Valerie Francescutti

Breast-fed infants achieve a higher rate of brain and whole body docosahexaenoate accumulation than formula-fed infants not consuming dietary docosahexaenoate.

Docosahexaenoate (DHA) has been increasingly recognized as an important fatty acid for neural and visual development during the first 6 mon of life. One important point of controversy that remains is the degree to which adequate levels of DHA can be acquired from endogenous synthesis in infants vs. what should be provided as dietary DHA. We have approached this problem by a retrospective analysis of published body composition data to estimate the actual accumulation of DHA in the human infant brain, liver, adipose tissue, remaining lean tissue, and whole body. Estimating whether infants can synthesize sufficient DHA required comparison to and extrapolation from animal data. Over the first 6 mon of life, DHA accumulates at about 10 mg/d in the whole body of breast-fed infants, with 48% of that amount appearing in the brain. To achieve that rate of accumulation, breast-fed infants need to consume a minimum of 20 mg DHA/d. Virtually all breast milk provides a DHA intake of at least 60 mg/d. Despite a store of about 1,050 mg of DHA in body fat at term birth and an intake of about 390 mg/d α-linolenate (α-LnA), the brain of formula-fed infants not consuming DHA accumulates half the DHA of the brain of breast-fed infants while the rest of the body actually loses DHA over the first 6 mon of life. No experimental data indicate that formula-fed infants not consuming DHA are able to convert the necessary 5.2% of α-LnA intake to DHA to match the DHA accumulation of breast-fed infants. We conclude that dietary DHA should likely be provided during at least the first 6 mon of life.

A contemporary analysis of morbidity and outcomes in cytoreduction/hyperthermic intraperitoneal chemoperfusion

The risks and benefits of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CS/HIPEC) continue to be debated by the oncology community. A retrospective analysis of contemporary data (2003–2011) was performed to provide objective information regarding surgical morbidity, mortality, and survival for patients undergoing CS/HIPEC at a comprehensive cancer center. While procedure‐associated morbidity was comparable to other major surgical oncology procedures, there was no operative or 30‐day mortality and 60‐day mortality was 2.7%. Increasing numbers of bowel resections were found to correlate to an increased incidence of deep surgical site infections (including abscess and enterocutaneous fistula) and need for reoperation which was in turn associated with a decreased overall survival (OS) and progression‐free survival (PFS). Five‐year OS rates varied by site of tumor origin and histology (disseminated peritoneal adenomucinosis [91.3%], Mesothelioma [80.8%], Appendiceal Adenocarcinoma [38.7%], and Colorectal Adenocarcinoma [38.2%]). With an acceptable morbidity and mortality rate, CS/HIPEC should be included as an effective treatment modality in the multidisciplinary care of select patients with peritoneal metastases.

Protein kinase Cα negatively regulates cell spreading and motility in MDA-MB-231 human breast cancer cells downstream of epidermal growth factor receptor

Previous work has shown that phorbol esters modulate chemotaxis. Here, we demonstrate that PKC activation via phorbol 12-myristate 13-acetate (PMA) treatment of MDA-MB-231 cells inhibits EGF-induced cell spreading, the initial event of motility and chemotaxis. Of five PKC isoforms (alpha,iota,lambda,delta,and epsilon) identified in this cell line, PMA treatment only induced PKCalpha translocation from the cytosol to the membrane, an event that correlated with the development of the rounded morphology. Cell recovery was linked to PKCalpha downregulation in part via the proteasome pathway since treatment with MG101 in the presence of PMA did not lead to PKCalpha degradation and cell recovery. Co-immunoprecipitation and immunolocalization demonstrated that EGF co-localized with PKCalpha and EGFR, however, PMA did not abrogate EGFR transactivation. This work suggests that PKCalpha is the primary target of PMA acting as a transient negative regulator of cell spreading and motility in MDA-MB-231 breast cancer cells.

