Serum LAMC2 enhances the prognostic value of a multi-parametric panel in non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) lacks reliable serological biomarkers for predicting patients' survival and response to treatment. The present study examined the capability of serum LAMC2 and four known tumour markers for disease prognosis and patients' risk stratification. METHODS: LAMC2, CA 125, CEA, CYFRA 21-1 and SCC levels were retrospectively measured in sera obtained from 127 patients diagnosed with NSCLC by commercial immunoassays. Prognostic performance of the markers was compared with established clinical parameters and multivariate models were constructed to assess the prognostic complementarity of variables. RESULTS: LAMC2 showed significant prognostic ability for overall survival (hazards ratio: 1.607, 95% confidence interval: 1.268-2.037, P<0.0001) in the full cohort. LAMC2 and CYFRA 21-1 combination enhanced prognostic models based on common clinical parameters (c-index: 0.81 vs 0.72, P=0.00018), further enabling stratification of patients into clear risk groups. A bootstrap-based cross-validation analysis was supportive of our findings. Combination of LAMC2 and CA 125 showed similar performance. CONCLUSIONS: Our preliminary study proposes LAMC2 as a novel NSCLC prognostic factor. LAMC2 combined with CA 125 and CYFRA 21-1 could aid in clinical prediction of NSCLC patients' overall survival and inform clinical practice. Larger studies are necessary to unravel LAMC2's full potential as a new NSCLC biomarker.

Predictor Biomarkers of Nonelective Hospital Readmission and Mortality in Malnourished Hospitalized Older Adults.

BACKGROUND: 90-day mortality and rehospitalizations are important hospital quality metrics. Biomarkers that predict these outcomes among malnourished hospitalized patients could identify those at risk and help direct care plans. OBJECTIVES: To identify biomarkers that predict 90-day (primary) and 30-day (secondary) mortality or nonelective rehospitalization. DESIGN AND PARTICIPANTS: An analysis of the ability of biomarkers to predict 90- and 30-day mortality and rehospitalization among malnourished hospitalized patients. SETTING: 52 blood biomarkers were measured in 193 participants in NOURISH, a randomized trial that determined the effects of a nutritional supplement on 90-day readmission and death in patients >65 years. Composite outcomes were defined as readmission or death over 90-days or 30-days. Univariate Cox Proportional Hazards models were used to select best predictors of outcomes. Markers with the strongest association were included in multivariate stepwise regression. Final model of hospital readmission or death was derived using stepwise selection. MEASUREMENTS: Nutritional, inflammatory, hormonal and muscle biomarkers. RESULTS: Mean age was 76 years, 51% were men. In univariate models, 10 biomarkers were significantly associated with 90-day outcomes and 4 biomarkers with 30-day outcomes. In multivariate stepwise selection, glutamate, hydroxyproline, tau-methylhistidine levels, and sex were associated with death and readmission within 90-days. In stepwise selection, age-adjusted model that included sex and these 3 amino-acids demonstrated moderate discriminating ability over 90-days (C-statistic 0.68 (95%CI 0.61, 0.75); age-adjusted model that included sex, hydroxyproline and Charlson Comorbidity Index was predictive of 30-day outcomes (C-statistic 0.76 (95%CI 0.68, 0.85). CONCLUSIONS: Baseline glutamate, hydroxyproline, and tau-methylhistidine levels, along with sex and age, predict risk of 90-day mortality and nonelective readmission in malnourished hospitalized older patients. This biomarker set should be further validated in prospective studies and could be useful in prognostication of malnourished hospitalized patients and guiding in-hospital care.

Changes in plasma TIMP-1 levels after resection for primary colorectal cancer.

BACKGROUND: Increased plasma levels of tissue inhibitor of metalloproteinases (TIMP-1) are associated with poor outcome in colorectal cancer (CRC), however postoperative changes in plasma TIMP-1 levels after resections for CRC have not been thoroughly evaluated. MATERIALS AND METHODS: Plasma samples were collected from 45 patients with primary CRC, preoperatively, 2 hours after surgery, and at days 1, 2, 7, 28, 45, 60, 75 and 90 after surgery. TIMP-1 and CEA levels were determined using the ARCHITECT Immunoanalyzer. RESULTS: Postoperatively, the mean (geometric) TIMP-1 level increased and had a maximum level at day 1 (p < 0.0001). The mean TIMP-1 level then declined to a level at day 90 similar to the mean preoperative level. CONCLUSION: A mean decline in plasma TIMP-1 levels was not observed within 90 days. However, individual significant reductions of plasma TIMP-1 levels did occur within 28-60 days postoperatively.

