A RETROSPECTIVE STUDY OF DISEASE PROCESSES IN MANED WOLVES (CHRYSOCYON BRACHYURUS) IN NORTH AMERICAN ZOOLOGICAL INSTITUTIONS WITH EMPHASIS ON UROLITHIASIS, INFLAMMATORY BOWEL DISEASE, AND NEOPLASIA.

The objective of this retrospective study is to summarize causes of disease and mortality in maned wolves (Chrysocyon brachyurus) in the North American Species Survival Plan Program (SSP) population. This information will inform and enhance animal health, husbandry, and conservation efforts. Pathology reports were requested from all zoological institutions housing maned wolves between 1930 and 2021. Data were reviewed and cause of death (COD) and reported diseases were summarized and compared by age group, organ system and disease process. One hundred and seventy-one wolves, 82 females and 89 males, met the inclusion criteria. The majority were geriatric (>11 yr; n = 96) or adult (2-11 yr; n = 67). Noninfectious diseases were the most common COD by process (n = 94; 54.9%). For COD by organ system, diseases of the digestive (n = 41) and urinary (n = 34) systems were most common. Neoplasia was the most common noninfectious COD and was the primary COD in 37 wolves (21.6% overall; 39.4% of noninfectious diseases). A total of 145 benign (n = 72) and malignant (n = 73) neoplasms were diagnosed in 44 individuals. Dysgerminoma was the most commonly reported tumor (n = 18), and was the most common neoplastic COD (n = 8). Cystinuria or urolithiasis (n = 71) and gastritis, enteritis, enterocolitis, or colitis (n = 50) (overall and grouped in each system due to presumed common underlying cause) were also common but were more often reported as comorbidities than as COD (n = 16 and n = 11, respectively). Infectious COD were reported in 17 wolves and included babesiosis (n = 4), acanthocephalans (n = 2), and one viral infection. Infections with a variety of bacteria in different organ systems were a COD in eight wolves.

Diagnosis and treatment of a poorly differentiated carcinoma in a male chimpanzee (Pan troglodytes)-A case study.

This study reports the occurrence of a poorly differentiated carcinoma in a captive-born 28 year-old male chimpanzee (Pan troglodytes) who has a familial history of cancer. Pathological findings, surgical interventions, and experimental treatments are discussed.

An Exploratory Randomized Trial of Physical Therapy for the Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Background. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxane treatment and cannot currently be prevented or adequately treated. Physical therapy is often used for neural rehabilitation following injury but has not been evaluated in this patient population. Methods. Single-blind, randomized controlled exploratory study compared standard care to a physical therapy home program (4 visits) throughout adjuvant taxane chemotherapy for stage I-III patients with breast cancer (n = 48). Patient questionnaires and quantitative sensory testing evaluated the treatment effect throughout chemotherapy to 6 months post treatment. Nonrandomized subgroup analysis observed effect of general exercise on sensory preservation comparing those reporting moderate exercise throughout chemotherapy to those that did not exercise regularly. Clinical Trial Registration. clinicaltrials.gov (NCT02239601). Results. The treatment group showed strong trends toward less pain (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.17-1.01; P = .053) and pain decreased over time (OR 0.85, 95% CI 0.76-0.94; P = .002). Pain pressure thresholds (P = .034) and grip dynamometry (P < .001) were improved in the treatment group. For the nonrandomized subgroup analysis, participants reporting general exercise had preservation of vibration (Left P = .001, Right P = .001) and normal heat pain thresholds (Left P = .021, Right P = .039) compared with more sedentary participants. Conclusion. Physical therapy home program may improve CIPN pain in the upper extremity for patients with breast cancer, and general exercise throughout chemotherapy treatment was observed to have correlated to preservation of sensory function. Further research is required to confirm the impact of a physical therapy home program on CIPN symptoms.

RETROSPECTIVE EVALUATION OF HEPATOCELLULAR NEOPLASMS IN NILE LECHWE (KOBUS MEGACEROS) FROM TWO FLORIDA ZOOLOGICAL INSTITUTIONS.

