NTRK-1 fusion in endocervical fibroblastic malignant peripheral nerve sheath tumor marking eligibility for larotrectinib therapy: A case report.

•<1% of cervical cancers are sarcomas.•Data on neurofibrosarcoma management is scarce.•Larotrectinib is approved for NTRK1 gene fusion tumors without acquired resistance.•Targeted therapy of tumor genes may expand treatment for a rare cervical sarcoma.

What are the differences among occupational groups related to their palliative care-specific educational needs and intensity of interprofessional collaboration in long-term care homes?

BACKGROUND: The purpose of this study was to compare the differences across occupational groups related to their end-of-life care-specific educational needs and reported intensity of interprofessional collaboration in long-term care (LTC) homes. METHODS: A cross-sectional survey, based on two questionnaires, was administered at four LTC homes in Ontario, Canada using a modified Dilman's approach. The first questionnaire, End of Life Professional Caregiver Survey, included three domains: patients and family-centered communication, cultural and ethical values, effective care delivery. The Intensity of Interprofessional Collaboration Scale included two subscales: care sharing activities, and interprofessional coordination. In total, 697 LTC staff were given surveys, including personal support workers, support staff (housekeeping, kitchen, recreation, laundry, dietician aids, office staff), and registered staff (licensed nurses, physiotherapists, social workers, pharmacists, physicians). RESULTS: A total of 317 participants completed the survey (126 personal support workers, 109 support staff, 82 registered staff) for a response rate of 45%. Significant differences emerged among occupational groups across all scales and subscales. Specifically, support staff rated their comfort of working with dying patients significantly lower than both nurses and PSWs. Support staff also reported significantly lower ratings of care sharing activities and interprofessional coordination compared to both registered staff and personal support workers. CONCLUSIONS: These study findings suggest there are differing educational needs and sense of interprofessional collaboration among LTC staff, specific to discipline group. Both the personal support workers and support staff groups appeared to have higher needs for education; support staff also reported higher needs related to integration on the interdisciplinary team. Efforts to build capacity within support staff related to working with dying residents and their families are needed. Optimal palliative care may require resources to increase the availability of support for all staff involved in the care of patients.

Mass Spectrometry-Based Methodology for Identification of Native Histone Variant Modifications From Mammalian Tissues and Solid Tumors.

Histone posttranslational modifications (PTMs) are key epigenetic marks involved in gene silencing or activation. Histone modifications impact chromatin organization and transcriptional processes through the changes in charge density between histones and DNA. They also serve as recognition and binding sites for specific binding proteins. Histone tails and globular cores contain many basic amino acid residues, which are subject to various dynamic modifications, making the modification repertoire extremely diverse. Consequently, determination of histone PTM identity and quantity has been a challenging task. In recent years, mass spectrometry-based methods have proven useful in histone PTM characterization. This chapter provides a brief overview of these methods and describes the approach to analyze the PTMs of the histone variant CENP-A, essential for the cell cycle progression, when present in minute amounts from tumor and mammalian tissues. Because this method does not rely on antibody-based immunopurification, we anticipate that these tools could be readily adaptable to the investigation to other histone variants in a range of mammalian tissues and solid tumors.

Long term renal survival in patients undergoing T-Cell depleted versus conventional hematopoietic stem cell transplants.

