An observational study to understand burden and cost of care in adults diagnosed with refractory chronic cough (RCC) or unexplained chronic cough (UCC).

BACKGROUND: Refractory and unexplained chronic cough (RCC and UCC) necessitate frequent referral for specialist evaluations, but data on healthcare resource utilisation and costs are lacking. METHODS: This observational study enrolled adults with RCC or UCC attending a specialist cough clinic and included a control cohort, both from North West England, matched 1:5 for age, gender and smoking history. Primary and secondary care data were obtained for the 5 years prior to and 2 years post initial clinic visit (index). The primary endpoint was the total 5-year healthcare cost to the UK NHS pre-RCC or UCC diagnosis compared to the control cohort. RESULTS: Mean age at index for the 200 RCC or UCC consented patients was 62.2 ± 11.4 years; 71% were female, and 68% had never smoked. Mean duration of symptoms pre-diagnosis was 8.0 ± 9.4 years. Mean cough severity score was 63.7 ± 23.2 mm at index on a Visual Analog Scale, and Leicester Cough Questionnaire total score was 10.9 ± 4.1. GP data were available for 80 patients and mean total cost over the 5 years pre-diagnosis (index date) was 3.0-fold higher (95% CI 2.3, 3.9) than in the control cohort (p < 0.001). Most excess costs were related to visits and procedures carried out in secondary care. RCC- or UCC-associated costs decreased post-diagnosis, but remained higher than those of controls. CONCLUSION: Diagnosis of RCC or UCC requires significant health resource utilisation in the 5 years prior to a specialist clinic diagnosis. Resource utilisation was less after diagnosis, but remained higher than in a matched control cohort.

The influence of skeletal muscle mitochondria and sex on critical torque and performance fatiguability in humans.

Critical torque (CT) represents the highest oxidative steady state for intermittent knee extensor exercise, but the extent to which it is influenced by skeletal muscle mitochondria and sex is unclear. Vastus lateralis muscle biopsy samples were collected from 12 females and 12 males -matched for relative maximal oxygen uptake normalized to fat-free mass (FFM) (F: 57.3 (7.5) ml (kg FFM)-1  min-1 ; M: 56.8 (7.6) ml (kg FFM)-1  min-1 ; P = 0.856) - prior to CT determination and performance fatiguability trials. Males had a lower proportion of myosin heavy chain (MHC) I isoform (40.6 (18.4)%) compared to females (59.5 (18.9)%; P = 0.021), but MHC IIa and IIx isoform distributions and protein markers of mitochondrial content were not different between sexes (P > 0.05). When normalized to maximum voluntary contraction (MVC), the relative CT (F: 42.9 (8.3)%; M: 37.9 (9.0)%; P = 0.172) and curvature constant, W' (F: 26.6 (11.0) N m s (N m)-1 ; M: 26.4 (6.5) N m s (N m)-1 ; P = 0.962) were not significantly different between sexes. All protein biomarkers of skeletal muscle mitochondrial content, as well as the proportion of MHC I isoform, positively correlated with relative CT (0.48 < r < 0.70; P < 0.05), and the proportion of MHC IIx isoform correlated positively with relative W' (r = 0.57; P = 0.007). Indices of performance fatiguability were not different between males and females for MVC- and CT-controlled trials (P > 0.05). Greater mitochondrial protein abundance was associated with attenuated declines in potentiated twitch torque for exercise at 60% MVC (P < 0.05); however, the influence of mitochondrial protein abundance on performance fatiguability was reduced when exercise was prescribed relative to CT. Whether these findings translate to whole-body exercise requires additional research. KEY POINTS: The quadriceps critical torque represents the highest intensity of intermittent knee extensor exercise for which an oxidative steady state is attainable, but its relationship with skeletal muscle mitochondrial protein abundance is unknown. Matching males and females for maximal oxygen uptake relative to fat-free mass facilitates investigations of sex differences in exercise physiology, but studies that have compared critical torque and performance fatiguability during intermittent knee extensor exercise have not ensured equal aerobic fitness between sexes. Skeletal muscle mitochondrial protein abundance was correlated with critical torque and fatigue resistance for exercise prescribed relative to maximum voluntary contraction but not for exercise performed relative to the critical torque. Differences between sexes in critical torque, skeletal muscle mitochondrial protein abundance and performance fatiguability were not statistically significant. Our results suggest that skeletal muscle mitochondrial protein abundance may contribute to fatigue resistance by influencing the critical intensity of exercise.

