Correction to: Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

C.R. Farley and M.C. Perez contributed equally to this publication and are co-first authors. J.S. Zager and M.C. Lowe contributed equally to this publication and are co-corresponding authors.

Merkel Cell Carcinoma Outcomes: Does AJCC8 Underestimate Survival?

INTRODUCTION: The eighth edition of the American Joint Committee on Cancer (AJCC8) Staging Manual provides important information for staging and prognostication; however, survival estimates for patients with Stage I-III Merkel cell carcinoma (MCC), a rare disease, may be as practical using data from large-volume centers as that collated for the AJCC analysis. As such, we compared our institutional outcomes to AJCC8. METHODS: Patients who presented from 2005 to 2017 with MCC to two high-volume centers were included. Demographics, clinicopathologic characteristics, survival and recurrence data were compiled, and outcomes compared to AJCC8. RESULTS: A total of 409 patients were included. Median age was 75 (range 29-98) years, and 68% were male. Median follow-up was 16 months (0-157). Five-year overall survival (OS) was 70%; 5-year disease-specific survival (DSS) was 84%. When stratified by extent of disease, 5-year OS was higher for patients with local disease compared to those with nodal disease (72.6% vs 62.7%, p=0.005). Similarly, patients with local disease had higher 5-year DSS than those with nodal disease (90.1% vs 76.8%, p=0.002). Five-year recurrence-free survival was 59.2% for all patients, 65.0% for local disease and 48.3% for nodal disease (p=0.033). CONCLUSIONS: Here, MCC patients with local or nodal disease have substantially higher OS rates than predicted in AJCC8 (5-year: 72.6% vs 50.6%; 62.7% vs 35.4%, respectively). Importantly, 5-year DSS was significantly better than the OS rates reported presently and in AJCC8. As clinicians and patients rely on AJCC to accurately prognosticate and guide treatment decisions, these estimates should be reassessed and updated to more accurately predict survival outcomes.

Dual islet transplantation modeling of the instant blood-mediated inflammatory reaction.

Islet xenotransplantation is a potential treatment for diabetes without the limitations of tissue availability. Although successful experimentally, early islet loss remains substantial and attributed to an instant blood-mediated inflammatory reaction (IBMIR). This syndrome of islet destruction has been incompletely defined and characterization in pig-to-primate models has been hampered by logistical and statistical limitations of large animal studies. To further investigate IBMIR, we developed a novel in vivo dual islet transplant model to precisely characterize IBMIR as proof-of-concept that this model can serve to properly control experiments comparing modified xenoislet preparations. WT and α1,3-galactosyltransferase knockout (GTKO) neonatal porcine islets were studied in nonimmunosuppressed rhesus macaques. Inert polyethylene microspheres served as a control for the effects of portal embolization. Digital analysis of immunohistochemistry targeting IBMIR mediators was performed at 1 and 24 h after intraportal islet infusion. Early findings observed in transplanted islets include complement and antibody deposition, and infiltration by neutrophils, macrophages and platelets. Insulin, complement, antibody, neutrophils, macrophages and platelets were similar between GTKO and WT islets, with increasing macrophage infiltration at 24 h in both phenotypes. This model provides an objective and internally controlled study of distinct islet preparations and documents the temporal histology of IBMIR.

Systematic review and meta-analysis of enhanced recovery programmes in surgical patients.

BACKGROUND: Enhanced recovery programmes (ERPs) have been developed over the past 10 years to improve patient outcomes and to accelerate recovery after surgery. The existing literature focuses on specific specialties, mainly colorectal surgery. The aim of this review was to investigate whether the effect of ERPs on patient outcomes varies across surgical specialties or with the design of individual programmes. METHODS: MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials were searched from inception to January 2013 for randomized or quasi-randomized trials comparing ERPs with standard care in adult elective surgical patients. RESULTS: Thirty-eight trials were included in the review, with a total of 5099 participants. Study design and quality was poor. Meta-analyses showed that ERPs reduced the primary length of stay (standardized mean difference -1·14 (95 per cent confidence interval -1·45 to -0·85)) and reduced the risk of all complications within 30 days (risk ratio (RR) 0·71, 95 per cent c.i. 0·60 to 0·86). There was no evidence of a reduction in mortality (RR 0·69, 95 per cent c.i. 0·34 to 1·39), major complications (RR 0·95, 0·69 to 1·31) or readmission rates (RR 0·96, 0·59 to 1·58). The impact of ERPs was similar across specialties and there was no consistent evidence that elements included within ERPs affected patient outcomes. CONCLUSION: ERPs are effective in reducing length of hospital stay and overall complication rates across surgical specialties. It was not possible to identify individual components that improved outcome. Qualitative synthesis may be more appropriate to investigate the determinants of success.