This case series describes hepatocellular neoplasms in 10 Nile lechwe (Kobus megaceros) at two separate zoological institutions in Florida. Histologically, the neoplasms were classified as hepatocellular carcinoma (n = 7), hepatocellular adenoma (n = 2), and hepatobiliary carcinoma (n = 1). Common clinical signs were nonspecific and included thin body condition (n =7), lethargy (n =6), lameness (n =3), and acute recumbency (n =5). Four males and six females were affected, and the mean age at death was 12.7 yr with a range of 4-18 yr. All cases were diagnosed postmortem, and metastasis to various sites, including lung, lymph nodes, and omentum, was found in 40% of cases (n = 4). A single case of hepatocellular carcinoma in a Nile lechwe was described in 2007; however, this is the first reported series of neoplasms in Reduncinae. The pathogenesis behind the development of hepatocellular neoplasms in Nile lechwe has not yet been identified.

Neuropathic Pain in Taxane-Induced Peripheral Neuropathy: Evidence for Exercise in Treatment.

One in 2 Canadians is expected to acquire cancer in their lifetime. Many cancers, including breast, ovarian, and lung cancer, are treated using taxane chemotherapy with curative intent. A major adverse effect with the use of taxane chemotherapeutic agents is taxane-induced peripheral neuropathy (TIPN). Both positive (spontaneous pain, heightened sensitivity with light touch, tingling, itching, burning) and negative (loss of touch, loss of hot/cold sensations, and loss of pain) sensory symptoms can be experienced in the hands and feet and worsen with increasing dose and treatment duration. The pathophysiology of TIPN is still unknown but likely involves multiple mechanisms, including microtubule impairment, neuroimmune and inflammatory changes, ion channel remodeling, impaired mitochondrial function, and genetic predisposition. This review highlights current theories on the pathophysiology for TIPN, the cellular responses thought to maintain neuropathic pain, and the growing support for exercise in the treatment and prevention of peripheral neuropathy and neuropathic pain in both animal and human models.

Quantitative sensory profiles of upper extremity chemotherapy induced peripheral neuropathy: Are there differences in sensory profiles for neuropathic versus nociceptive pain?

Aims: The aim of this study was to define the sensory phenotypes of taxane-induced peripheral neuropathy (TIPN) between neuropathic and nonneuropathic symptoms in a breast cancer population to identify future targets for mechanism-based pain management. Methods: Participants (n = 48) with stage I-III breast cancer. Self-report questionnaires and quantitative sensory testing were used to assess sensory symptoms. The self-report version of the Leeds Assessment for Neuropathic Symptoms and Signs (S-LANSS) divided the groups into neuropathic and nonneuropathic sensory phenotypes. In total, five visits over approximately 8 months assessed each participant from pre-chemotherapy to 6 months post-chemotherapy. Results: Out of 191 nerve assessments, 150 had an S-LANSS <12 defined as "nonneuropathic" and 41 scored >12, which was defined as "neuropathic." Numeric Pain Rating Scale (NPRS) was analyzed based on percentages of those experiencing 1+ pain (graded 1/10 or higher) versus no pain. The neuropathic group had 82.9% of 1+ pain vs. 28.7% in the nonneuropathic group (odds ratio = 7.49; 95% confidence interval, 2.76-20.3; P = 0.001). The neuropathic group reported impaired function on the Disability of the Arm, Shoulder, and Hand (DASH) questionnaire (P = 0.002). Heat pain threshold resulted in statistical differences for the left hand but not the right hand in the neuropathic group (P = 0.05). No other quantitative data on warm/cool or cold or vibration demonstrated sensory differences between the groups. Conclusions: Few differences in sensory profiles measured using quantitative sensory testing (QST) were found. Heat pain thresholds were normalized, possibly suggesting that the neuropathic group retained C-fiber and transient potential vanilloid 1 (TRPV1) function. Participants with neuropathic pain demonstrated significant differences with increased pain and decreased function.

