Prognostic value of pathological node status after neoadjuvant radiotherapy for rectal cancer.

BACKGROUND: The prognostic value of pathological lymph node status following neoadjuvant radiotherapy (ypN) remains unclear. This study was designed to determine whether ypN status predicted overall survival. METHODS: Patients with locally advanced rectal adenocarcinoma who underwent neoadjuvant long-course radiation between 2005 and 2014 were identified from the National Cancer Data Base, and divided into ypN0, ypN1 and ypN2 groups. The primary outcome was overall survival. Univariable and multivariable analyses were used to determine factors associated with overall survival. RESULTS: Of 12 271 patients, 3713 (30·3 per cent) were found to have residual nodal positivity. A majority of patients with ypN1 (1663 of 2562) and ypN2 (878 of 1151) disease had suspected lymph node-positive disease before neoadjuvant therapy, compared with 3959 of 8558 with ypN0 tumours (P < 0·001). Moreover, ypN1 and ypN2 were significantly associated with ypT3-4 disease (65·7 and 83·0 per cent respectively versus 39·4 per cent for ypN0; P < 0·001). In unadjusted analyses, survival differed significantly between ypN groups (P < 0·001). Five-year survival rates were 81·6, 71·3 and 55·0 per cent for patients with ypN0, ypN1 and ypN2 disease respectively. After adjustment for confounding variables, ypN1 and ypN2 remained independently associated with overall survival: hazard ratio (HR) 1·61 (95 per cent c.i. 1·46 to 1·77) and 2·63 (2·34 to 2·95) respectively (P < 0·001). Overall survival was significantly longer in patients with ypN1-2 combined with ypT0-2 status than among those with ypT3-4 tumours even with ypN0 status (P = 0·031). Clinical nodal status before neoadjuvant therapy was not significantly associated with overall survival (HR 1·05, 0·97 to 1·13; P = 0·259). CONCLUSION: Both ypT and ypN status is of prognostic significance following neoadjuvant therapy for rectal cancer.

A systematic review of minimally invasive surgery for retrorectal tumors.

Retrorectal tumors are rare tumors that require resection for symptoms, malignancy and potential malignant transformation. Traditional approaches have included laparotomy, perineal excision or a combination. Multiple minimally invasive techniques are available which have the potential to minimize morbidity and enhance recovery. We performed a systematic review of the literature to determine the feasibility and surgical outcomes of retrorectal tumors approached using minimally invasive surgical techniques. Publications in which adult patients (≥ 18 years) had a minimally invasive approach (laparoscopic or robotic) for resection of a primary retrorectal tumor were included. Data were collected on approach, preoperative investigation, size and sacral level of the tumor, operating time, length of stay, perioperative complications, margins and recurrence. Thirty-five articles which included a total of 82 patients met the inclusion criteria. The majority of patients were female (n = 65; 79.2%), with a mean age of 41.7 years (range 18-89 years). Seventy-three patients (89.0%) underwent laparoscopic or combined laparoscopic-perineal resection, and 9 (10.8%) had a robotic approach. The conversion rate was 5.5%. The overall 30-day morbidity rate was 15.7%, including 1 intraoperative rectal injury (1.2%). Ninety-five percent (n = 78) of the retrorectal tumors were benign. Median length of stay was 4 days for both laparoscopic and robotic groups, with ranges of 1-8 and 2-10 days, respectively. No tumor recurrence was noted during follow-up [median 28 months (range 5-71 months)]. A minimally invasive approach for the resection of retrorectal tumors is feasible in selected patients. Careful patient selection is necessary to avoid incomplete resection and higher morbidity than traditional approaches.

Canine Circovirus 1 (CaCV-1) and Canine Parvovirus 2 (CPV-2): Recurrent Dual Infections in a Papillon Breeding Colony.