Assessment of the biological variation of plasma tissue inhibitor of metalloproteinases-1.

BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) measurements in plasma may be useful for the early detection and prognosis of colorectal cancer (CRC). Data on analytical performance and normal intra- and interindividual biological variation are required in order to interpret the utility of TIMP-1 in CRC. The aim of this study was to establish the biological and analytical variation of plasma TIMP-1 in volunteers. MATERIAL AND METHODS: Three separate studies were undertaken. 1: Plasma was collected from 23 volunteers 6 times within a 3-week period, first in September 2004 (round [R] 1), then repeated in May 2005 (R2) and May 2006 (R3) in the same group of individuals. TIMP-1 levels were determined by the MAC15 ELISA assay and with the Abbott ARCHITECT i2000 Immunoanalyzer. 2: Circadian variation was evaluated in plasma collected 7 times within a 24-hour period (n=16). 3: Effects of physical exercise were evaluated in plasma collected before and after bicycling (n=14). In studies 2 and 3 TIMP-1 levels were determined with the MAC15 ELISA assay only. RESULTS: A significant correlation between TIMP-1 MAC15 and ARCHITECT i2000 was shown (rs=0.78, p<0.002), with consistently higher levels being detected by the ARCHITECT i2000. Median levels of TIMP-1 (ARCHITECT) at 8 a.m. in each round were 74.9 ng/mL (range 65.7-89.9) (R1), 87.3 ng/mL (range 72.7-127.9) (R2), and 81.9 ng/mL (range 66.8-113.6) (R3). The within-subject variation was 10.7%, the variation between rounds was 7.4%, and the intraclass correlation was 46.2%. Comparison between the 3 rounds and time of collection showed that TIMP-1 values decreased by 11% after storage for more than 16 months (p=0.0002). A systematic circadian variation in plasma TIMP-1 levels was not observed (p=0.17). No significant variation of plasma TIMP-1 was found in relation to physical exercise (p=0.92 [global test]). CONCLUSION: Levels of plasma TIMP-1 in volunteers show limited circadian, day-to-day, week-to-week and season-to-season variation. In addition, physical exercise has no impact on plasma TIMP-1 levels. Possible storage-dependent decreases in plasma TIMP-1 levels warrant further investigation.

Metastatic renal cell carcinoma presenting as a circumscribed orbital mass.

PURPOSE: To report a case of renal cell carcinoma presenting as a well-circumscribed orbital tumor. METHODS: Retrospective interventional case report. RESULTS: A 60-year-old woman presented with proptosis of the left eye. Imaging showed a well circumscribed tumor in the region of the medial rectus muscle. Excision biopsy revealed a diagnosis of metastatic renal cell carcinoma that was confirmed on abdominal imaging. CONCLUSIONS: Renal cell carcinoma can rarely present as a well-circumscribed orbital mass and should be included in the differential diagnosis of such lesions.

Outcome and prognostic factors following curative-intent surgery for oral tumours in dogs: 234 cases (2004 to 2014).

OBJECTIVES: To describe the long-term outcomes and prognostic factors associated with curative-intent surgery for oral tumours in a large series of dogs. METHODS: Retrospective review of records for dogs with oral tumours treated with curative-intent surgery. Data collected included signalment, weight, surgical procedure, lymph node staging results, computed tomography results, tumour size, histopathology results including margin evaluation, complications, adjunctive therapies, local recurrence or metastasis, date and cause of death and owner satisfaction. RESULTS: Median cause-specific survival was shortest for malignant melanoma (206 days) and osteosarcoma (209 days). Local recurrence rate was highest for fibrosarcoma (54·2%) and distant metastatic rate was highest for malignant melanoma (30%). Curative-intent surgery resulted in complete surgical margins in 85·2% of cases. CLINICAL SIGNIFICANCE: Results suggest tumour type, completeness of excision, tumour size, and age may affect disease-free interval and cause-specific survival. Fibrosarcoma had a higher risk of recurrence compared to other tumour types.