Objectif: Déterminer les phénotypes sensoriels associés à la neuropathie périphérique induite par le taxane dans une population de personnes atteintes de cancer du sein, selon qu'elles présentent des symptômes de neuropathie ou non, afin de déterminer les cibles futures pour la prise en charge de la douleur axée sur les mécanismes.Méthodes: Participants (n = 48) atteints d'un cancer du sein de stade I-III. Des questionnaires d'auto-évaluation et des tests sensoriels quantitatifs ont été utilisés pour évaluer les symptômes sensoriels. À l'aide de la version d'auto-évaluation de l'outil d'évaluation des symptômes et des signes de la douleur neuropathique de Leeds (S-LANSS), les groupes ont été divisés en phénotypes sensoriels avec neuropathie et sans neuropathie. Au total, cinq visites échelonnées sur une période d'environ huit mois ont permis d'évaluer chaque participant avant le début de la chimiothérapie jusqu'à six mois après le début de celle-ci.Résultats: 191 évaluations des nerfs, parmi lesquelles 150 participantes ont obtenu une note < 12 pour le S-LANSS, définis comme «sans neuropathie ¼, tandis que 41 participantes ont obtenu une note > 12, définie comme « avec neuropathie ¼. L'échelle numérique d'évaluation de la douleur a été analysée sur la base du pourcentage de participantes éprouvant une douleur égale ou supérieure à 1 (note de 1/10 ou plus) comparativement à aucune douleur. 82,9 % des patientes du groupe avec neuropathie éprouvaient une douleur égale ou supérieure à 1 comparativement à 28,7% pour le groupe sans neuropathie (RR = 7,49, CI 95 % 2,76-20,3, p = 0,001). Le groupe avec neuropathie a fait état d'une altération du fonctionnement selon le questionnaire DASH (p = 0,002). Des différences significatives ont été observées en ce qui concerne le seuil de la douleur thermique pour la main gauche, mais pas pour la main droite dans le groupe avec neuropathie (p = 0,05). Aucune autre donnée quantitative portant sur la sensibilité aux températures chaudes, tièdes ou froides, ou encore à la vibration, n'a révélé de différences sensorielles entre les groupes.Conclusions: On a constaté peu de différences entre les profils sensoriels mesurés par les tests sensoriels qualitatifs. Les seuils de douleur thermique ont été normalisés, ce qui indique probablement le maintien du fonctionnement des fibres de C et du TRPV1 chez le groupe avec neuropathie. Des différences significatives ont été observées chez les personnes souffrant de douleur neuropathique, dont une augmentation de la douleur et une diminution du fonctionnement.

Should extended blastocyst culture include Day 7?

Extended culture to the blastocyst stage is widely practised, improving embryo selection and promoting single embryo transfer. Selection of useable blastocysts typically occurs on Days 5 and 6 of embryo culture. Embryos not suitable for transfer, biopsy or cryopreservation after Day 6 are routinely discarded. Some embryos develop at a slower rate, however, forming blastocysts on Day 7 of culture. Day 7 blastocysts can be viable, they can be of top morphological grade, euploid and result in a healthy live birth. Since ending culture on Day 6 is current practice in most clinics, viable Day 7 blastocysts may be prematurely discarded. Although Day 7 blastocysts make up only 5% of useable blastocysts, those which are suitable for cryopreservation or biopsy are clinically significant. Overall, culturing embryos an additional day increases the number of useable embryos per IVF cycle and provides further opportunity for pregnancy for patients, especially those who have only a few or low-quality blastocysts.

DISSEMINATED TOXOPLASMOSIS IN A CAPTIVE ADULT DROMEDARY CAMEL (CAMELUS DROMEDARIUS).