Recurrent outbreaks of sudden death and bloody diarrhea were reported in March 2013 and February 2014 in a breeding colony of Papillon dogs. During the first outbreak, 1 adult dog and 2 eight-month-old puppies died. During the second outbreak, 2 ten-week-old puppies died. One puppy from the first outbreak and 2 puppies from the second outbreak were examined at necropsy. Histologically, all 3 puppies had severe segmental crypt necrosis of the small intestine and marked lymphoid follicle depletion in the spleen and Peyer's patches. Real-time (RT) polymerase chain reaction (PCR) demonstrated abundant canine parvovirus (CPV-2) DNA (Ct<15) in the affected small intestine, and immunohistochemistry detected large amounts of CPV-2 antigen in intestinal crypt epithelium and Kupffer cells but few positive macrophages in lymphoid organs. All puppies had marked sinusoidal histiocytosis and multifocal granulomatous inflammation in mesenteric lymph nodes and spleen, prompting additional RT-PCR testing for canine circovirus 1 (CaCV-1). Very high levels of CaCV-1 DNA (Ct<13) were detected in small intestine, lymph nodes, and spleen. In situ hybridization for CaCV-1 detected rare positive nuclei of regenerating crypt epithelium but abundant amounts of CaCV-1 nucleic acid in the cytoplasm and nuclei of histiocytes in all lymphoid tissues, including granulomatous inflammatory foci and hepatic Kupffer cells. Significant levels of CaCV-1 DNA were detected in blood and serum (Ct as low as 13) but not feces from 3 surviving dogs at 2 months or 1 year after the outbreak, respectively. We hypothesize that CPV-2 infection predisposed dogs to CaCV-1 infection and ultimately resulted in more severe clinical disease.

Distinguishing Intestinal Lymphoma From Inflammatory Bowel Disease in Canine Duodenal Endoscopic Biopsy Samples.

Inflammatory bowel disease (IBD) and intestinal lymphoma are intestinal disorders in dogs, both causing similar chronic digestive signs, although with a different prognosis and different treatment requirements. Differentiation between these 2 conditions is based on histopathologic evaluation of intestinal biopsies. However, an accurate diagnosis is often difficult based on histology alone, especially when only endoscopic biopsies are available to differentiate IBD from enteropathy-associated T-cell lymphoma (EATL) type 2, a small cell lymphoma. The purpose of this study was to evaluate the utility of histopathology; immunohistochemistry (IHC) for CD3, CD20, and Ki-67; and polymerase chain reaction (PCR) for antigen receptor rearrangement (T-cell clonality) in the differential diagnosis of severe IBD vs intestinal lymphoma. Endoscopic biopsies from 32 dogs with severe IBD or intestinal lymphoma were evaluated. The original diagnosis was based on microscopic examination of hematoxylin and eosin (HE)-stained sections alone followed by a second evaluation using morphology in association with IHC for CD3 and CD20 and a third evaluation using PCR for clonality. Our results show that, in contrast to feline intestinal lymphomas, 6 of 8 canine small intestinal lymphomas were EATL type 1 (large cell) lymphomas. EATL type 2 was uncommon. Regardless, in dogs, intraepithelial lymphocytes were not an important diagnostic feature to differentiate IBD from EATL as confirmed by PCR. EATL type 1 had a significantly higher Ki-67 index than did EATL type 2 or IBD cases. Based on the results of this study, a stepwise diagnostic approach using histology as the first step, followed by immunophenotyping and determining the Ki67 index and finally PCR for clonality, improves the accuracy of distinguishing intestinal lymphoma from IBD in dogs.

MRI in radiotherapy - Is it time to rethink the current radiotherapy fixation solutions?

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Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior.

Currently, prognostic and therapeutic determinations for canine cutaneous mast cell tumors (MCTs) are primarily based on histologic grade. However, the use of different grading systems by veterinary pathologists and institutional modifications make the prognostic value of histologic grading highly questionable. To evaluate the consistency of microscopic grading among veterinary pathologists and the prognostic significance of the Patnaik grading system, 95 cutaneous MCTs from 95 dogs were graded in a blinded study by 28 veterinary pathologists from 16 institutions. Concordance among veterinary pathologists was 75% for the diagnosis of grade 3 MCTs and less than 64% for the diagnosis of grade 1 and 2 MCTs. To improve concordance among pathologists and to provide better prognostic significance, a 2-tier histologic grading system was devised. The diagnosis of high-grade MCTs is based on the presence of any one of the following criteria: at least 7 mitotic figures in 10 high-power fields (hpf); at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; at least 3 bizarre nuclei in 10 hpf; karyomegaly (ie, nuclear diameters of at least 10% of neoplastic cells vary by at least two-fold). Fields with the highest mitotic activity or with the highest degree of anisokaryosis were selected to assess the different parameters. According to the novel grading system, high-grade MCTs were significantly associated with shorter time to metastasis or new tumor development, and with shorter survival time. The median survival time was less than 4 months for high-grade MCTs but more than 2 years for low-grade MCTs.