Hemifacial Microsomia in a Cat.

A 7-month-old domestic medium hair cat presented with facial asymmetry affecting the bony and soft tissue structures of the right side of the head including the maxilla, nose, eye and pinna of the ear. Additionally, neurological dysfunction of the facial and vestibulocochlear nerves on the affected side was present. A congenital malformation affecting the first and second embryologic pharyngeal arches was suspected. This is the first case of hemifacial microsomia of likely congenital origin reported in a cat.

Testosterone: activation or organization of spatial cognition?

Previous studies in animals have revealed effects of both prenatal and current testosterone on brain organization and behavior. However, it is unclear how these effects translate to the human brain. Here, we refine previous procedures to clarify the relative contribution of prenatal versus current testosterone indices to cognitive function. Sixty-nine subjects performed four computerized tasks measuring mental rotation, targeting, figure-disembedding and perceptual discrimination. Using stepwise regression analyses, performance was related to free testosterone assayed in saliva samples and to second-to-fourth finger length ratios (2D:4D), a putative index of prenatal testosterone exposure. The exclusive predictor for mental rotation was found to be sex, while 2D:4D was found to be the sole predictor of targeting, exhibiting a curvilinear relation, and figure-disembedding performance, showing a linear relation. These findings suggest a substantial role for prenatal testosterone but not current testosterone in determining cognitive performance.

Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer.

PURPOSE: The goal of the computer program Adjuvant! is to allow health professionals and their patients with early breast cancer to make more informed decisions about adjuvant therapy. METHODS: Actuarial analysis was used to project outcomes of patients with and without adjuvant therapy based on estimates of prognosis largely derived from Surveillance, Epidemiology, and End-Results data and estimates of the efficacy of adjuvant therapy based on the 1998 overviews of randomized trials of adjuvant therapy. These estimates can be refined using the Prognostic Factor Impact Calculator, which uses a Bayesian method to make adjustments based on relative risks conferred and prevalence of positive test results. RESULTS: From the entries of patient information (age, menopausal status, comorbidity estimate) and tumor staging and characteristics (tumor size, number of positive axillary nodes, estrogen receptor status), baseline prognostic estimates are made. Estimates for the efficacy of endocrine therapy (5 years of tamoxifen) and of polychemotherapy (cyclophosphamide/methotrexate/fluorouracil-like regimens, or anthracycline-based therapy, or therapy based on both an anthracycline and a taxane) can then be used to project outcomes presented in both numerical and graphical formats. Outcomes for overall survival and disease-free survival and the improvement seen in clinical trials, are reasonably modeled by Adjuvant!, although an ideal validation for all patient subsets with all treatment options is not possible. Additional speculative estimates of years of remaining life expectancy and long-term survival curves can also be produced. Help files supply general information about breast cancer. The program's Internet links supply national treatment guidelines, cooperative group trial options, and other related information. CONCLUSION: The computer program Adjuvant! can play practical and educational roles in clinical settings.

Toxicologic evaluation of ofloxacin.

Results of studies conducted to characterize local, systemic, reproductive, and mutagenic effects indicate that ofloxacin is well tolerated within reasonable multiples of the intended clinical dose. Quinolone-associated arthropathic effects characterized by blister, erosion, and increased synovial fluid occurred in rats and dogs and appeared to be both age- and dose-related. Maternal toxicity and embryotoxicity were noted, but there was no teratogenicity in rats or rabbits. There was no impairment of fertility, and no adverse effects on late fetal development, labor, delivery, lactation, neonatal viability, or growth of offspring occurred. Target-organ studies revealed no evidence of ocular toxicity in rats, nephrotoxicity in rabbits, or antigenicity or ototoxicity in guinea pigs. Overall, the toxicologic evaluation of ofloxacin has shown this compound to be a drug with a low toxicologic potential.

Survival of rabbit limbal stem cell allografts.

