Stage I Breast Cancer in the Modern Era: A Retrospective Cohort Study of 328 Patients Diagnosed from 2002 to 2006 with a 14-Year Median Follow-Up.

INTRODUCTION: This study aimed to evaluate the long-term outcomes of stage I breast cancer (BC) patients diagnosed during the current era of screening mammography, immunohistochemistry receptor testing, and systemic adjuvant therapy. METHODS: A retrospective cohort study was conducted on 328 stage I BC patients treated consecutively in a single referral center with a follow-up period of at least 12 years. The primary endpoints were invasive disease-free survival (IDFS) and overall survival (OS). The influence of tumor size, grade, and subtype on the outcomes was analyzed. RESULTS: Most patients were treated by lumpectomy, sentinel node biopsy, and adjuvant endocrine therapy, and most (82%) were of subtype luminal A. Adjuvant chemotherapy was administered to 25.6% of our cohort. Only 24 patients underwent gene expression testing, which was introduced toward the end of the study period. Mean IDFS was 14.64 years, with a 15-year IDFS of 75.6%. Mean OS was 15.28 years with a 15-year OS of 74.9%. In a Cox multivariate analysis, no clinical or pathologic variable impacted on OS and only tumor size (<1 cm vs. 1-2 cm) impacted significantly on IDFS. During follow-up, 20.1% of the cohort developed second primary cancers, including BC. The median time to diagnosis of a second BC was 6.49 years. CONCLUSION: The study results emphasize the importance of long-term follow-up and screening for subsequent malignancies of patients with stage I BC and support the need for using prognostic and predictive indicators beyond the routine clinicopathological characteristics in luminal A patients.

Monitoring Bioindication of Plankton through the Analysis of the Fourier Spectra of the Underwater Digital Holographic Sensor Data.

The study presents a bioindication complex and a technology of the experiment based on a submersible digital holographic camera with advanced monitoring capabilities for the study of plankton and its behavioral characteristics in situ. Additional mechanical and software options expand the capabilities of the digital holographic camera, thus making it possible to adapt the depth of the holographing scene to the parameters of the plankton habitat, perform automatic registration of the "zero" frame and automatic calibration, and carry out natural experiments with plankton photostimulation. The paper considers the results of a long-term digital holographic experiment on the biotesting of the water area in Arctic latitudes. It shows additional possibilities arising during the spectral processing of long time series of plankton parameters obtained during monitoring measurements by a submersible digital holographic camera. In particular, information on the rhythmic components of the ecosystem and behavioral characteristics of plankton, which can be used as a marker of the ecosystem well-being disturbance, is thus obtained.

Features of phototropic response of zooplankton to paired photostimulation under adverse environmental conditions.

Our previous studies showed that the change in the plankton response to light could be an indicator of environmental pollution. This study experimentally reveals that the response of Daphnia magna Straus and Daphnia pulex plankton ensembles to photostimulation depends on the intensity of the attracting light. This makes it difficult to identify the occurrence and change of pollutant concentration. The large variability in the magnitude of the behavioral response is caused by the nonlinear response of plankton ensembles to the intensity of the attractor stimulus. As the intensity of the photostimulation increases, the variability of the phototropic response passes through increase, decrease, and relative stabilization phases. The paper proposes a modification of the photostimulation method-paired photostimulation involving successive exposure to two photostimuli of increasing intensity. The first stimulus stabilizes the behavioral response, while the increase in response to the second stimulus makes it possible to more accurately assess the responsiveness of the plankton ensemble. The paper studies the sensitivity of the method of paired stimulation of the behavioral response of different types of freshwater plankton ensembles: Daphnia magna Straus, Daphnia pulex to the effects of pollutants (potassium bichromate, microplastic). The study demonstrates good reliability and increased sensitivity of this method of detecting changes in environmental toxicity compared to single photostimulation or traditional bioindication through the survival rate of test organisms.

Neoadjuvant therapy with doxorubicin-cyclophosphamide followed by weekly paclitaxel in early breast cancer: a retrospective analysis of 200 consecutive patients treated in a single center with a median follow-up of 9.5 years.