Characterization of acute 4,4'-methylene dianiline hepatotoxicity in the rat.

Methylene dianiline (DDM) is a chemical intermediate in the production of isocyanates and other industrial chemicals, and it is hepatotoxic in humans. The acute hepatotoxicity of orally administered DDM was characterized in rats. Rats receiving DDM (25-225 mg/kg, per os) demonstrated a dose-dependent elevation in serum alanine aminotransferase activity, g-glutamyltransferase activity, and serum bilirubin concentration. DDM also caused a decrease in bile flow and an elevation in liver weight. Significant changes in these markers of liver injury occurred between 8 and 12 hr after a single, oral administration of DDM. Histologically, DDM caused multifocal, necrotizing hepatitis with neutrophil infiltration. Changes in the portal regions consisted of bile ductular necrosis, portal edema, neutrophil infiltration, mild fibrin exudation, and segmental necrotizing vasculitis. The role of cytochrome P450 monooxygenase (MO)-mediated metabolism in DDM hepatotoxicity was evaluated using the MO inhibitors, aminobenzotriazole and SKF-525A and the MO inducers phenobarbital and beta-naphthoflavone. Aminobenzotriazole provided protection from DDM-induced hepatotoxicity, whereas SKF-525A had no effect. The effect of phenobarbital pretreatment depended on the dose of DDM administered. At a dose of DDM that produced a maximal hepatotoxic response, phenobarbital did not influence hepatotoxicity. However, phenobarbital pretreatment provided protection against the hepatotoxic effects of a lower dose of DDM. beta-naphthoflavone pretreatment had a more modest effect on DDM-induced hepatic insult. These results demonstrate that DDM causes acute hepatotoxicity in the rat that is dose and time dependent. Results using inducers and inhibitors of MO suggest that DDM requires bioactivation to exert toxicity; however, the relationship between metabolism and toxicity may be complex.

Characterization of eae+ Escherichia coli isolated from healthy and diarrheic calves.

Strains of Escherichia coli from 101 healthy and 114 diarrheic calves were screened by PCR for the eae (intimin) gene and Shiga toxin genes (stx). Each eae+ and eae/stx+ strain was examined for antimicrobial susceptibility, enterohemolysin activity, and the somatic O antigen was determined. An immunoassay was used to detect Shiga toxin antigens for the eae/stx+ E. coli. Significantly more (p = 0.005) of the healthy calves carried eae+ and eae/stx+ E. coli in their feces when compared to strains from diarrheic calves. Moreover, Shiga toxin antigens were detected significantly more (p = 0.001) often among the eae/stx+ strains from healthy calves when compared to eae/stx+ strains from diarrheic calves. However, significantly more (p = 0.001) of the eae+ and eae/stx+ strains from diarrheic calves were resistant to at least one of the antimicrobials tested, and the strains from diarrheic calves had a significantly (p = 0.05) higher rate of antimicrobial resistance to at least two different antimicrobial classes. No significant difference (p> or =0.05) was detected among the eae+ and eae/stx+ strains from healthy and diarrheic calves for enterohemolysin production. Serogroups O-negative, O5, O26, and O111 were predominate among both healthy and diarrheic calves.

Prevalence of teaching apical patency and various instrumentation and obturation techniques in United States dental schools.

Maintaining an open apex beyond the apical constriction with an endodontic file during canal instrumentation is a concept that has been advocated by several authors and clinicians. To ascertain the prevalence of teaching the patency concept as well as various instrumentation and obturation techniques in the United States dental schools, a survey was conducted. Forty-eight out of a total of 53 dental schools (91%) responded to the survey. Results indicate that 50% of the schools surveyed teach the concept of patency to their undergraduates or graduates or both; 83% teach a step-back instrumentation technique; and 89.6% teach lateral condensation of gutta percha as their primary obturation technique.