Establishing a Gold Standard for Quantitative Menstrual Cycle Monitoring.

Background and Objectives: The Quantum Menstrual Health Monitoring Study will measure four key reproductive hormones in the urine (follicle-stimulating hormone, FSH; estrone-3-glucuronide, E13G; luteinizing hormone, LH; and pregnanediol glucuronide, PDG) to characterize patterns that predict and confirm ovulation, referenced to serum hormones and the gold standard of the ultrasound day of ovulation in participants with regular cycles. These normal cycles will provide a reference for comparison to irregular cycles in subjects with polycystic ovarian syndrome (PCOS) and athletes. Materials and Methods: Participants will track their menstrual cycles for 3 months and be provided with an at-home urine hormone monitor (Mira monitor) to predict ovulation. The day of ovulation will be confirmed with serial ultrasounds completed in a community clinic. Urine results will be compared to serum hormone values. Other markers of menstrual health, such as bleeding patterns and temperature changes, will be determined using a customized app. Three groups will be recruited. Group 1 will include those with consistent regular cycle lengths (between 24-38 days), and will be compared to two groups with irregular cycle lengths (with increased cycle length variability and longer cycles). Group 2 will include those with polycystic ovarian syndrome (PCOS) with irregular cycles and Group 3 will include individuals participating in high levels of exercise with irregular cycles. Hypothesis: The Mira monitor quantitative urine hormone pattern will accurately correlate with serum hormonal levels and will predict (with LH) and confirm (with PDG) the ultrasound day of ovulation in those with regular cycles as well as those with irregular cycles. Rationale: Once the ultrasound validation is complete, tools like the Mira monitor with a customized app may become a new standard for at-home and remote clinical monitoring of the menstrual cycle without having to use labor-intensive follicular-tracking ultrasound or follow serum hormone changes. Conclusions: Precision monitoring of the menstrual cycle is expected to impact individuals who want to increase their menstrual health literacy and guide decisions about fertility.

Spread of Makoyoh'sokoi (Wolf Trail): a community led, physical activity-based, holistic wellness program for Indigenous women in Canada.

Globally, Indigenous populations have been impacted by colonization. Populations who have endured colonization are at higher risk of developing chronic diseases. Canada's Truth and Reconciliation Commission emphasizes reducing barriers to participation in physical activity and recommends the creation of culturally relevant and supportive policies and programing. Physical activity is a cornerstone in health promotion and public health to combat chronic diseases; however, in Canada, Indigenous developed physical activity programing is sparse, and those targeting women are non-existent in some regions. Makoyoh'sokoi (The Wolf Trail Program) is an 18-week long, holistic wellness program that was created by and for Indigenous women. Makoyoh'sokoi was developed by communities following extensive consultation and cultural oversight. Makoyoh'sokoi's core program consists of 12 weeks of weekly physical activity programing and health education, followed by another 6 weeks of weekly health education. Notably, communities have control over the program to modify based on individual needs and challenges. Programs commence and conclude with a ceremony with Elders giving a blessing and opening each other to connection. The goals of Makoyoh'sokoi are to empower women, improve health outcomes, and to implement a sustainable program by training a network of community members in their respective communities to facilitate delivery.

Early breast cancer survival of black and white American women with equal diagnostic and therapeutic management.