PURPOSE: We analyzed outcomes of doxorubicin-cyclophosphamide (AC) followed by weekly paclitaxel as neoadjuvant chemotherapy (NAC) for breast cancer (BC), in an everyday practice with long-term follow-up of patients. METHODS: All patients (n = 200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007 (n = 99); and subsequently every 2-week dose dense (dd) (n = 101). Clinical pathologic features, treatment course, and outcome information were recorded. Complete pathologic response (pCR) was analyzed according to BC subtype, dose regimen, and stage. RESULTS: Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human epidermal growth factor receptor-2 (HER2)-positive 32.5% (of whom 82% received trastuzumab), hormone receptor-positive/HER2-negative 53%, and triple negative 14.5%. Breast-conserving surgery (BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival (EFS) and overall survival (OS) are 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. CONCLUSION: NAC for BC with AC-paclitaxel can be safely administered in the "real-world' setting with high efficacy. Current efforts are aimed at increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

In Situ Measurements of Plankton Biorhythms Using Submersible Holographic Camera.

The paper presents a diagnostic complex for plankton studies using the miniDHC (digital holographic camera). Its capabilities to study the rhythmic processes in plankton ecosystems were demonstrated using the natural testing in Lake Baikal in summer. The results of in situ measurements of plankton to detect the synchronization of collective biological rhythms with medium parameters are presented and interpreted. The most significant rhythms in terms of the correlation of their parameters with medium factors are identified. The study shows that the correlation with water temperature at the mooring site has the greatest significance and reliability. The results are verified with biodiversity data obtained by the traditional mesh method. The experience and results of the study can be used for the construction of a stationary station to monitor the ecological state of the water area through the digitalization of plankton behavior.

Underwater Holographic Sensor for Plankton Studies In Situ including Accompanying Measurements.

The paper presents an underwater holographic sensor to study marine particles-a miniDHC digital holographic camera, which may be used as part of a hydrobiological probe for accompanying (background) measurements. The results of field measurements of plankton are given and interpreted, their verification is performed. Errors of measurements and classification of plankton particles are estimated. MiniDHC allows measurement of the following set of background data, which is confirmed by field tests: plankton concentration, average size and size dispersion of individuals, particle size distribution, including on major taxa, as well as water turbidity and suspension statistics. Version of constructing measuring systems based on modern carriers of operational oceanography for the purpose of ecological diagnostics of the world ocean using autochthonous plankton are discussed. The results of field measurements of plankton using miniDHC as part of a hydrobiological probe are presented and interpreted, and their verification is carried out. The results of comparing the data on the concentration of individual taxa obtained using miniDHC with the data obtained by the traditional method using plankton catching with a net showed a difference of no more than 23%. The article also contains recommendations for expanding the potential of miniDHC, its purpose indicators, and improving metrological characteristics.

Holography of particles for diagnostics tasks [Invited].

The opportunities and special features of using a multi-purpose digital holographic camera (DHC) adapted for particle research for various diagnostic tasks, such as plankton investigation in its habitat, optical glass diagnostics, and study of defects in single crystals, are investigated. Experimental research with the DHC carried out and described in this paper has demonstrated the universality of the DHC measurement technology and its effectiveness for solving a number of diagnostic tasks in the study of small particles of different natures in various media.

Mutation in TDRD9 causes non-obstructive azoospermia in infertile men.

BACKGROUND: Azoospermia is diagnosed when sperm cells are completely absent in the ejaculate even after centrifugation. It is identified in approximately 1% of all men and in 10%-20% of infertile males. Non-obstructive azoospermia (NOA) is characterised by the absence of sperm due to either a Sertoli cell-only pattern, maturation arrest, hypospermatogenesis or mixed patterns. NOA is a severe form of male infertility, with limited treatment options and low fertility success rates. In the majority of patients, the cause for NOA is not known and mutations in only a few genes were shown to be causative. AIM: We investigated the cause of maturation arrest in five azoospermic infertile men of a large consanguineous Bedouin family. METHODS AND RESULTS: Using whole genome genotyping and exome sequencing we identified a 4 bp deletion frameshift mutation in TDRD9 as the causative mutation with a Lod Score of 3.42. We demonstrate that the mutation results in a frameshift as well as exon skipping. Immunofluorescent staining with anti-TDRD9 antibody directed towards the N terminus demonstrated the presence of the protein in testicular biopsies of patients with an intracellular distribution comparable to a control biopsy. The mutation does not cause female infertility. CONCLUSION: This is the first report of a recessive deleterious mutation in TDRD9 in humans. The clinical phenotype recapitulates that observed in the Tdrd9 knockout mice where this gene was demonstrated to participate in long interspersed element-1 retrotransposon silencing. If this function is preserved in human, our data underscore the importance of maintaining DNA stability in the human male germ line.

Expression of IL-18, IL-18 binding protein, and IL-18 receptor by normal and cancerous human ovarian tissues: possible implication of IL-18 in the pathogenesis of ovarian carcinoma.