Effect of Incorporation of Pretreatment Serum Carcinoembryonic Antigen Levels Into AJCC Staging for Colon Cancer on 5-Year Survival

IMPORTANCE The American Joint Committee on Cancer (AJCC) has proposed the inclusion of pretreatment serum carcinoembryonic antigen (CEA) levels (C stage) into the conventional TNM staging system of colon cancer. The latter proposal has yet to be widely adopted because of the lack of long-term survival estimates of after C-stage incorporation into AJCC staging. OBJECTIVES To evaluate whether long-term overall and cancer-specific survival is affected by inclusion of C stage into the standard AJCC TNM staging and to study the implications on survival estimates. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective study of all patients diagnosed as having histologically proven colonic adenocarcinoma from January 1, 2004, through December 31, 2005, from the National Cancer Institutes Surveillance, Epidemiology, and End Results database. We stratified each AJCC stage as C0 (normal) or C1 (elevated) based on the pretreatment serum CEA level. Median follow-up was 71 months. MAIN OUTCOME AND MEASURES Five-year estimates of overall and disease-specific survival and hazard ratios (HRs) for estimates of risk of overall and disease-specific mortality. RESULTS A total of 16 619 patients were evaluated, and of these, 8878 patients had C0 disease and 7741 had C1 disease. C1 stage was independently associated with a 51% and 59% increased risk of overall (HR, 1.51; 95% CI, 1.44-1.59; P < .001) and disease-specific mortality (HR, 1.59; 95% CI, 1.49-1.69; P < . 001) at a median follow-up of 71 months. Analysis of survival of the AJCC stages subdivided as C0 or C1 revealed a significant worse prognosis of C1 AJCC stages compared with the respective C0 AJCC stages. The magnitude of change in survival was large enough to cause clustering of survival estimates of C1 vs C0 cancers across various AJCC stages. Analysis of patients with stage I, II, and III cancer revealed that node-negative C1 disease was associated with prognosis similar or worse than node-positive C0 disease. CONCLUSIONS AND RELEVANCE Inclusion of C stage into the AJCC TNM staging of colon cancer revealed significant differences dependent on C stage in terms of 5-year survival. C-stage inclusion resulted in substantial change in survival estimates, with C1 status portending a prognosis to certain stages similar to or worse than higher AJCC TNM stages with C0 status. We recommend routine pretreatment CEA testing as standard of care in colon cancer and use of C stage for multimodality treatment planning and risk stratification in prospective studies and randomized clinical trials.

Gastrectomy and Esophagogastrectomy for Proximal and Distal Gastric Lesions: A Comparison of Open and Laparoscopic Procedures

Laparoscopic gastrectomy is safe for benign lesions; however, such surgery for cancer remains controversial. The aim of this study is to compare outcomes in open versus laparoscopic gastrectomy. Data on patients undergoing open (n = 15) or laparoscopic (n = 52) gastrectomy revealed a mean age of 61.7 and 70.5 years, respectively (P = .06). Mean operative time was 32.3 minutes longer in the laparoscopic group (P = .24). The difference in median length of hospital stay was 3 days (open 12 days, laparoscopic 9 days). Postoperative morbidity (< 30 days) was not different; however, there were more early respiratory complications in the open group (P = .009). There were 4/6 (66.7%) open and 2/29 (6.9%) cancer recurrences. Laparoscopic approach for treatment of gastric lesions is safe and does not have a deleterious effect on cancer-related outcome.

Current Delivery of Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery (CS/HIPEC) and Perioperative Practices: An International Survey of High-Volume Surgeons.