An 11-yr-old dromedary camel (Camelus dromedarius) at a zoo in south Florida presented with diarrhea while being treated with enrofloxacin and dexamethasone for a chronic skin condition. Three weeks after initiation of therapy with dexamethasone, the camel developed diarrhea, which worsened despite treatment with antibiotics. The animal became increasingly debilitated, developed hemorrhagic diarrhea, declined rapidly over the next 3 days, and died despite aggressive fluid therapy and supportive care. Histologic examination revealed intralesional protozoal tissue cysts consistent with Toxoplasma gondii in the intestines, lungs, and liver, as well as lymphoid depletion of the spleen suggesting immunosuppression. To the author's knowledge this is the first reported case of disseminated toxoplasmosis that clinically manifested as hemorrhagic enterocolitis in a camel.

Population-based analysis of breast cancer treatment by intrinsic sub-type in Manitoba, Canada.

BACKGROUND: Few descriptive epidemiological studies on the incidence, treatment and survival can accurately reflect a whole population. Manitoba, Canada has an accurate cancer registry, a drug information program network and a breast screening program since 1995. This combined with a stable population provides true population data that can accurately describe the region. METHODS: Using a retrospective cohort design all Breast Cancer cases were obtained from 2004-2010 (N=5399) and grouped by Intrinsic sub-type. Identifiable co-morbidities, prescribed endocrine therapy, staging, surgery, treatment and overall and disease-free survival by intrinsic sub-type were evaluated. RESULTS: Prevalence of Luminal A (41.7%), Luminal B HER2- (15.6%), Luminal B HER2+ (8.9%), Basal-like(10.8%), and HER2+ non-luminal (5.1%) were consistent with other descriptive studies in Canada and Spain. Over this time period the number of lumpectomies increased 1.7% per year (P=0.007). There was a steady increase of 3.4% per year in the use of aromatase inhibitors (P=0.005). Pre-menopausal patients had an increased proportion of HER2+ and Basal-like sub-types. The 7year overall/disease-free survival percentages for Luminal A, Luminal B HER2-, Luminal B HER2+, Basal-like, and HER2+ non-luminal were 88.7%/83.6, 78.2%/73.0, 81.5%/73.3%, 67.7%/63.2%, 70.4%/65.6% respectively. CONCLUSIONS: Reasons for variability in the prevalence of intrinsic sub-type by region is not fully understood. Manitoba is unique due the stability of the population, completeness of the registry and length of breast cancer screening program. Few true population-based studies grouped by intrinsic sub-type are available. IMPACT: Descriptive epidemiological studies guide future research by identifying factors that can affect treatment, recurrence, and survival.

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline.

PURPOSE: To provide recommendations on appropriate use of breast tumor biomarker assay results to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer. METHODS: A literature search and prospectively defined study selection sought systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies published from 2006 through 2014. Outcomes of interest included overall survival and disease-free or recurrence-free survival. Expert panel members used informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 50 relevant studies. One randomized clinical trial and 18 prospective-retrospective studies were found to have evaluated the clinical utility, as defined by the guideline, of specific biomarkers for guiding decisions on the need for adjuvant systemic therapy. No studies that met guideline criteria for clinical utility were found to guide choice of specific treatments or regimens. RECOMMENDATIONS: In addition to estrogen and progesterone receptors and human epidermal growth factor receptor 2, the panel found sufficient evidence of clinical utility for the biomarker assays Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, and urokinase plasminogen activator and plasminogen activator inhibitor type 1 in specific subgroups of breast cancer. No biomarker except for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was found to guide choices of specific treatment regimens. Treatment decisions should also consider disease stage, comorbidities, and patient preferences.

Oocyte mitochondrial deletions and heteroplasmy in a bovine model of ageing and ovarian stimulation.