Failure of a specialized population of corneal epithelial stem cells found in the peripheral cornea and limbus results in ocular surface disease, which may be amenable to treatment by transplantation of limbal tissue. This study was designed to investigate donor limbal stem cell allograft survival in rabbits with ocular surface disease. Rabbits underwent corneal epithelial debridement and limbal ablation to induce ocular surface disease and were then treated by limbal stem cell allotransplantation, by allotransplantation plus topical steroid, or by topical steroid only (n = 7 for each group). Donors and recipients were sex mismatched. Recipients were followed for up to 5 months. Outcome was assessed by daily slit-lamp examination, weekly impression cytology and photographic record, end-point sex chromatin and fluorescent cell tracer analyses, histology, and immunohistochemistry. In no case was a completely normal ocular surface regained, but some animals that received grafts plus corticosteroids fared best by all criteria used. In the absence of immunosuppression, graft hemorrhagia (believed to be a manifestation of graft rejection) occurred within the first month, the cornea became resurfaced with conjunctiva-derived cells, and no donor cells survived centrally in the long term. Topical corticosteroids reduced the number and severity of these episodes significantly, and were associated with survival of some donor-derived cells in the central cornea of some grafted animals. Thus, rabbit limbal stem cell allografts appeared to undergo rejection, which could be modified by immunosuppression, but useful regeneration of the ocular surface occurred only where rejection was circumvented.

Neuropathology of "spinning syndrome" induced by prenatal intoxication with a PCB in mice.

A striking motor dysfunction, "spinning syndrome," developed with a high frequency in weaning mice whose dams received oral 3,4,3',4'-tetrachlorobiphenyl (4-CB) during gestation (day 10 through day 16). The syndrome is permanent and is characterized by swift circling movements sustained in one direction at a minimal rate of 40 turns/min (usually 50 to 150 turns/min), restlessness, and hyperkinesia. Twenty-four spinners and 4-CB nonspinners and age-matched controls were subjected to histopathologic, histofluorescent, histochemical, and electron microscopic studies. The most reliable histopathologic marker for prenatal 4-CB injury to the CNS is the presence of cylindrical CNS peninsulas (CCPs) in the spinal and cranial nerve roots. The CCPs consist of either CNS-type myelinated fibers, unmyelinated fibers, or astroglial bundles in varying proportions, and are enclosed by a basement membrane. The CCPs are also observed in 4-CB nonspinners but in none of 12 controls studied. A selective defect in synaptogenesis induced prenatally by 4-CB is proposed as the primary event pursuant to the development of the CCPs, while interference with synaptogenesis may have occurred selectively in the striatonigral dopaminergic system. This is suggested by electron microscopy on the nucleus accumbens and also by the responses to administration of dopaminergic agonists and antagonist. The 4-CB induced clinico-pathologic anomaly may serve as a singular model for understanding human neurologic disorders, in particular, Werdnig-Hoffmann disease and minimal brain dysfunction syndrome.

Patterns of injury. Blunt and sharp.

The pathologist, by virtue of his or her observations and documentation of injuries with concomitant attempts to discern patterns of injury and correlate autopsy findings with investigative details, will often play an integral and primary role in the death investigation process. The information gleaned during this process, both pertinent positive and pertinent negative findings, however unimportant or insignificant they may seem during the initial examination, may potentially be of critical importance in answering future questions of a wide variety of interested parties, including law enforcement officials, prosecuting attorneys, defense attorneys, loved ones of the deceased, insurance companies, organ procurement officials, and news media. The pathologist, by virtue of his or her position in the process, is often the one best individual to collate and synthesize all findings of the process, both medical and investigative.

A retrospective and prospective study of cerebral tissue pulmonary embolism in severe head trauma.

In an attempt to determine the incidence of pulmonary embolization of cerebral tissue as the result of severe head trauma with and without dural penetration, we have collected the autopsy reports at our institution of all head injury victims over the past 3.5 years. The retrospective and prospective histologic examination of these cases revealed a total of 10% to have emboli of cerebral tissue within the pulmonary vasculature. Immunohistochemical staining of the emboli confirmed the neural origin of the tissue. The dura mater proved to be intact in 70% of the cases of cerebral embolization. We feel this provides evidence that embolization of cerebral tissue may occur without rupture of the dura and/or large venous sinuses. This observation is of clinical as well as forensic importance, as cerebral tissue emboli are a rich source of thromboplastin in the systemic and pulmonary vasculature and may contribute to the morbidity and mortality of head injuries.