A comparative study of apical leakage with endodontic implant stabilizers.

The apical seals of 75 extracted teeth that were treated with three methods of endodontic implant stabilizers were compared with the seals of 25 teeth filled with silver cones and 25 teeth filled with laterally condensed gutta-percha. Apical leakage was measured with the use of methylene blue dye solution. Statistical analysis showed that there were significant differences between the apical leakage obtained from the teeth treated with endodontic implant stabilizers and those teeth filled with silver cones and with laterally condensed gutta-percha.

Is endodontics losing its identity in our dental schools?

The program presented at the Section on Endodontics of the American Association of Dental Schools Annual Meeting in March 1990 in Cincinnati focused on the issue of identity loss of endodontics in dental schools. Program participants, comprising representatives from various institutions with different educational backgrounds and experiences, were posed a series of questions on the topic. Key issues were discussed and perspectives on the future of the specialty were presented relative to dental school reorganizations and restructuring.

Toleration of high concentrations of dietary zinc by mink.

Adult and kit male and female natural dark ranch mink (Mustela vison) were fed a conventional diet supplemented with 0, 500, 1,000, or 1,500 ppm zinc, as ZnSO4.7H2O, for 144 days. No marked adverse effects were observed in feed consumption, body weight gains, hematologic parameters, fur quality, or survival. Zinc concentrations in liver, kidney, and pancreas of the mink increased in direct proportion to the zinc content of the diet. Histopathologic examination of the livers, kidneys, and pancreata revealed no lesions indicative of zinc toxicosis. The results indicate that mink can tolerate at least 1,500 ppm dietary zinc, as ZnSO4.7H2O, for several months without apparent adverse effects.

Immunohistochemical diagnosis of eastern equine encephalomyelitis.

An immunohistochemical (IHC) assay was developed for the detection of eastern equine encephalomyelitis (EEE) virus antigen in formalin-fixed, paraffin-embedded tissues. All cases of EEE diagnosed at the Michigan State University Animal Health Diagnostic Laboratory from 1991 through 1994 were evaluated. The diagnosis was based on histopathologic examination of the brain and confirmatory virus, isolation. Sections of cerebrum from 26 equids and 5 birds were assessed by IHC. Histologically normal brain tissues from 2 horses and 1 pheasant and brain tissues from 2 cases of equine neurologic disease with diagnoses other than EEE served as negative controls. The IHC assay was based on standard streptavidin-biotin technology, using a commercially available kit and a monospecific polyclonal primary antibody preparation derived from murine ascitic fluid. Nineteen of 20 equids and all 5 birds positive by histopathology and virus isolation were positive for EEE virus antigen by IHC. Three equids with histologic lesions compatible with a diagnosis of EEE but negative by virus isolation also were negative for virus antigen by IHC. In 3 other equids, histopathology and IHC were positive for EEE, but virus isolation was not attempted because of contamination of the brain specimen. The IHC assay of formalin-fixed, paraffin-embedded brain tissues for EEE virus antigen is a rapid, effective test for confirming a histopathologic diagnosis of EEE, and assay results correlate well with virus isolation results.

Biopsy mineral analysis by inductively coupled plasma-atomic emission spectroscopy with ultrasonic nebulization.

Liver copper concentration is generally considered the best measure of copper nutritional status in cattle. Ultrasonic nebulization in conjunction with inductively coupled plasma-atomic emission spectroscopy (ICP-AES) was investigated as a method to provide adequate sensitivity to allow accurate simultaneous measurement of copper and 14 additional elements from needle biopsy samples. The element concentration frequency distribution profile of 12 elements routinely present in liver was compared to profiles of the elements in fat, muscle, vena cava, kidney, and clotted blood. The profiles could be used to confirm the authenticity of the liver biopsy sample. Element concentrations in biopsy samples taken in triplicate from the five lobes of a bovine liver were compared to those from triplicate wedge sections taken adjacent to the biopsies and analyzed by conventional ICP-AES. Precision between biopsies was equal to or better than precision between wedge samples. Some element concentrations determined by the biopsy procedure differed statistically from those determined by the wedge procedure, but differences were not sufficient to influence clinical interpretation of data.

Otitis media in preweaned Holstein dairy calves in Michigan due to Mycoplasma bovis.