STUDY HYPOTHESIS: Maternal ageing and ovarian stimulation result in the accumulation of mitochondrial DNA (mtDNA) deletions and heteroplasmy in individual oocytes from a novel bovine model for human assisted reproductive technology (ART). STUDY FINDING: The levels of mtDNA deletions detected in oocytes increased with ovarian ageing. Low levels of mtDNA heteroplasmy were apparent across oocytes and no relationship was identified with respect to ovarian ageing or ovarian stimulation. WHAT IS KNOWN ALREADY: Oocyte quality decreases with ovarian ageing and it is postulated that the mtDNA may have a role in this decline. The impact of ovarian stimulation on oocyte quality is poorly understood. Human studies investigating these effects are often limited by the use of low quality oocytes and embryos, variation in age and ovarian stimulation regimens within the patients studied, as well as genetic and environmental variability. Further, no study has investigated mtDNA heteroplasmy in individual oocytes using next-generation sequencing (NGS), and little is known about whether the oocyte accumulates heteroplasmic mtDNA mutations following ageing or ovarian stimulation. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: A novel bovine model for the effect of stimulation and age in human ART was undertaken using cows generated by somatic cell nuclear transfer (SCNT) from one founder, to produce a homogeneous population with reduced genetic and environmental variability. Oocytes and somatic tissues were collected from young (3 years of age; n = 4 females) and old (10 years of age; n = 5 females) cow clones following multiple natural ovarian cycles, as well as oocytes following multiple mild (FSH only) and standard (based on human a long GnRH agonist protocol) ovarian stimulation cycles. In addition, oocytes were recovered in a natural cycle from naturally conceived cows aged 4-13.5 years (n = 10) to provide a heterogeneous cohort for mtDNA deletion studies. The presence or absence of mtDNA deletions were investigated using long-range PCR in individual oocytes (n = 62). To determine the detection threshold for mtDNA heteroplasmy levels in individual oocytes, a novel NGS methodology was validated; artificial mixtures of the Bos taurus and Bos indicus mitochondrial genome were generated at 1, 2, 5, 15 and 50% ratios to experimentally mimic different levels of heteroplasmy. This NGS methodology was then employed to determine mtDNA heteroplasmy levels in single oocytes (n = 24). Oocyte mtDNA deletion and heteroplasmy data were analysed by binary logistic regression with respect to the effects of ovarian ageing and ovarian stimulation regimens. MAIN RESULTS AND THE ROLE OF CHANCE: Ovarian ageing, but not ovarian stimulation, increased the number of oocytes exhibiting mtDNA deletions (P = 0.04). A minimum mtDNA heteroplasmy level of 2% was validated as a sensitive (97-100%) threshold for variant detection in individual oocytes using NGS. Few mtDNA heteroplasmies were detected across the individual oocytes, with only 15 oocyte-specific variants confined to two of the 24 oocytes studied. There was no relationship (P > 0.05) evident between ovarian ageing or ovarian stimulation and the presence of mtDNA heteroplasmies. LIMITATIONS, REASON FOR CAUTION: The low number of oocytes collected from the natural ovarian cycles limited the analysis. Fertilization and developmental potential of the oocytes was not assessed as the oocytes were destroyed for mtDNA deletion and heteroplasmy analysis. WIDER IMPLICATIONS OF THE FINDINGS: If the findings of this model apply to the human, this study suggests that the incidence of mtDNA deletions increases with age, but not with degree of ovarian stimulation, while the frequency of mtDNA heteroplasmies may be low regardless of ovarian ageing or level of ovarian stimulation. STUDY FUNDING AND COMPETING INTERESTS: Funding was provided by Fertility Associates, the Nurture Foundation for Reproductive Research, the Fertility Society of Australia, and the Auckland Medical Research Foundation. J.C.P. is a shareholder of Fertility Associates and M.P.G. received a fellowship from Fertility Associates. The other authors of this manuscript declare no conflict of interest that could be perceived as prejudicing the impartiality of the reported research.

Assessing embryo quality by combining non-invasive markers: early time-lapse parameters reflect gene expression in associated cumulus cells.