Calcineurin inhibitor (CNI)-sparing T-cell depleted (TCD) hematopoietic stem cell transplants (HSCTs) are presumed to be less nephrotoxic than conventional HSCTs. We evaluated incidence and risk factors for kidney failure and chronic kidney disease (CKD) in 231 TCD and 212 conventional HSCT recipients. Kidney failure required a median glomerular filtration rate (GFR) <60 ml/min/1.73 m2 for ⩾100 days anytime after 180-days post-HSCT. Two-year cumulative incidence (CI) of kidney failure was 42% in the conventional versus 31% in the TCD group (P=0.005). TCD, age, acute kidney injury and number of toxic CNI levels all impacted on kidney failure, which was associated with increased all-cause mortality (hazard ratio 2.86 (95% CI: 1.88-4.36), P<0.001). Renal recovery occurred in 28% of kidney failure patients whereas the remaining patients were defined to have CKD. In those with baseline GFR>60 ml/min/1.73 m2, only exposure to nephrotoxic medications was associated with CKD (P=0.033). In the myeloablative-conditioning subgroup only total body irradiation was associated with CKD (P=0.013). Of all patients, five (1.13%) required dialysis. These results confirm an impact of TCD on kidney failure but not CKD for which other risk factors such as radiation or nephrotoxic drug exposure may have a role.

Diagnostic assessment of osteosarcoma chemoresistance based on Virtual Clinical Trials.

Osteosarcoma is the most common primary bone tumor in pediatric and young adult patients. Successful treatment of osteosarcomas requires a combination of surgical resection and systemic chemotherapy, both neoadjuvant (prior to surgery) and adjuvant (after surgery). The degree of necrosis following neoadjuvant chemotherapy correlates with the subsequent probability of disease-free survival. Tumors with less than 10% of viable cells after treatment represent patients with a more favorable prognosis. However, being able to predict early, such as at the time of the pre-treatment tumor biopsy, how the patient will respond to the standard chemotherapy would provide an opportunity for more personalized patient care. Patients with unfavorable predictions could be studied in a protocol, rather than a standard setting, towards improving therapeutic success. The onset of necrotic cells in osteosarcomas treated with chemotherapeutic agents is a measure of tumor sensitivity to the drugs. We hypothesize that the remaining viable cells, i.e., cells that have not responded to the treatment, are chemoresistant, and that the pathological characteristics of these chemoresistant tumor cells within the osteosarcoma pre-treatment biopsy can predict tumor response to the standard-of-care chemotherapeutic treatment. This hypothesis can be tested by comparing patient histopathology samples before, as well as after treatment to identify both morphological and immunochemical cellular features that are characteristic of chemoresistant cells, i.e., cells that survived treatment. Consequently, using computational simulations of dynamic changes in tumor pathology under the simulated standard of care chemotherapeutic treatment, one can couple the pre- and post-treatment morphological and spatial patterns of chemoresistant cells, and correlate them with patient clinical diagnoses. This procedure, that we named 'Virtual Clinical Trials', can serve as a potential predictive biomarker providing a novel value-added decision support tool for oncologists.

Apoptosis of osteosarcoma cultures by the combination of the cyclin-dependent kinase inhibitor SCH727965 and a heat shock protein 90 inhibitor.

Osteosarcoma (OS) is an aggressive bone cancer typically observed in adolescents and young adults. Metastatic relapse accounts primarily for treatment failure, and obstacles to improving cure rates include a lack of efficacious agents. Our studies show apoptosis of OS cells prepared from localized and metastatic tumors by a novel drug combination: SCH727965 (SCH), a cyclin-dependent kinase inhibitor, and NVP-AUY922 (AUY) or other heat shock protein 90 inhibitor. SCH and AUY induced apoptosis when added simultaneously to cells and when AUY was added to and removed from cells before SCH addition. Sequential treatment was most effective when cells received AUY for ~12 h and when SCH was presented to cells immediately after AUY removal. The apoptotic protein Bax accumulated in mitochondria of cotreated cells but was primarily cytosolic in cells receiving either agent alone. Additional data show that SCH and AUY cooperatively induce the apoptosis of other sarcoma cell types but not of normal osteoblasts or fibroblasts, and that SCH and AUY individually inhibit cell cycle progression throughout the cell cycle. We suggest that the combination of SCH and AUY may be an effective new strategy for treatment of OS.

Primary cutaneous osteoblastic osteosarcoma: a case report and review of the current literature.

