemental diets (control, arginine, arginine plus omega-3 fatty acids) to be taken each day for 7 days before surgery. Blood samples were obtained upon enrollment, on the morning of surgery, and on postoperative day 1 for analysis of immunologic function. RESULTS: Mean serum ornithine (a metabolite of arginine) levels were significantly higher compared with controls, but no significant increase in mean serum arginine levels was noted on the morning of surgery for those patients who received arginine as part of the supplement. In conjunction with these findings, there were no differences among groups in mean lymphocyte mitogenesis, mean peripheral blood mononuclear cell production of cytokines, or clinical outcomes. CONCLUSIONS: Use of oral liquid supplements in this fashion did not improve lymphocyte proliferation or monocyte functions in patients with cancer undergoing major surgery.

Altered macrophage intracellular signaling induced by protein-calorie malnutrition.

Protein-calorie malnutrition (PCM) contributes to increased morbidity and mortality through impairment of host defense mechanisms and reduced macrophage function. The present study examined alterations in macrophage intracellular signaling associated with the impairment in host defense capabilities. Mice were randomized to either control (regular diet) or protein-free diets (PCM) and pair-fed for 1 week. Following endotoxin stimulation, peritoneal macrophages from PCM mice produce significantly less TNF-alpha and IL-6 product and had significantly less cell-associated IL-6 when compared to macrophages from control mice. Similarly, macrophages from PCM mice had a significant reduction in mRNA levels for both TNF-alpha and IL-6. Other macrophage intracellular signaling mechanisms, such as calcium flux and tyrosine kinase phosphorylation were also altered by PCM. The etiology of PCM-induced defects in macrophage function and intracellular signaling remain unknown but may be related to the neuroendocrine response to PCM.

Trauma-induced alterations in macrophage function.

BACKGROUND: The juxtaposition of immune suppression and a hyperactive inflammatory response after injury represents a paradox in immune function. The aim of this study was to evaluate the delayed macrophage hypersecretion of inflammatory mediators in relation to functional macrophage defects. METHODS: BALB/c mice were randomized to control or trauma (femur fracture plus 40% blood volume hemorrhage) groups. One and 7 days after injury, splenic macrophages were isolated and assayed for antigen presentation and the production of inflammatory mediators tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, prostaglandin E2, H2O2, and nitric oxide. RESULTS: One day after injury, there were significantly diminished macrophage antigen presentation and decreased mean production of TNF-alpha, IL-6, and H2O2. In contrast, 7 days after injury, splenic macrophages produced significantly increased mean amounts of TNF-alpha, IL-6, prostaglandin E2, H2O2, and nitric oxide, with a persistent functional defect in antigen presentation. CONCLUSIONS: This phasic response to trauma suggests a persistent state of macrophage dysregulation that may help explain the paradox of immune suppression, manifested by functional defects predisposing patients to increased infections, in the setting of inflammatory mediator hypersecretion, predisposing patients to the systemic inflammatory response syndrome/multiple organ dysfunction syndrome.

Candida infection following severe trauma exacerbates Th2 cytokines and increases mortality.

Following trauma, there is an increase of Th2 cytokines (IL-4, IL-6, and IL-10) and a decrease in Th1 cytokines (IFN-gamma and IL-2) that may account for impaired cellular immunity. However, the functional significance of a dominant Th2 pattern to the host remains unclear. The aim of this study was to evaluate whether Candida albicans (CA) sepsis in the setting of a Th2 response to trauma leads to increased mortality and to examine the mediators involved. Female BALB/c mice were randomized (12 per group) to receive no injury (C); trauma, consisting of a combined femur fracture and 40% total blood loss (T); no injury plus CA infection (C+CA); and CA infection 1 week following trauma (T+CA). Survival was then followed for 3 weeks. In a separate study, mice were treated as above (5 per group) and sacrificed. Harvested splenocytes were evaluated for concanavalin A-stimulated cytokine production and liver and kidney homogenates were plated to evaluate CA growth per organ and examined histologically. Candida infection at 1 week following trauma resulted in significantly increased mortality compared to infected controls. Furthermore, the Th2 dominant cytokine pattern was significantly augmented in the presence of CA infection in both C+CA and T+CA groups. Additional analysis showed significant growth of CA in liver and kidney homogenates from T+CA compared to C+CA mice. These results suggest that injured and infected mice demonstrate augmentation of Th2 dominant responses above that of injury or infection alone, as well as a decreased ability to clear Candida which may partially explain the increase in mortality observed. Therapies designed to neutralize Th2 cytokines or augment Th1 cytokines may prove beneficial in the setting of sepsis following trauma.