STUDY QUESTION: Are there associations between early time-lapse parameters, expression of candidate embryo viability genes in cumulus cells and embryo quality on Day 5? SUMMARY ANSWER: Early time-lapse parameters correlate to the expression levels of candidate embryo viability genes in cumulus cells but a combined analysis including both time-lapse and candidate gene expression did not identify significant predictors of embryo quality on Day 5. WHAT IS KNOWN ALREADY: Recent evidence suggests that early time-lapse parameters are predictive of blastocyst development. Similarly, a number of candidate genes in cumulus cells have been identified as potential markers of embryo viability. Relationships between time-lapse parameters and candidate gene expression in cumulus cells have not been investigated, and a combined analysis of these markers has not been attempted in relation to embryo quality. STUDY DESIGN, SIZE, DURATION: A total of 78 embryos obtained by ICSI from 22 patients were studied by time-lapse and measurement of cumulus cell gene expression of known markers of embryo viability. Time-lapse and cumulus cell gene expression data were assessed in relation to embryo quality on Day 5. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women, aged 32-40 years, underwent ICSI treatment for male infertility. Embryos with annotatable time to pronuclear breakdown (tPNB), division to two cells (t2C), three cells (t3C), four cells (t4C) and five cells (t5C) were included in the study. Expression levels of 27 candidate genes for embryo viability were measured in 78 associated cumulus cell masses using quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Cumulus cell expression of 11 candidate genes involved in energy metabolism (ATPase, H+ transporting, lysosomal 70 kDa, V1 subunit A (ATP6V1A), NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5 kDa (NDUFA1), lactate dehydrogenase A (LDHA), phosphofructokinase platelet (PFKP) and solute carrier family 2 member 4 (SLC2A4), mitochondrial biogenesis (DNA directed RNA polymerase, mitochondrial (POLRMT) and transcription factor A, mitochondrial (TFAM), signalling (prostaglandin-endoperoxide synthase 2), steroidogenesis (cytochrome P450, family 11, subfamily A, polypeptide 1 (CYP11A1) and cell stress (heat shock 70 kDa protein 5 (HSPA5) and peroxiredoxin 3 (PRDX3)) correlated to time-lapse parameters of the developing embryo, largely for t3C onwards (all P < 0.05). Expression of ATP synthase, H+ transporting, mitochondrial Fo complex, subunit E (ATP51), HSPA5, PFKP, PRDX3 and versican (VCAN) and the parameter t4C were also related to embryo quality on Day 5 (all P < 0.05). Ordinal logistic regression, where gene expression and time-lapse parameters were combined, did not identify any significant predictors of embryo quality on Day 5. LIMITATIONS AND REASON FOR CAUTION: Data are from a preliminary study, limited by a small sample size and using more than one ovarian stimulation protocol. A possible limitation is that each follicle was treated as an independent observation, although a considerable fraction of embryos were from the same patient. WIDER IMPLICATIONS OF THE FINDINGS: Results presented in this study suggest that some of the variation of time-lapse parameters may be related to cumulus cell gene expression and thus the ovarian microenvironment in which the oocyte developed. Although the current study did not identify significant predictors of embryo quality on Day 5, investigation in a larger cohort may determine whether cumulus cell gene expression and time-lapse parameters can be combined to predict embryo quality. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by Fertility Associates Ltd, the Auckland Medical Research Foundation and the University of Auckland. J.C.P. has a 0.5% shareholding in Fertility Associates. All other authors of this manuscript have nothing to declare and no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Consensus statement with recommendations on active surveillance inclusion criteria and definition of progression in men with localized prostate cancer: the critical role of the pathologist.

Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols.

Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG) 94-08.

PURPOSE: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08. METHODS AND MATERIALS: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria. RESULTS: In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation. CONCLUSIONS: High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.

Is advanced age a barrier to effective cancer treatment? The experience of nonagenarians receiving radiation therapy.