PURPOSE: Breast cancer (BC) survival favors White versus Black Americans despite advances in screening and treatment. We hypothesized that these differences were dependent upon quality of care by analyzing long-term outcomes of 3139 early BC patients at our quaternary care center where uniform access and management of BC is provided to women irrespective of race. METHODS: Prospectively collected data for clinical stage I-II BC patients from our quaternary care cancer center were analyzed, focusing on disease-specific survival (DSS). Subgroup analyses included the overall cohort, triple-negative BC (TNBC), non-TNBC and HER2/neu positive patients. Multivariable analyses to evaluate associations of variables with DSS were performed for each subgroup. RESULTS: The overall cohort consisted of 3139 BC patients (1159 Black, 1980 White). Black and White patients did not differ by most baseline variables. Black patients had higher rates of TNBC (18% versus 10%, p < 0.0001). Kaplan-Meier analysis of all subgroups (overall, TNBC, non-TNBC, HER2/neu positive) did not reveal DSS differences between Black and White patients. Multivariable analysis of subgroups also did not find race to be associated with DSS. CONCLUSION: In this large, carefully controlled, long term, single-institution prospective cohort study DSS in Black and White early BC patients with equal access to high quality care, did not differ. While BC patients with adverse molecular markers did slightly worse than those with more favorable markers, there is no observable difference between Black and White women with the same markers. These observations support the conclusion that equal access to, and quality, of BC care abolishes racial disparities in DSS.

The PshX subunit of the photochemical reaction center from Heliobacterium modesticaldum acts as a low-energy antenna.

The anoxygenic phototrophic bacterium Heliobacterium modesticaldum contains a photochemical reaction center protein complex (called the HbRC) consisting of a homodimer of the PshA polypeptide and two copies of a newly discovered polypeptide called PshX, which is a single transmembrane helix that binds two bacteriochlorophyll g molecules. To assess the function of PshX, we produced a ∆pshX strain of Hbt. modesticaldum by leveraging the endogenous Hbt. modesticaldum Type I-A CRISPR-Cas system to aid in mutant selection. We optimized this system by separating the homologous recombination and CRISPR-based selection steps into two plasmid transformations, allowing for markerless gene replacement. Fluorescence and low-temperature absorbance of the purified HbRC from the wild-type and ∆pshX strains showed that the bacteriochlorophylls bound by PshX have the lowest site energies in the entire HbRC. This indicates that PshX acts as a low-energy antenna subunit, participating in entropy-assisted uphill energy transfer toward the P800 special bacteriochlorophyll g pair. We further discuss the role that PshX may play in stability of the HbRC, its conservation in other heliobacterial species, and the evolutionary pressure to produce and maintain single-TMH subunits in similar locations in other reaction centers.

Clinicopathological Evaluation of the Potential Anatomic Pathways of Systemic Metastasis from Primary Breast Cancer Suggests an Orderly Spread Through the Regional Lymph Nodes.

BACKGROUND: Two conflicting hypotheses as to how breast cancer (BC) accesses the systemic circulation dominated the 20th century and affected surgical treatment. We hypothesized that tumor lymphovascular invasion (LVI) at the primary tumor site favors lymphatic and not blood vessel, capillaries, and systemic metastases (Smets) are dependent upon regional lymph node (RLN) mets. METHODS: Data from BC patients undergoing RLN biopsy was professionally abstracted and maintained in a prospective, precisely managed, single-institution database. Associations of RLN, LVI, and Smets were estimated by univariate and multivariate backward logistic regression models and patient-affiliated demographic, clinicopathologic, treatment type, and molecular marker data. RESULTS: Of 3329 patients, followed 1-22 years (mean 7.8), 463 of 3329 (13.9%) showed LVI, 742 of 3329 (22.3%) had RLN mets, and 262 of 3329 (7.9%) had Smets. Smets occurred in 52 of 252 (21% with LVI+/RLN+); 116 of 2301 (5% with LVI-/RLN-); 65 of 465 (14% with LVI-/RLN+); and 17 of 207 (8% with LVI+/RLN-), p = 0.021 for association between LVI and Smets for RLN+ patients but not for RLN- patients (p = 0.051). Positive RLN, larger tumor size, and higher grade (all p < 0.001) were predictive of Smets by the multivariable model, whereas positive LVI was not. CONCLUSIONS: LVI predicts RLN mets in BC. RLN is critical to Smets from BC, whereas LVI on its own is not. Smets occur significantly more commonly when both LVI and RLN mets occur together. LVI is, thus, likely to be primarily lymphatic invasion, and rarely, blood vessel invasion, supporting the Halsted paradigm. LVI and RLN together predict clinical outcome better than either alone.