Osteosarcoma is a malignant bone-forming tumour that typically arises within the metaphysis of long bones. Extraskeletal osteosarcoma is a rare variant that usually arises in the deep soft tissues, especially in the legs. We report a 65-year-old white man with an ulcerated, nodular lesion of the forearm. Based on the histological features and immunohistochemical profile of the tumour, a diagnosis of osteoblastic osteosarcoma was made. Osteosarcoma arising in the skin is a rare condition that has seldom been reported in the English literature.

Small-cell tumors of the liver: a cytological study of 91 cases and a review of the literature.

This study was designed to consider the cytomorphological spectrum, differential diagnosis, and the role of ancillary studies in small-cell tumors of the liver. Three independent pathologists reviewed cytological slides from 91 cases of small-cell tumors of the liver. The results were compared with the findings of three recently published studies (Cytopathology 11 (2000) 262-267; Diagn Cytopathol 19 (1998) 29-32; and Acta Cytol 40 (1996) 937-947). The role of immunohistochemistry in reaching timely and specific diagnoses was also examined. The diagnostic categories included 44 cases of metastatic small-cell undifferentiated carcinoma, 15 cases of metastatic neuroendocrine carcinoma, 10 cases of metastatic adenocarcinoma, 7 cases of malignant lymphoma, 4 cases of hepatocellular carcinoma with small-cell features, 2 cases of cholangiocarcinoma, 1 case of poorly differentiated carcinoma, and 8 cases of rare tumors including granulosa cell tumor (2 cases), sarcoma (4 cases), malignant melanoma with small-cell features (1 case), and meningioma with small-cell features (1 case). Metastatic granulosa cell-tumor, metastatic melanoma, and metastatic meningioma should be included in the differential diagnoses of small-cell malignancies found in the liver.

Phacoemulsification with intraocular lens implantation in patients with uveitis.

BACKGROUND: Cataract remains a challenge for ophthalmologists in uveitic eyes. The aim of this study is to report the clinical course of phacoemulsification with intraocular lens implantation in eyes suffering from uveitis. PATIENTS AND METHODS: Patients presenting a uveitis were prospectively followed from June 2001 to June 2003. Ocular surgery was performed according to a standard protocol, autoimmune follow-up visits were focused on the early detection of complications of uveitis: increased ocular inflammation, synechiae, retraction of the rhexis, opacification of the posterior capsule or onset of cystoid macular edema. RESULTS: Thirty-two eyes of 24 patients suffering from uveitis were operated with cataract surgery between June 2001 and June 2003. The mean age at surgery was 56 years (range 24 - 86 years). Mean preoperative visual acuity in uveitis patients presenting cataract was 0.3 +/- 0.3, and final visual acuity was 0.8 +/- 0.3. Three patients presented minor postoperative complications. One patient had a cystoid macular edema that appeared 5 months after surgery and one patient had a relapse of herpetic dendritic keratopathy despite topical antiviral therapy combined with steroid drops. The latter presented a slight increase of intraocular pressure (24 mm Hg). CONCLUSIONS: In patients with uveitis requiring cataract surgery, intraocular lens implantation is safe. Visual prognosis is better when pre- and postoperative inflammation is minimized. Macular scars or other retinal lesions are poor prognostic indicators.

Decreased glutathione in patients with anorexia nervosa. Risk factor for toxic liver injury?