AIM: Decision-making about elderly patients is difficult due to the absence of clinical experience or evidence-based results to develop optimal treatment plans. This study aims to determine the tolerability and impact of radiation therapy (RT) when delivered to patients aged >89 years. METHODS: A retrospective review was conducted on all nonagenarian patients (defined as aged 90 years or over) managed with RT between 2005 and 2007. Patients' records were reviewed in regard to their characteristics, the presence of significant medical comorbidities, performance status, management intent, cancer diagnosis and RT modality. Outcome end-points were overall survival and the tolerability of RT (presence of grade 3 or 4 morbidity, hospital admission or treatment interruption). RESULTS: Between 2005 and 2007, 2762 new courses of RT were delivered to patients at the Northern Sydney Cancer Centre, of whom 55, or 2%, were nonagenarians. Median age at treatment was 92 years, with range 90-104 years. A total of 56% were managed with radical intent, 31% had significant comorbidities, 55% had non-skin primary tumors and 78% received linac-based treatment. The mean follow up for survivors was 19.8 months (10.2-41.8 months). RT was well tolerated, with 89% completing planned RT and only 18% requiring interruption. One patient was hospitalized due to RT toxicity. Median survival post-RT was 13.0 months, with 56% of patients alive at 12 months. Survival duration was associated with radical management intent (P= 0.001), cutaneous primary site (P= 0.001) and female gender (P= 0.043). CONCLUSION: Nonagenarian patients receiving treatment had satisfactory tolerability and achieved expected survival rates post-RT.

Evaluation of MDM2, p16, and p53 staining levels as biomarkers of biochemical recurrence following salvage radiation therapy for recurrent prostate cancer.

BACKGROUND AND PURPOSE: The selection of appropriate candidates for salvage radiation therapy (SRT) to address a rising PSA following radical prostatectomy remains challenging. Herein, we provide the first evaluation of the ability of staining levels of the tumor based biomarkers MDM2, p16, and p53 to aid in prediction of biochemical recurrence (BCR) among men undergoing SRT for recurrent prostate cancer. MATERIAL AND METHODS: We identified 152 patients who were treated with SRT between July 1987 and July 2003. Staining levels of MDM2, p16, and p53 in primary tumor samples removed during prostatectomy were detected using monoclonal antibodies and quantified by use of a computer-assisted method. Associations of staining levels with BCR were evaluated using Cox proportional hazards regression models; relative risks (RRs) and 95% confidence intervals (CIs) were estimated. RESULTS: Compared to patients with low staining (≤median) as measured by percentage of cells with nuclear staining, there was no significant difference in risk of BCR for patients with high MDM2 staining (RR: 0.90, 95% CI: 0.57-1.45, P = 0.67), high p16 staining (RR: 0.88, 95% CI: 0.54-1.44, P = 0.62), or high p53 staining (RR: 1.33, 95% CI: 0.84-2.11, P = 0.23) in multivariable analysis. These results were consistent when considering alternate percentile cutpoints and alternate quantifications of biomarker staining. CONCLUSIONS: Our results provide evidence that MDM2, p16, and p53 staining levels are not useful in the prediction of BCR after SRT. As such, these biomarkers are of little clinical use in the selection of appropriate candidates for SRT.

Longitudinal evaluation of microvessel density in survivors vs. nonsurvivors of cardiac pathologic antibody-mediated rejection.

BACKGROUND: Antibody-mediated rejection (AMR) of cardiac allografts is associated with reduced long-term graft survival, but not every patient with AMR develops premature graft failure. The tissue level mechanisms leading to graft failure in some patients with antibody-mediated rejection are poorly characterized. METHODS: We assessed changes in myocardial microvessel density (number of capillaries per unit area) in endomyocardial biopsies over time using whole-slide microscopic imaging of CD34-stained slides and computer-assisted image analysis. Changes were compared among eight heart transplant recipients with multiple episodes of pathologic AMR who died from cardiovascular causes, eight age- and gender-matched patients with pathologic AMR who were still alive at a similar follow-up interval, and six matched controls without AMR or cellular rejection. RESULTS: Microvessel density decreased in the last biopsies (mean 6.52 years post-transplant) from patients with pathologic AMR and cardiovascular mortality compared to their biopsies at 6 and 12 months post-transplant [respectively, -22% (P=.02) and -25% (P=.02)]. A similar decrease was not seen for the other groups. CONCLUSIONS: Significantly reduced myocardial microvessel density does occur in a subset of patients with pathologic AMR who have a worse outcome. These data provide insights into the interplay between AMR, microvascular injury, and clinical outcomes.