Early postoperative enteral feeding following major upper gastrointestinal surgery.

For a variety of reasons, enteral feeding is frequently delayed following major abdominal surgery. The purpose of this study was to evaluate prospectively the feasibility and tolerance of early jejunal feeding following major upper gastrointestinal surgery. Beginning on postoperative day 1, patients (n = 167) received a full-strength enteral formula at the rate of 25 ml/hr through a jejunal feeding tube. Diets were advanced to the calculated target rate (25 kcal/kg/day) by postoperative day 4. Complications of tube feeding, calories received, and patient symptoms were recorded daily. There were no major complications or deaths resulting from placement of a jejunal tube or from early enteral feeding. Patients had abdominal symptoms such as cramping, distention, nausea, and diarrhea on 9%, 18%, 4%, and 24% of all feeding days, respectively. The majority of these symptoms, with the exception of diarrhea, were graded as mild. Patients undergoing surgery for pancreatic malignancy had significantly more diarrhea than patients undergoing esophagectomy or gastrectomy. Despite these differences in symptoms, patients received an average of 78% of their targeted caloric goal by postoperative day 4 and maintained this level throughout the study. Early enteral feeding for patients undergoing esophageal, gastric, or pancreatic resections is both safe and feasible despite the occurrence of predominantly mild gastrointestinal symptoms.

Dominance of T-helper 2-type cytokines after severe injury.

OBJECTIVE: To determine whether severe injury leads to a dominance of splenocyte-produced T-helper (Th) 2-type cytokines, partly explaining the observed defects in cellular immune responses in the posttraumatic state. DESIGN: Female BALB/c mice (n = 6 per group) were randomized to receive anesthesia alone (control) or a combined femur fracture and a hemorrhage of 40% of total blood volume (trauma). On days 1 and 7 after injury, mice were killed and spleens were harvested. Splenocytes were stimulated in vitro with 2.5 micrograms of concanavalin A per milliliter. After 72 hours of incubation, splenocyte proliferation was determined by means of tritiated thymidine uptake. Production of interferon-gamma and interleukins (IL) -2, -4, -5, -6, and -10 from supernatants harvested after 24 or 72 hours of incubation was quantified by enzyme-linked immunosorbent assay. SETTING: Surgical immunology research laboratory of a medical college. MAIN OUTCOME MEASURES: Mouse spleen weight, splenocyte number, and proliferation in addition to cytokine production (interferon-gamma, IL-2, IL-4, IL-5, IL-6, and IL-10). RESULTS: Splenocyte proliferative capacity was unaffected at day 1 after injury but was significantly suppressed (P < .05) by day 7 after injury. Similarly, there were no changes in splenocyte cytokine production in a comparison of control and injured mice at day 1. At day 7, however, there was nearly a 90% decrease in the Th1-type cytokines (interferon-gamma and IL-2; P < or = .002) and at least a 30% increase in the Th2-type cytokines IL-4, IL-5, IL-6, and IL-10 (P = .06 for IL-6 and P < or = .03 for IL-4, IL-5, and IL-10). CONCLUSIONS: These data indicate that a shift to a Th2-type splenocyte cytokine response occurs late, at 7 days after injury. Modulation of Th cell cytokine responses may partially explain defects observed in cellular immune responses in postinjury states. Therapies that augment Th1-type cytokine production and/or neutralize Th2-type cytokines may prove beneficial.

Diarrhea and Clostridium difficile-associated diarrhea on a surgical service.