OBJECTIVE: To investigate glutathione and amino acids related to glutathione metabolism in patients with anorexia nervosa in order to test the hypothesis that these patients exhibit a deficiency of glutathione and therefore might be at an increased risk of developing toxic liver injury. DESIGN: Controlled observatory study and case report. SETTING: University Hospital. SUBJECTS: Subjects included 11 female patients with anorexia nervosa and 12 healthy female controls. INTERVENTIONS: Determination of fasting free and total glutathione, homocysteine, vitamins B(6) and B(12) and folic acid in plasma. RESULTS: A 14-y-old patient with a body mass index of 12.6 kg/m(2) presented with markedly elevated transaminases (ALAT >50 x upper limit of normal), and paracetamol was detected in her blood. Patients with anorexia nervosa exhibited lower circulating concentrations of free cysteine (8.9+/-1.5 vs 12.0+/-1.4 micromol/l) and free and total glutathione (5.0+/-1.3 vs 7.1+/-1.2 and 11.2+/-3.8 vs 16.2+/-5.0 micromol/l, respectively). The plasma concentrations of homocysteine (17.5+/-4.9 vs 12.0+/-3.8 micromol/l) and also of glycine (194+/-37 vs 143+/-41 micromol/l) and glutamine (422+/-51 vs 353+/-51 micromol/l) were significantly higher in patients with anorexia nervosa who were not deficient in folic acid, vitamin B(6) and B(12). CONCLUSIONS: Lower plasma concentrations of glutathione suggest lower intracellular concentrations of the tripeptide. Higher homocysteine, glycine and glutamine concentrations point to a decreased utilization of these amino acids for glutathione synthesis and an impairment of trans-sulfuration. Consequently, the capacity of patients with anorexia nervosa to detoxify electrophilic metabolites and reactive oxygen species via glutathione may be impaired.

Arterial wall MRI characteristics are associated with elevated serum markers of inflammation in humans.

Inflammation contributes to atherosclerosis, but assessment in humans is largely restricted to measurement of markers in blood. We determined whether MRI properties of large arteries were associated with markers of inflammation in serum. Double inversion recovery, fast spin-echo images of the common carotid arteries and infrarenal aorta were obtained at 1.5 T both before and after gadolinium-DTPA (0.1 mmol/kg) in 52 subjects > or =40 years of age, 17 of whom had no risk factors for atherosclerosis and thus served as controls. Twenty-two study participants had increases in wall thickness (14), T2-weighted signal intensity (11), and/or contrast enhancement values (7) that were >2 standard deviations (SDs) from control group mean values. Ten subjects in this group had evidence of focal plaques in the carotids (5) and/or aorta (6). Compared with the remaining 30 subjects, these 22 had significantly higher levels of interleukin-6 (3.53 +/- 2.46 vs. 1.97 +/- 1.37 pg/mL, P = 0.004), C-reactive protein (0.56 +/- 0.98 vs. 0.30 +/- 0.52 mg/dL, P = 0.019), vascular cell adhesion molecule-1 (572 +/- 153 vs. 471 +/- 130 ng/mL, P = 0.012), and intercellular adhesion molecule-1 (244 +/- 80 vs. 202 +/- 45 ng/mL, P = 0.015), and nonsignificant differences in levels of E-selectin (46.1 +/- 18.9 vs. 42.3 +/- 11.3 ng/mL, P = 0.369). Thus, MRI characteristics of the aorta and carotid arteries were associated with elevated serum markers of inflammation, frequently in the absence of definite atheroma. MRI of large arteries may provide a new approach to investigate the contribution of inflammation to atherogenesis.

Prognostic factors and molecular markers for renal cell carcinoma.

Renal cell carcinoma is the most common cancer in the kidney, affecting nearly 30,000 Americans every year and is associated with over 12,000 deaths annually. If detected early, renal cell carcinomas can be cured surgically. However, once metastatic disease develops the prognosis for long-term survival is poor. Unfortunately, one-third of patients have metastatic disease at the time of diagnosis and approximately 50% of the patients undergoing surgical resection for less advanced disease eventually relapse. This review examines the clinical and molecular prognostic tools currently available or under investigation for kidney cancer.

Calyceal diverticula. Ureteroscopic management.