Nonfracture-associated fatal fat embolism in a case of child abuse.

Fatal fat embolism is usually thought of as a sequel to long-bone fracture, although cases secondary to soft tissue injury and atraumatic conditions have been infrequently reported. In this case of a two-year-old child-abuse victim who sustained multiple blunt traumatic injuries without skeletal fractures, pulmonary and systemic (brain and kidney) fat emboli were identified. At autopsy, all thoracic and abdominal viscera were intact; cranial contents exhibited only diffuse symmetrical petechial hemorrhages of the white matter. Because of the severe and widespread nature of soft tissue hemorrhage, and the absence of a grossly discernible cause of death, fat embolism was suspected. Using a combination of frozen section with oil red O staining and formalin-fixed osmium stained tissues, the immediate cause of death was determined to be diffuse fat embolism. Review of the literature reveals a pathophysiologic basis for fat embolism in the absence of fracture, both as a consequence of an acute increase in local pressure at the site of trauma and an alteration of the emulsification of blood lipids during shock. In light of these findings, we present this case to remind the forensic science community to consider fat embolism as the cause of death in cases of blunt-force injury without fracture.

Extensive fibrofatty infiltration of the left ventricle in two cases of sudden cardiac death.

Replacement of the myocardium by fibrous and adipose tissue is well documented in the right ventricle, but has been rarely described in the left ventricle. We present two cases of extensive fibrofatty infiltration of the left ventricle without significant right ventricular involvement in young men whose presenting symptom was sudden death.

Fetal death due to nonlethal maternal carbon monoxide poisoning.

Fetal death due to acute carbon monoxide poisoning is rarely reported in the medical literature. Of the eight cases found in literature review, only one documented the fetal carboxyhemoglobin concentration. This paper reports a fetal death due to accidental nonlethal maternal carbon monoxide intoxication in which both maternal and fetal carboxyhemoglobin concentrations were obtained. The corrected carboxyhemoglobin concentration was 61% at the time of death in utero, while the maternal carboxyhemoglobin was measured at 7% after one hour of supplemental oxygen. The authors review the mechanisms of fetal death and emphasize the different carbon monoxide kinetics in the fetal circulation.

Cerebral tissue pulmonary embolization due to head trauma: a case report with immunohistochemical confirmation.

Pulmonary embolization of cerebral tissue as the result of severe head trauma is an uncommon, if not rare, phenomenon, and few cases have been reported in the literature. The authors discuss the case of a 51-year-old male who died six days after suffering extensive head trauma in a motor vehicle collision. At autopsy, white-gray emboli were found in several subsegmental pulmonary arteries. The results of histologic examination with the hematoxylineosin stain gave the impression that the emboli were necrotic cerebral tissue; however, routine special stains for neural tissue produced inconclusive results. Immunohistochemical staining of the emboli with monoclonal mouse anti-human neurofilament protein (Dako Corp., Carpinteria, California) confirmed the cerebral nature of the emboli. To the authors' knowledge, this is the first reported case of pulmonary embolization of cerebral tissue confirmed by immunohistochemistry.

Two chondrosarcomas in the urethra of a German shepherd dog.

An eight-year-old, male castrated German shepherd dog was presented with signs consistent with urinary obstruction. Cystoscopy and contrast radiography showed two distinct urethral masses. Penile amputation and perineal urethrostomy were performed to alleviate the clinical signs. Histopathology of the masses revealed two low-grade chondrosarcomas. At the time of writing, 18 months after surgery, the dog remained disease free.

Thoracic empyema due to Streptococcus intermedius.

With improved laboratory identification procedures, Streptococcus milleri (intermedius) is becoming recognized as an important human pathogen with the potential to form abscesses in a wide range of organs. The occurrence of a rapidly progressive and toxic empyema due to this organism in an otherwise healthy young adult without a predisposing lower respiratory tract infection allows us to examine the possibility that this microbe may be a significant but frequently unrecognized cause of adult empyema.