Xanthogranulomatous endometritis mimicking endometrial carcinoma: A case report and review of literature.

Xanthogranulomatous endometritis (XGE) is an extremely rare chronic inflammatory condition, which may be associated with endometrial hyperplasia, endometrial carcinoma, or cervical stenosis. Imaging features can be easily misdiagnosed as an aggressive malignancy. We present a case of XGE, which is the first case of XGE with serial multimodality imaging examinations, in addition to clinical, surgical and pathologic correlations. As such, this unique case illustrates the evolution of this rare disease.

A Retrospective Analysis of Concurrent Pathology in ACL-Reconstructed Knees of Elite Alpine Ski Racers.

BACKGROUND: Anterior cruciate ligament (ACL) tear is the most frequent injury in alpine ski racing, and there is a high prevalence of ACL reinjury. Limited data exist on the concurrent pathology with primary ACL tears in elite alpine ski racers and the magnitude of injury progression after primary ACL reconstruction (ACLR). PURPOSE: To evaluate (1) the involvement of intra-articular and multiligament pathologies at the time of primary ACLR, (2) the subsequent progression in meniscal/chondral injuries, and (3) the occurrence of ACL reinjury in elite alpine ski racers. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Primary ACLR operative reports (n = 28) were obtained for 32 elite alpine ski racers along with the reports of 20 operative procedures that occurred subsequent to primary ACLR. Operative reports were evaluated to identify the presence/location of multiligament injury, meniscal tears, and chondral lesions. RESULTS: At the time of primary ACLR, a majority of knees (82%; 23/28) demonstrated concurrent injury compared with isolated ACL tears; 32% of knees sustained multiligament injuries (9/28), and 8 involved the ipsilateral medial collateral ligament (MCL). Of the ACL-injured knees, 54% had chondral lesions, of which 73% were sustained in the lateral knee compartment, and 82% of meniscal tears (14/17) were complex in nature. Bilateral ACL tears were seen in 22% of the participants, and 28% underwent ACL revision. In the case of ACL revision or future meniscal/chondral surgery, 60% of meniscal tears and 80% of chondral lesions had worsened since the time of primary ACLR. CONCLUSION: Concurrent injury was common in this group of elite ski racers. Primary ACL tears were typically accompanied by lateral compartment chondral lesions and complex meniscal tears that worsened over time. ACL/MCL tears were the most common multiligament injury pattern.

Atypical cells in a voided urine cytology specimen in a renal transplant recipient.

Voided urine is routinely collected from renal transplant patients to screen for polyomavirus. In rare cases, atypical lymphoid cells can be detected in voided urine and raise the suspicion of post-transplant lymphoproliferative disorder (PTLD). However, further immunohistochemistry of the cell block and flow cytometry is frequently limited by the low cellularity and poor preservation of voided urine. Therefore, PTLD of the renal allograft is usually diagnosed from tissue biopsy or nephrectomy specimens. Herein, we report a rare case of atypical cells in a voided urine cytology specimen from a kidney transplant recipient. Needle core biopsy of the renal allograft showed monomorphic PTLD. Diagn. Cytopathol. 2017;45:69-72. © 2016 Wiley Periodicals, Inc.

Preclinical Validation of a Single-Treatment Infusion Modality That Can Eradicate Extremity Melanomas.