In selected cases, RIRS management of calyceal diverticula and its related problems has been shown to be more efficacious than ESWL monotherapy and avoids the potential complications and discomfort of percutaneous and laparoscopic procedures. The advent of the Holmium laser energy source, with innovations such as the flexible ureteroscope and the tipless stone basket, have expanded the role of RIRS in the management of calyceal diverticula and associated problems. Presently, RIRS is the initial treatment choice for the management of low to moderate stone burdens that are contained in calyceal diverticula or trapped behind any narrowed intrarenal segment (e.g., infundibular stenosis). If repair of the stenotic segment is not successful, thereby excluding stone treatment, then under the same anesthesia, the patient undergoes a percutaneous antegrade renal surgery. The authors feel that the percutaneous approach as a first choice is more suitable for posteriorly located diverticula with a large stone burden. In selected cases of anteriorly located diverticula with large stone burdens, the laparoscopic approach is more expedient.

Assessment of Her-2/neu overexpression in primary breast cancers and their metastatic lesions: an immunohistochemical study.

Since the development of novel immunotherapy using Herceptin as the first agent specifically indicated for HER-2/neu overexpression in metastatic breast cancer, there has been interest in using HercepTest as a predictor of response to such therapy. There is debate whether it is justifiable to perform HercepTest on every newly diagnosed breast cancer, since only approximately 43% of the cases will have related metastatic disease, and Herceptin is indicated only for breast cancer with metastatic disease. It may be more cost-effective to limit HercepTest to the related metastatic lesions. Therefore, it is important to assess whether the pattern of HER-21neu overexpression of metastatic breast cancer is also present in the primary lesion. HercepTest was performed on formalin-fixed, paraffin-embedded tissue sections of 56 primary breast cancers and their corresponding metastatic lesions. The protocol and scoring guidelines recommended by the manufacturer were followed. Tissue sections (5 microm) of a primary and the metastatic lesion from the same case were placed parallel on a single glass slide. The pattern and intensity of HER-2/neu overexpression (32%) in the primary and metastatic lesions were found to be nearly identical. Heterogeneity was observed in only one case. The score of primary cancer was 3+, and the metastatic lesion was 2+. Both were reported as positive. Intratumor heterogeneity (1+ to 3+) was also noted in two (4%) cases. However, the same pattern was found in both the primary and related metastatic lesions. The nearly identical HercepTest results in the primary and metastatic lesions suggest the potentiality of limiting the HercepTest to breast cancer-related metastases. Currently, any superficial and most deep-seated metastatic lesions can be easily sampled by fine needle aspiration biopsy or core biopsy, providing adequate samples for HercepTest. Eliminating unnecessary use of the HercepTest may provide a cost-effective alternative approach to the management of breast cancer patients.

Molecular predictive factors for local recurrence and distant metastasis of breast cancer after lumpectomy with postoperative radiation therapy.

To determine the risk factors associated with the recurrence and metastasis of breast cancer after lumpectomy with postoperative radiation therapy, 112 cases were studied who had been treated during a period of 11 years at the University of Florida Health Science Center/Jacksonville. The patients were evaluated for their age, race, and clinical stage, as well as the tumor grade, stage, histological type, and node involvement. Among these cases, four (4%) recurred locally within a year of treatment; 10 (9%) cases presented with distant metastasis within three years. No obvious clinical risk factors were identified for local recurrence; however, positive-node status seemed to be associated with distant metastasis. The primary tumors of these cases were then studied using immunohistochemical staining to evaluate the potential prognostic value of tumor markers such as estrogen receptor (ER), progesterone receptor (PR), tumor suppressor gene p53, HER-2/neu oncogene, and multi-drug resistance gene (MDR). The expression of p53 was associated with all local recurrence cases as well as 50% of those who had metastasis. The expression of MDR was observed in 80% of the distant metastatic cases. This preliminary result may warrant further studies on larger number of cases to assess the predictive value of p53 and MDR in the outcome of breast cancers in patients treated with postoperative radiation therapy.

Fluorescence in situ hybridization (FISH) for detection of HER-2/neu amplification in breast cancer: a multicenter portability study.