OBJECTIVE: To identify the incidence, risk factors, and treatment of diarrhea and Clostridium difficile-associated diarrhea (CDAD) in surgery patients. DESIGN: Prospective and historical retrospective analysis. SETTING: Major urban tertiary care referral hospital. PATIENTS: Consecutive patients (N = 475) admitted to the vascular, trauma, and general surgical surgery services, prospectively evaluated during a 10-week period. A retrospective historical control of the same surgical services was used for comparison. INTERVENTION: None. MAIN OUTCOME MEASURES: Incidence of diarrhea and CDAD, use of bowel preparations, surgical procedure, use of C difficile toxin assay, white blood cell count, symptoms, treatment, and delay in hospital discharge. RESULTS: The incidence of diarrhea in surgery patients analyzed prospectively was 6.1%; the incidence of CDAD during the prospective and retrospective periods was 2%. Preoperative bowel preparations were associated with an increased risk of diarrhea (relative risk, 4.2; 95% confidence interval, 2.6-6.8; P < .001) and CDAD (relative risk, 3.2; 95% confidence interval, 1.5-7.2; P < .03). Leukocytosis (white blood cell count > 11 x 10(9)/L) was significantly higher in the CDAD group compared with the diarrhea group only on the day of diagnosis (P < .05). By subjective analysis, diarrhea was directly responsible for a delay in discharge in 7 of 29 patients for a mean (+/-SEM) of 4.0 +/- 1.0 days. CONCLUSIONS: Patients undergoing preoperative bowel preparations are at increased risk of experiencing diarrhea and CDAD. Among patients with diarrhea, an elevated white blood cell count may help identify those with C difficile. Early treatment of diarrhea with oral metronidazole while awaiting the results of the stool toxin assay is recommended for treating diarrhea in surgery patients. Prophylactic treatment of surgery patients undergoing bowel preparations should be considered.

Cholestyramine resin ameliorates chronic aminonucleoside nephrosis.

We chose to assess the role of cholesterol reduction in chronic aminonucleoside nephrosis by pharmacologically lowering serum cholesterol with cholestyramine. Two groups of rats were made nephrotic with a single intravenous dose of puromycin aminonucleoside (PA): one group (PA/resin) received 5% (w:w in diet) cholestyramine resin and the dietary control group (PA/cell) received 5% cellulose. Cholestyramine-treated rats demonstrated significant functional and histological protection. Recurrent proteinuria was significantly lower in PA/resin animals. Whole-kidney glomerular filtration rate in the PA/resin group was preserved at a level equivalent to normal age-matched control rats whereas the PA/cell group had a significantly lower value than did the normal animals. The extent of segmental glomerulosclerosis 24 wk after PA delivery was significantly lower in the PA/resin group. These results suggest a role for hyperlipidemia as one of the mechanisms involved in the pathogenesis of progressive glomerular disease.

Altered functional characteristics of rat macrophages during nephrosis. Synergistic effects of hypercholesterolemia.

The effects of alimentary hypercholesterolemia and nephrotic hyperlipidemia, alone and in combination, on rat peritoneal macrophage phagocytosis, basal eicosanoid production, and glomerular macrophage number during peak PA nephrosis were evaluated in rats fed four different diets: 1) normal/standard chow; 2) PA/standard chow; 3) normal/cholesterol-supplemented diet; and 4) PA/cholesterol-supplemented diet. Both PA/standard chow and normal/cholesterol-supplemented rodent groups manifested significantly greater peritoneal macrophage phagocytosis and glomerular macrophage number when compared with normal/standard chow animals. However, the combination of the nephrotic state with superimposed alimentary hypercholesterolemia (PA/cholesterol-supplemented group) produced the greatest rise in these parameters, a rise that was significantly greater than was produced in the three other groups. Regarding basal eicosanoid production by macrophages, there was a numerical trend toward increased production of thromboxane B2 in the PA/standard chow animals and normal/cholesterol-supplemented rats when compared with normal/standard chow. Again, the combination of nephrosis and alimentary hypercholesterolemia in the PA/cholesterol-supplemented group was associated with a significantly greater amount of thromboxane B2 generated when compared with the other three groups. Regarding PGE2 production, there were no significant differences among the groups, despite marked differences in fasting serum lipid levels. This data suggest that there is a synergistic effect between alimentary hypercholesterolemia and the secondary hyperlipidemia of nephrosis in producing these macrophage functional alterations. Because fasting triglyceride values between the two nephrotic groups were indifferent, one can further speculate that it is the elevation of the serum cholesterol value that predominantly evokes these changes in macrophage function.