Mycoplasma bovis was isolated from the tympanic bullae of dairy calves with an exudative otitis media. The history, clinical signs, gross and histologic lesions, and bacteriologic findings are described for 5 preweaned Holstein calves with otitis media from a 600-cow dairy in Michigan. Clinical findings consisted of unilateral or bilateral ear droop, epiphora, head tilt, and recumbency in severely affected calves. Postmortem examination revealed unilateral or bilateral fibrinosuppurative to caseous exudate in the tympanic bullae. Histologically, a marked fibrinosuppurative to caseous exudate filled the tympanic air spaces. The partially ulcerated tympanic mucosa was markedly thickened with mononuclear cell infiltration and proliferation of fibrous connective tissue. Bone remodeling and periosteal hyperostosis were present in some osseous septa. Mycoplasma bovis was isolated from the tympanic bullae of all 5 calves and from the lungs of 2 calves and the frontal sinus of 1 calf. Mycoplasma bovis was isolated at > 100,000 colony forming units/ml from the bulk milk tank of the farm of origin. The isolation of M. bovis from the bulk milk tank, indicating subclinical mycoplasmal mastitis coupled with the feeding of waste milk from mastitic cows to calves is suggestive of a possible source of the infection resulting in otitis media in preweaned dairy calves.

A mechanical auxiliary ventricle. Histologic responses to long-term, intermittent pumping in calves.

The mechanical auxiliary ventricle (MAV) is an avalvular, inseries left ventricular assist device (LVAD) comprised of a 60 cc Biomer blood pump implanted in the descending thoracic aorta, a percutaneous access device (PAD), and an external pneumatic drive. In four calves the MAV was implanted and activated intermittently for 192, 249, 423, and 785 days, respectively; no anticoagulants were administered. When the animals were killed, the implants were retrieved, and autopsies, including gross, light microscopic, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) examinations, were performed. The MAV was securely attached to the aorta in every animal. A thin, even smooth, pseudoneointimal layer (PNI) contiguous with the aorta at the level of the suture line covered the MAV's blood-contacting surface. Areas of calcification beneath the PNI, expected in growing animals with implanted pumping devices, were noted. At autopsy there was no evidence of thrombosis or infection in the regions of the blood pump or the PAD. These findings confirm the calves' benign histologic response to the MAV, and together with the results of hematologic and biochemiccal studies, and bench tests of system components being reported elsewhere, indicate the system's readiness for limited clinical investigation in selected patients with chronic congestive failure.

Iron toxicity in neonatal foals.

Newborn Shetland foals died of acute hepatic failure following oral administration of approximately 16 mg/kg body weight ferrous fumarate. Lesions in these foals were indistinguishable from lesions in foals given an oral digestive inoculant containing ferrous fumarate and were also similar to the syndrome characterised as 'toxic hepatopathy' in foals in the United States in 1983. We conclude that foals are susceptible to toxicity from low doses of iron compounds in the first few days of life. Vitamin E and selenium deficiency may contribute to this susceptibility.

Effect of 131I-induced hypothyroidism on indices of reproductive function in adult male dogs.

Hypothyroidism has been cited as a cause of infertility, abnormal semen quality, and poor libido in people and animals. The purpose of this study was to evaluate the effect of hypothyroidism on variables indicative of reproductive function in adult male dogs. Nine normal dogs were randomly assigned to 2 groups. Hypothyroidism was induced with 131I in 6 dogs. Three dogs remained untreated, normal, and euthyroid. Thyroid hormone concentrations, body weight, clinical signs, and reproductive function were determined for each dog every 3 months for 2 years. Reproductive function was assessed by determining daily sperm output, total scrotal width, spermatozoal motility and morphology, libido, and serum testosterone and luteinizing hormone concentration responses to exogenous gonadotropin-releasing hormone. The 131I-treated dogs developed clinical and laboratory signs of hypothyroidism. In the hypothyroid dogs, serum concentrations of thyroid hormones were consistently below the reference range and were significantly lower than that in the euthyroid dogs. There was no difference in reproductive function between the hypothyroid and euthyroid dogs. The results of this study show that 131I-induced hypothyroidism does not affect indices of reproductive function in adult male dogs.