Isolated limb perfusion (ILP) with the chemotherapeutic agent melphalan is an effective treatment option for extremity in-transit melanoma but is toxic and technically challenging to deliver locoregionally. CBL0137 is an experimental clinical drug with broad anticancer activity in animal models, owing to its ability to bind DNA in a nongenotoxic manner and inactivate the FACT chromatin modulator essential for tumor cell viability. Here, we report that CBL0137 delivered by ILP in a murine melanoma model is as efficacious as melphalan, displaying antitumor activity at doses corresponding to only a fraction of the systemic MTD of CBL0137. The ability to bind DNA quickly combined with a favorable safety profile made it possible to substitute CBL0137 in the ILP protocol, using an intra-arterial infusion method, to safely achieve effective tumor suppression. Our findings of a preclinical proof of concept for CBL0137 and its administration via intra-arterial infusion as a superior treatment compared with melphalan ILP allows for locoregional treatment anywhere a catheter can be placed. Cancer Res; 76(22); 6620-30. ©2016 AACR.

Selected topics in peritoneal pathology.

This essay considers selected peritoneal lesions many of which were the subject of studies coauthored by Dr Robert E. Scully. His article on multilocular peritoneal inclusion cysts has largely led to these lesions being considered non-neoplastic, eschewing the term cystic mesothelioma. These cysts are often associated with reactive mural mesothelial proliferations that can potentially lead to a misdiagnosis of mesothelioma. Clinical findings, such as a common association with endometriosis or prior operations, can prompt consideration of a reactive lesion. Mesothelial hyperplasia may be difficult to distinguish, when florid, from mesothelioma but a variety of gross and microscopic features will aid their recognition. Nodular peritoneal aggregates of histiocytes (sometimes admixed with mesothelial cells) may occasionally be a striking finding that can be misdiagnosed as a metastasis if the patient has a known neoplasm. Appreciation of their bland nuclear features and histiocytic nature, confirmed by immunohistochemical markers, facilitate the diagnosis. Various forms of peritonitis are briefly considered including sclerosing peritonitis, a process sometimes associated with luteinized thecomas (thecomatosis) of the ovaries, an entity first appreciated by Dr Scully. Mesotheliomas are briefly reviewed emphasizing the caution that should be used in applying the designation "well-differentiated papillary mesothelioma." Many interpret the latter as benign, but multifocal lesions must be thoroughly examined histologically because of potential overlapping features with malignant mesothelioma. The morphologic spectrum of malignant mesothelioma and its usually straightforward distinction from müllerian neoplasms is considered, as is its occasional presentation as a dominant ovarian mass. The spectrum of low-grade serous peritoneal neoplasms including the "psammocarcinoma" is reviewed. Finally, various benign müllerian lesions, particularly endometriosis and endosalpingiosis, may be conspicuous in peritoneal specimens and sometimes are grossly striking. The usual presence of benign endometrioid epithelium and stroma should facilitate the correct diagnosis of endometriosis, but in cases in which the stroma is atrophic or the sole component (stromal endometriosis), diagnostic problems may arise.

Friendship networks and physical activity and sedentary behavior among youth: a systematized review.

BACKGROUND: Low levels of physical activity and increased participation in sedentary leisure-time activities are two important obesity-risk behaviors that impact the health of today's youth. Friend's health behaviors have been shown to influence individual health behaviors; however, current evidence on the specific role of friendship networks in relation to levels of physical activity and sedentary behavior is limited. The purpose of this review was to summarize evidence on friendship networks and both physical activity and sedentary behavior among children and adolescents. METHOD: After a search of seven scientific databases and reference scans, a total of thirteen articles were eligible for inclusion. All assessed the association between friendship networks and physical activity, while three also assessed sedentary behavior. RESULTS: Overall, higher levels of physical activity among friends are associated with higher levels of physical activity of the individual. Longitudinal studies reveal that an individual's level of physical activity changes to reflect his/her friends' higher level of physical activity. Boys tend to be influenced by their friendship network to a greater extent than girls. There is mixed evidence surrounding a friend's sedentary behavior and individual sedentary behavior. CONCLUSION: Friends' physical activity level appears to have a significant influence on individual's physical activity level. Evidence surrounding sedentary behavior is limited and mixed. Results from this review could inform effective public health interventions that harness the influence of friends to increase physical activity levels among children and adolescents.

Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist.