BackgroundCytoreductive surgery and heated intraperitoneal chemotherapy (CS/HIPEC) is performed for selected indications at a limited number of specialized centers worldwide. Currently there is no standardized approach to the perioperative care process. We sought to capture current practices in the perioperative management of patients who undergo CS/HIPEC at high-volume centers.MethodsSurgeon members of the American Society of Peritoneal Surface Malignancies working at high-volume CS/HIPEC centers (>10 cases/year) were invited to complete an online survey. The survey included questions relating to preoperative preparation of patients, intraoperative practices, and postoperative care.ResultsNinety-seven surgeons from five continents completed the survey (response rate 55%). The majority (80%) practiced in academic environments. Most respondents (68%) indicated that a formal preoperative preparatory pathway for CS/HIPEC surgery existed at their centers, but few (26%) had used enhanced recovery protocols in this group of patients. Whereas the intraoperative technical practices of the CS/HIPEC procedure were relatively consistent across respondents, there was little agreement on pre- and postoperative care practices, including use of mechanical bowel preparation, nutritional supplementation, methods of perioperative analgesia, timing of physical therapy and ambulation, nasogastric tube and Foley removal, intravenous fluids, blood transfusion parameters, and postoperative use of deep-vein thrombosis prophylaxis and antibiotics.ConclusionsPerioperative care practices for CS/HIPEC are widely variable nationally and internationally. Standardization of such practices offers an opportunity to incorporate evidence-based interventions and may enhance patient outcomes and improve care standards across all centers that offer this procedure.Cytoreductive surgery and heated intraperitoneal chemotherapy (CS/HIPEC) is performed for selected indications at a limited number of specialized centers worldwide. Currently there is no standardized approach to the perioperative care process. We sought to capture current practices in the perioperative management of patients who undergo CS/HIPEC at high-volume centers. Surgeon members of the American Society of Peritoneal Surface Malignancies working at high-volume CS/HIPEC centers (>10 cases/year) were invited to complete an online survey. The survey included questions relating to preoperative preparation of patients, intraoperative practices, and postoperative care. Ninety-seven surgeons from five continents completed the survey (response rate 55%). The majority (80%) practiced in academic environments. Most respondents (68%) indicated that a formal preoperative preparatory pathway for CS/HIPEC surgery existed at their centers, but few (26%) had used enhanced recovery protocols in this group of patients. Whereas the intraoperative technical practices of the CS/HIPEC procedure were relatively consistent across respondents, there was little agreement on pre- and postoperative care practices, including use of mechanical bowel preparation, nutritional supplementation, methods of perioperative analgesia, timing of physical therapy and ambulation, nasogastric tube and Foley removal, intravenous fluids, blood transfusion parameters, and postoperative use of deep-vein thrombosis prophylaxis and antibiotics. Perioperative care practices for CS/HIPEC are widely variable nationally and internationally. Standardization of such practices offers an opportunity to incorporate evidence-based interventions and may enhance patient outcomes and improve care standards across all centers that offer this procedure.

Current Immunotherapies for Sarcoma: Clinical Trials and Rationale

Sarcoma tumors are rare and heterogeneous, yet they possess many characteristics that may facilitate immunotherapeutic responses. Both active strategies including vaccines and passive strategies involving cellular adoptive immunotherapy have been applied clinically. Results of these clinical trials indicate a distinct benefit for select patients. The recent breakthrough of immunologic checkpoint inhibition is being rapidly introduced to a variety of tumor types including sarcoma. It is anticipated that these emerging immunotherapies will exhibit clinical efficacy for a variety of sarcomas. The increasing ability to tailor immunologic therapies to sarcoma patients will undoubtedly generate further enthusiasm and clinical research for this treatment modality.

The benefit of intraperitoneal chemotherapy for the treatment of colorectal carcinomatosis

The clinical practice of hyperthermic intraperitoneal chemoperfusion (HIPEC) for carcinomatosis has lacked preclinical justification. A standardized mouse model was created to evaluate the independent effects of intraperitoneal chemotherapy. Diffuse colorectal carcinomatosis was generated in mice prior to intraperitoneal lavage with mitomycin C (MMC) at clinically comparable dosing for variable lengths of time. Tumor volumes, MMC tissue concentrations and survival were measured in comparison to saline lavage and intravenous MMC. Magnetic resonance imaging revealed a direct correlation between tumor volume, MMC dose and exposure time and survival. Intravenous MMC demonstrated a rapid clearance from the blood, lower peritoneal tissue concentrations, less tumor growth inhibition and decreased survival compared to intraperitoneal administration. Intraperitoneal chemotherapy inhibited tumor growth independent of cytoreduction or hyperthermia, demonstrated improved peritoneal tissue concentration and was associated with increased survival. These data support the clinical utility of the intraperitoneal chemotherapy component of HIPEC.

Cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) in colorectal cancer: Evidence-based review of patient selection and treatment algorithms

Cytoreduction and heated intraperitoneal chemotherapy (CS/HIPEC) is increasingly utilized as a treatment strategy for patients with peritoneal metastases from various primary tumor sites. For this heterogenous procedure, related to patient characteristics, patient selection, and the extent of surgical completeness of cytoreduction, high level evidence (ex: multiple randomized controlled trials) is not available to support efficacy. This review of the available literature supporting application of the procedure, focusing on colorectal cancer, provides a summary of current evidence for patient selection and treatment algorithms based on patient presentation.

Fatty acid profiles of maternal adipose tissue in relation to infant development.