Amplification and/or overexpression of HER-2/neu has been shown to be both a prognostic and predictive marker in breast cancer. Recent studies have also confirmed the efficacy of Herceptin (trastuzumab) as adjuvant therapy for patients with overexpression of HER-2/neu. Therefore, it is critical that precise and reproducible assays be used in the clinical laboratory setting for determination of the HER-2/neu status in patients with breast cancer. The objective of this study was to determine the portability (reproducibility between different institutions) of the PathVysion HER-2 fluorescence in situ hybridization (FISH) assay used for detection of amplification of the HER-2/neu gene in formalin-fixed, paraffin-embedded tissue sections of invasive ductal carcinoma of the breast. Study specimens consisted of one breast tumor with a normal HER-2/neu copy number, two tumors with a low level, and one tumor with a high level of HER-2/neu amplification. The PathVysion HER-2 assay was shown to be highly reproducible on different assay days (n = 3) and between different institutions (n = 5) in the detection of amplification of the HER-2/neu gene in routinely processed clinical specimens of breast carcinoma. In addition, this study examined the feasibility of enumerating FISH signals in 20 nuclei in contrast to 60 nuclei per specimen. Although a modest increase in variation was observed when analyzing 20 compared to 60 nuclei, the mean ratios were similar. Therefore, analysis of as few as 20 nuclei with this FISH HER-2/neu assay may be sufficient for determining the amplification level of the HER-2/neu gene.

An ecological study of determinants of coronary heart disease rates: a comparison of Czech, Bavarian and Israeli men.

BACKGROUND: The large differences in cardiovascular disease rates between Eastern and Western Europe have largely developed over the last few decades, and are only partly explained by classical risk factors. This study was set up to identify other potential determinants of these differences. METHODS: This was an ecological study comparing random samples of men aged 45-64 years selected from three cities representing populations with different rates of cardiovascular mortality: Pardubice (Czech Republic), Augsburg (Bavaria, Germany), and Jerusalem (Israel). In total, 191 (response rate 70%), 153 (70%) and 162 (62%) men, respectively, participated. All centres followed the same study protocol. Lifestyle, anthropometry and biochemical risk factors were assessed by identical questionnaires, standardized medical examination, and central analyses of fasting blood samples. RESULTS: The mortality rates in the study populations, as well as the prevalence of coronary heart disease in study samples, were highest in Czech, intermediate in Bavarian and low in Israeli men. This pattern was replicated across the three samples by mean blood pressure (P < 0.001), cigarette smoking (not significant), triglycerides (P < 0.05), fibrinogen or D-dimer levels (P < 0.05). On the other hand, the prevalence of diabetes and obesity were similar; total and high density lipoprotein (HDL)-cholesterol, apolipoprotein B, lipoprotein (Lp(a)) and glucose did not differ between Czech and Bavarian men; and Czechs had particularly low levels of serum insulin and factor VIIc. Israelis had low fasting glucose and total cholesterol, as well as HDL-cholesterol levels and a high Lp(a) (each P < 0.001) compared with the two other samples. Striking differences were found for plasma homocysteine (10.5 in Czechs versus 8.9 mumol/l in Bavarians, P < 0.001) and for alpha-carotene (geometric mean in Czechs 16, Bavarians 21 and Israelis 30 micrograms/l), beta-carotene (60, 110 and 102 micrograms/l), and lycopene (84, 177 and 223 micrograms/l), respectively; all P-values < 0.001). Adjustment for obesity or smoking did not change these estimates. There were no differences in the levels of tocopherol and retinol. CONCLUSIONS: Czech men had high levels of blood pressure, triglycerides, fibrinogen and D-dimer but many other traditional risk factors, as well as indicators of metabolic disorders and vitamins A and E, did not differ between the study samples. The low levels of carotenoids and high concentrations of homocysteine in Czech men seem to reflect their low dietary intakes of fruit and vegetables. The results provide indirect support for the importance of dietary factors in the East-West morbidity and mortality divide.