Successful treatment of plastic bronchitis with low fat diet and subsequent thoracic duct ligation in child with fontan physiology.

Plastic bronchitis is a rare condition characterized by the formation and expectoration of long, branching bronchial casts that develop in the tracheobronchial tree and cause airway obstruction. Plastic bronchitis has become increasingly recognized as a feared complication of the Fontan operation with a mortality of up to 50%. We report an 11 year old boy who developed severe plastic bronchitis following Fontan repair and the successful long-term control of cast formation utilizing a low-fat diet and subsequent thoracic duct ligation.

A comparative study of open, laparoscopic intracorporeal, and laparoscopic assisted low anterior resection and anastomosis in pigs.

This study was done to investigate whether laparoscopic intracorporeal (LI) or laparoscopic assisted (LA) colon resection results in improved anastomotic healing compared with open colon resection (OR). Thirty-six domestic swine were randomly assigned to undergo either LI, LA, or OR of the rectosigmoid. For OR cases, the sigmoid was resected through a midline incision, and a transanal end-to-end stapled anastomosis was constructed with an ILS device. For LA and LI cases, the sigmoid was laparoscopically mobilized and divided distally, using 5 trocar sites. For LA cases, the proximal sigmoid was brought out through an enlarged trocar site and resected; the ILS anvil was secured to the proximal end, and the colon was replaced in the abdominal cavity where the anastomosis was completed by transanal insertion and firing of ILS device. For LI cases, the sigmoid was resected laparoscopically and retrieved through a 33 mm trocar. The ILS anvil was introduced via the same trocar, and the device was laparoscopically secured with two Endoloop (Ethicon Endo-Surgery, Cincinnati, OH) pursestring sutures. The anastomosis was completed the same way as for LA cases. Animals were killed at 7 days, at which time the anastomoses were evaluated by barium enema, bursting pressure, and histologic appearance. There were no radiographic anastomotic leaks. The mean bursting pressure was 205 +/- 65 mmHg for the 13 OR animals, 240 +/- 53 mmHg for 11 LA animals, and 242 +/- 43 mmHg for the 12 LI animals (N.S.). Histologic evaluation for inflammation indicated no significant differences.(ABSTRACT TRUNCATED AT 250 WORDS)

The utility of changes in cardiac weight as an index of drug-induced cardiotoxicity.

The effects of toxic doses of various drugs and of food or water deprivation upon heart weights of mice were evaluated over a four day period to test the validity of the hypothesis that changes in cardiac weights are indicators of cardiotoxicity. Drugs included in the study were actinomycin-D, methotrexate, 5-fluorouracil, adriamycin, daunomycin, N-dimethyladriamycin, N-trifluoroacetyladriamycin-14-valerate, isoproterenol, atropine, and acetylsalicylic acid. Additional groups of mice served as vehicle controls, or were deprived of food or water for the duration of the experiment to control for the anorexia and dehydration accompanying treatment with antineoplastic drugs. Body weights were taken at the start of the experiment (day 0), day 2, and day 4 (just prior to sacrifice). Heart ventricle wet weights were determined immediately, and dry weights after thorough desiccation of the samples. Statistical evaluation of the weights revealed that there were no ventricular weight changes unique to any particular drug, and that decreases in heart weights correlated well with decreases in body weights, thereby reflecting the general toxicities of the drugs, including inanition, and not any specific cardiotoxicities.

Immunohistochemical localization of catechol methyltransferase in normal and cancerous breast tissues of mice and rats.

The immunocytochemical localization of catechol methyltransferase was determined in normal and cancerous breast tissues of inbred female Swiss-Webster mice and in normal, lactating, and cancerous breast tissues of inbred Sprague-Dawley rats. The enzyme was found to be cytoplasmically localized in ductal epithelial cells of secretory tubules in both inactive and stimulated mammary glands, in endothelial cells lining blood vessels, in fibroblasts in the connective tissue matrix, and, especially, in tumor cells. Adipose cells were nonreactive. The intensity of the immunocytochemical reaction in tumor cells was stronger than that in lactating tissues, which, in turn, was more reactive than that in normal, unstimulated breast tissues.

Cytofluorescence localization of adriamycin-binding sites of cardiac tissue.