There is considerable debate at present about the merits of adding long-chain polyunsaturated fatty acids (LC-PUFA), namely docosahexaenoate (DHA) and arachidonate (AA), to infant formulas. Some agencies, especially in Europe, have endorsed this practice, resulting in the availability of LC-PUFA-enriched formulas. Others, including the recent Life Sciences Research Office report commissioned by the American Food and Drug Administration (LRSO Report, 1998), continue to recommend exclusion of LC-PUFA from infant formulas. One important reason for including DHA and AA in infant formulas is that their absence prevents the infant brain from accumulating DHA at a rate comparable to that in breast-fed infants (Farquharson et al. 1992; Makrideset al. 1994). Taking into account both brain growth rate and the actual amount of DHA in the brain, the rate of brain DHA accumulation in formula-fed infants not receiving DHA or AA is about 50 % of that in breast-fed infants (Cunnane et al. 1999) and is independent of the intake of a-linolenic acid (Farquharsonet al. 1992). Unlike most tissues, the brain is relatively resistant to changes in fatty acid intake so this degree of DHA depletion from the brain is a fairly clear indication of a conditional requirement by infants for dietary DHA. Normal reference values for the PUFA content of human tissues are only sparsely available but are valuable for better defining the conditional DHA requirement in infants. These measurements are semi-standardized in many laboratories and animal studies have clearly demonstrated the link between low brain DHA content and poor vision and cognitive function. Restricted access to human tissue material has meant that only the fatty acid profiles of infant plasma have really been studied in any depth. Nevertheless, infant brain fatty acid profiles are starting to become better known (Farquharsonet al. 1992; Martinez, 1992; Makrides et al. 1994), and, with further research, will clarify the importance of the reports that brain DHA accumulation is impaired in the absence of dietary DHA. By reporting the adipose tissue fatty acid profile of women of childbearing age, the paper by Pugo-Gunsam et al. (1999) makes an important contribution towards expanding the database for tissue fatty acid profiles of living humans. Maternal supplies of PUFA are predominantly in adipose tissue but little is known about the possible relationships between these maternal PUFA stores and pregnancy outcome, milk fatty acid profiles or infant health. In adults it is as ethically appropriate to collect a needle biopsy of fat as a blood sample, but the former may be more valuable because it represents long-term stores of PUFA. More information about adipose tissue fatty acid profiles is necessary to understand better how maternal PUFA supply to the fetus and/or breast-feeding infant may be related to infant health and development. Measuring fatty acid profiles of adipose tissue biopsies therefore provides a potentially important perspective on the PUFA adequacy of mothers, fetuses and infants. Fatty acid profiles of adipose tissue biopsies from living infants have not been reported but if they had a clear diagnostic value, this should become an acceptable, if limited, procedure. Further work with necropsy samples will still be required, but attempts to broaden the frame of reference linking tissue PUFA levels to normal v. abnormal infant development are needed to resolve the amount of dietary LC-PUFA that is required to support normal development fully in the first year of life. Fatty acid profiles of neonatal adipose tissue obtained at necropsy after sudden death indicate that breast-fed infants retain some adipose DHA 6 months postnatally but this store is completely depleted in formula-fed infants (Farquharsonet al. 1993). We have calculated that the term infant is born with about 1 g DHA in adipose tissue (Cunnane et al. 1999). Despite this store, the formula-fed infant that is not consuming DHA cannot sustain brain DHA accumulation equivalent to that of breast-fed infants (Farquharson et al. 1992). Estimated lean tissue DHA accumulation is also seriously impaired in formula-fed infants (Cunnane et al. 1999). Thus, while some studies may have difficulty in identifying functional deficits in infants that are not consuming DHA (LSRO Report, 1998), it may well be that such deficits are occurring in tissues other than the brain and eye. Hence, tissue fatty acid data provide some of the strongest evidence to date in support of a conditional DHA requirement in term infants. The paper by Pugo-Gunsam et al. (1999) also reports that growth over the first 6 weeks of life was comparable in healthy term infants born to French compared with Mauritian women, regardless of significant differences in infant erythrocyte fatty acid profiles in these two culturally and geographically distinct locations. They showed that a difference of almost two-fold can exist in the DHA content of infant erythrocyte phosphatidylethanolamine without growth being significantly different in the first 6 weeks of life, a period during which body weight increased about 40 %. Hence, erythrocyte and, by inference, plasma fatty acid profiles are not necessarily predictive of normal infant growth or health. British Journal of Nutrition(1999),82, 253–254 253