Vertebrate Toll-like receptor 5 (TLR5) recognizes bacterial flagellin proteins and activates innate immune responses to motile bacteria. In addition, activation of TLR5 signaling can inhibit growth of TLR5-expressing tumors and protect normal tissues from radiation and ischemia-reperfusion injuries. To understand the mechanisms behind these phenomena at the organismal level, we assessed nuclear factor kappa B (NF-κB) activation (indicative of TLR5 signaling) in tissues and cells of mice treated with CBLB502, a pharmacologically optimized flagellin derivative. This identified the liver and gastrointestinal tract as primary CBLB502 target organs. In particular, liver hepatocytes were the main cell type directly and specifically responding to systemic administration of CBLB502 but not to that of the TLR4 agonist LPS. To assess CBLB502 impact on other pathways, we created multireporter mice with hepatocytes transduced in vivo with reporters for 46 inducible transcription factor families and found that along with NF-κB, CBLB502 strongly activated STAT3-, phenobarbital-responsive enhancer module (PREM), and activator protein 1 (AP-1-) -driven pathways. Livers of CBLB502-treated mice displayed induction of numerous immunomodulatory factors and massive recruitment of various types of immune cells. This led to inhibition of growth of liver metastases of multiple tumors regardless of their TLR5 status. The changed liver microenvironment was not, however, hepatotoxic, because CBLB502 induced resistance to Fas-mediated apoptosis in normal liver cells. Temporary occlusion of liver blood circulation prevented CBLB502 from protecting hematopoietic progenitors in lethally irradiated mice, indicating involvement of a factor secreted by responding liver cells. These results define the liver as the key mediator of TLR5-dependent effects in vivo and suggest clinical applications for TLR5 agonists as hepatoprotective and antimetastatic agents.

Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2).

Bacterial lipoproteins (BLP) induce innate immune responses in mammals by activating heterodimeric receptor complexes containing Toll-like receptor 2 (TLR2). TLR2 signaling results in nuclear factor-kappaB (NF-κB)-dependent upregulation of anti-apoptotic factors, anti-oxidants and cytokines, all of which have been implicated in radiation protection. Here we demonstrate that synthetic lipopeptides (sLP) that mimic the structure of naturally occurring mycoplasmal BLP significantly increase mouse survival following lethal total body irradiation (TBI) when administered between 48 hours before and 24 hours after irradiation. The TBI dose ranges against which sLP are effective indicate that sLP primarily impact the hematopoietic (HP) component of acute radiation syndrome. Indeed, sLP treatment accelerated recovery of bone marrow (BM) and spleen cellularity and ameliorated thrombocytopenia of irradiated mice. sLP did not improve survival of irradiated TLR2-knockout mice, confirming that sLP-mediated radioprotection requires TLR2. However, sLP was radioprotective in chimeric mice containing TLR2-null BM on a wild type background, indicating that radioprotection of the HP system by sLP is, at least in part, indirect and initiated in non-BM cells. sLP injection resulted in strong transient induction of multiple cytokines with known roles in hematopoiesis, including granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC) and interleukin-6 (IL-6). sLP-induced cytokines, particularly G-CSF, are likely mediators of the radioprotective/mitigative activity of sLP. This study illustrates the strong potential of LP-based TLR2 agonists for anti-radiation prophylaxis and therapy in defense and medical scenarios.

Association of Mycoplasma hominis infection with prostate cancer.

The origin of chronic inflammation preceding the development of prostate cancer (PCa) remains unknown. We investigated possible involvement of mycoplasma infection in PCa by screening prostate biopsies from two groups of Russian men undergoing PCa diagnosis. M. hominis was detected by standard PCR in 15% of the 125 patients in the first group and by quantitative real-time PCR in 37.4% of the 123 men in the second group. In both groups, stratification of patients according to diagnosis showed that M. hominis was present at three times higher frequency in patients with PCa than in those with benign prostatic hyperplasia. No M. hominis was detected in the prostates of 27 men without detectable prostate disease. In addition, PCa-positive men had higher titers of antibodies against M. hominis and average PSA levels were higher in M. hominis-positive men. These data, together with previous observations linking mycoplasma infection with cell transformation, genomic instability and resistance to apoptosis, suggest that M. hominis infection may be involved in PCa development and may, therefore, be a potential PCa marker and/or target for improved prevention and treatment of this disease.

Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib.

Proteotoxic stress (PS) is generated in cells under a variety of conditions involving accumulation of misfolded proteins. To avoid the toxicity of unmitigated PS, cells activate the heat shock response (HSR). HSR involves upregulation of factors such as ubiquitin and the non-housekeeping chaperone Hsp70 which assist with metabolism of aberrant proteins. The PS-HSR axis is a potential anticancer treatment target since many tumor cells display constitutive PS and dependence on HSR due to their rapid rates of proliferation and translation. In fact, induction of PS via stimulation of protein misfolding (hyperthermia), inhibition of proteasomes (bortezomib) or inhibition of Hsp90 (geldanamycin) have all been considered or used for cancer treatment. We found that combination of bortezomib with an inducer of protein misfolding (hyperthermia or puromycin) resulted in enhanced PS. HSR was also induced, but could not mitigate the elevated PS and the cells died via largely p53-independent apoptosis. Thus, combination treatments were more cytotoxic in vitro than the component single treatments. Consistent with this, combination of non-toxic doses of puromycin with bortezomib significantly increased the antitumor activity of bortezomib in a mouse model of multiple myeloma. These results provide support for using combination treatments that disrupt the balance of PS and HSR to increase the therapeutic index of anticancer therapies.

Diagnosis of ovarian carcinoma cell type is highly reproducible: a transcanadian study.

Reproducible diagnosis of ovarian carcinoma cell types is critical for cell type-specific treatment. The purpose of this study was to test the reproducibility of cell type diagnosis across Canada. Analysis of the interobserver reproducibility of histologic tumor type was performed among 6 pathologists after brief training in the use of modified World Health Organization criteria to classify ovarian carcinomas into 1 of 6 categories: high-grade serous, endometrioid, clear cell, mucinous, low-grade serous, and other. These 6 pathologists independently reviewed a test set of 40 ovarian carcinomas. A validation set of 88 consecutive ovarian carcinomas drawn from 5 centers was subject to local review by 1 of the 6 study pathologists, and central review by a single observer. Interobserver agreement was assessed through calculation of concordance and kappa values for pair-wise comparison. For the test set, the paired concordance between pathologists in cell type diagnosis ranged from 85.0% to 97.5% (average 92.3%), and the kappa values were 0.80 to 0.97 (average 0.89). Inclusion of immunostaining results did not significantly improve reproducibility (P=0.69). For the validation set, the concordance between original diagnosis and local review was 84% and between local review and central review was 94%. The kappa values were 0.73 and 0.89, respectively. With a brief training exercise and the use of defined criteria for ovarian carcinoma subtyping, there is excellent interobserver reproducibility in diagnosis of cell type. This has implications for clinical trials of subtype-specific ovarian carcinoma treatments.

Intermediate-grade squamous intraepithelial lesion may be a valid diagnostic/interpretive category.

We undertook this study to assess the characteristics of smears with features intermediate between high-grade squamous intraepithelial lesion (HSIL) and low-grade squamous intraepithelial lesion (ISIL). We also wanted to determine how these smears correlate with high risk biopsy diagnosis and to compare this with the biopsy correlation of LSIL and HSIL. Seventy-four squamous intraepithelial lesion (SIL) smears were identified as intermediate-grade SIL smears taken at colposcopy in a 1 year period. They were correlated with concurrent colposcopically guided biopsies. Thirty-five percent of cases with intermediate-grade SIL smears had a biopsy diagnosis of moderate dysplasia or higher as compared with 12% for LSIL 74% for HSIL. This confirmed our hypothesis that intermediate-grade SIL smears have a rate of biopsy diagnosis of moderate dysplasia or higher intermediate to that of LSIL and HSIL.