A study of the cardiotoxicity induced by adriamycin (ADR) was done on the heart tissue of Sprague-Dawley rats receiving a single intravenous dose (15 mg/kg). Condensed bright orange-red fluoresced chromatin was observed in the nuclei of the myocardial cells of the left ventricle 2 h after drug injection. Just then, the intensity of the fluorescence emission started to decrease until it reached its minimum after 21 days, and disappeared completely 28 days after drug injection.

Local and systemic toxicity resulting from large-volume ip administration of doxorubicin in the rat.

Doxorubicin was administered to rats in a simulated "belly bath" protocol. Fifty milliliters of various concentrations of drug solution was administered ip and was allowed to remain in situ for either 4 or 36 hours prior to removal. Animals were analyzed at 2, 14, and 60 days after treatment. Doses ranged from lethal (75 and 150 micrograms/ml for 4 hours; 12 and 24 micrograms/ml for 36 hours) to nontoxic (5 micrograms/ml for 4 hours). The most common lesion in surviving animals was chronic fibrosing peritonitis. Grossly, there were large volumes of peritoneal fluid in animals exposed to low concentrations (12 and 24 micrograms/ml) for 36 hours, but peritoneal adhesions were the most commonly observed finding when higher concentrations (20-150 micrograms/ml) were used for 4 hours. Commonly observed systemic toxic effects (bone marrow, gastrointestinal tract, and heart) were not seen in this study. Vehicle-treated control animals were negative for all histologic lesions and gross observations.

Adriamycin and daunomycin dose-dependent effects upon contractions of isolated rat myocytes.

Chemotherapeutic usefulness of adriamycin (ADR) and daunomycin (DAU), members of a large class of antitumor anthracyclines, is limited by a unique cardiotoxicity. Using spontaneously beating isolated myocytes from adult rat hearts, we have observed a relatively unique effect of these agents upon maximal contraction times. ADR and DAU induce cessation of beating in an identical dose-dependent manner, while two related anthracyclines exhibit similar inhibitory effects but at different concentrations. Other cytotoxic and antitumor agents tested failed to significantly affect maximal contraction times. This system may be useful in the evaluation of anthracycline analogs for cardiotoxic potential relative to ADR and DAU, as well as in studying the mechanisms of that toxicity. It may also prove useful in selective examination of the direct effects of other agents upon myocardial cells.

Studies of idiopathic intestinal pseudoobstruction. I. Hereditary hollow visceral myopathy: clinical and pathological studies.

A 15-year-old girl with idiopathic intestinal pseudoobstruction is reported. She presented with a long term history of low grade obstructive symptoms, diarrhea, and poor nutrition culminating in an acute obstructive attack leading to exploratory laparotomy. At surgery, the small bowel and colon were dilated, with no mechanical obstruction found. Further evaluation revealed her to have a diffuse disorder of gastrointestinal smooth muscle function involving esophagus, small bowel, and colon. Because medical management failed to control symptom, a gastrojejunostomy was done to bypass a megaduodenum. A third laparotomy was necessary 2 months later because of intractable obstructive symptoms. At this last laparotomy, the afferent loop was taken down and a duodenoplasty and duodenojejunostomy were performed, resulting in clinical improvement. Light and electron microscopic study of the excised small intestine showed marked thinning and degeneraton of the smooth muscle, with replacement by fibrous tissue. The myenteric plexus was normal. This case demonstrates that a degenerative disease of smooth muscle may be one cause of idiopathic intestinal pseudoobstruction.

Human placental aryl hydrocarbon hydroxylase: studies with fluorescence histochemistry.

Tissue sections from human placentas taken at term were studied after time-sequential incubations with benzo[a]pyrene and appropriate cofactors for mixed-function oxidation. Fluorescence microscopy revealed that the enzymic reaction appeared to be most active in the syncytial trophoblast, though the fluorescence of hydroxylated metabolites also could be observed in other placental cell types. A comparison of sections from placentas with very low versus very high aryl hydrocarbon hydroxylase activities provided evidence that induction of the human placental enzyme system with pol7cyclic aromatic hydrocarbons also appeared to occur primarily in the syncytium. When considered in conjunction with previous studies on human placental aryl hydrocarbon hydroxylase, the results tended to indicate that fetal elements of the human placenta contain the necessary electron-transport components for catalysis of mixed-function oxidations of chemical carcinogens and other foreign compounds and that this hydroxtlase system is readily inducible in the same fetal cells by components present in cigarette smoke.