Proinflammatory cytokine IL-18 has been shown to be elevated in the sera of ovarian carcinoma patients. The aim of the study was to examine the levels and cellular origin of IL-18, IL-18 binding protein, and IL-18 receptor in normal and cancerous ovarian tissues. Ovarian tissue samples were examined by immunohistochemical staining for IL-18, IL-18BP, and IL-18R and mRNA of these cytokines was analyzed with semiquantitative PT-PCR. IL-18 levels were significantly higher in cancerous ovarian tissues (P = 0.0007), IL-18BP levels were significantly higher in normal ovarian tissues (P = 0.04), and the ratio of IL-18/IL-18BP was significantly higher in cancerous ovarian tissues (P = 0.036). Cancerous ovarian tissues expressed significantly higher IL-18 mRNA levels (P = 0.025), while there was no difference in the expression of IL-18BP mRNA and IL-18R mRNA between cancerous and normal ovarian tissues. IL-18 and IL-18BP were expressed dominantly in the epithelial cells of both cancerous and normal ovarian tissues, while IL-18R was expressed dominantly in the epithelial cells of cancerous ovarian tissues but expressed similarly in the epithelial and stromal cells of normal cancerous tissues. This study indicates a possible role of IL-18, IL-18BP, and IL-18R in the pathogenesis of epithelial ovarian carcinoma.

Phototropic response features for different systematic groups of mesoplankton under adverse environmental conditions.

Current trends in the application of bioindication methods are related to the use of submersible tools that perform real-time measurements directly in the studied aquatic environment. The methods based on the registration of changes in the behavioral responses of zooplankton, in particular Crustaceans, which make up the vast majority of the biomass in water areas, seem quite promising. However, the multispecies composition of natural planktonic biocenoses poses the need to consider the potential difference in the sensitivity of organisms to pollutants. This paper describes laboratory studies of the phototropic response of plankton to attracting light. The studies were carried out on a model natural community that in equal amounts includes Daphnia magna, Daphnia pulex, and Cyclops vicinus, as well as on the monoculture groups of these species. The phototropic response was initiated by the attracting light with a wavelength of 532 nm close to the local maximum of the reflection spectrum of chlorella microalgae. Standard potassium bichromate was used as the model pollutant. The largest phototropic response value is registered in the assemblage. The concentration growth rate of crustaceans in the illuminated volume was 4.5 ± 0.3 ind (L min)-1. Of the studied species, the phototropic response was mostly expressed in Daphnia magna (3.7 ± 0.4 ind (L min)-1), while in Daphnia pulex, it was reduced to 2.4 ± 0.2 ind (L min)-1, and in Cyclops vicinus, it was very small-0.16 ± 0.02 ind (L min)-1. This is caused by peculiar trophic behavior of phyto- and zoophages. The addition of a pollutant, namely potassium bichromate, caused a decrease in the concentration rate of crustaceans in the attracting light zone, while a dose-dependent change in phototropic responses was observed in a group of species and the Daphnia magna assemblage. The results of laboratory studies showed high potential of using the phototropic response of zooplankton to monitor the quality of its habitat thus ensuring the early diagnostics of water pollution. Besides, the paper shows the possibility of quantifying the phototropic response of zooplankton using submersible digital holographic cameras (DHC).

Hemoglobin Levels and Red Blood Cells Distribution Width Highlights Glioblastoma Patients Subgroup With Improved Median Overall Survival.

Glioblastoma multiforme (GBM) is known for its dismal prognosis, though its dependence on patients' readily available RBCs parameters is not fully established. In this work, 170 GBM patients, diagnosed and treated in Soroka University Medical Center (SUMC) over the last 12 years were retrospectively inspected for their survival dependency on pre-operative RBCs parameters. Besides KPS and tumor resection supplemented by oncological treatment, age under 70 (HR = 0.4, 95% CI 0.24-0.65, p = 0.00073), low hemoglobin level (HR = 1.79, 95% CI 1.06-2.99, p = 0.031), and Red Cell Distribution Width (RDW) < 14% (HR = 0.57, 95% CI 0.37-0.88, p = 0.018) were found to be prognostic of patients' overall survival in multivariate analysis, accounting for a false discovery rate of < 5% due to multiple hypothesis testing. According to these results, a stratification tree was made, from which a favorable route highlighted a subgroup of nearly 30% of the cohorts' patients whose median overall survival was 21.1 months (95% CI 16.2-27.2)-higher than the established chemo-radiation standard first-line treatment regimen overall median survival average of about 15 months. The beneficial or detrimental effect of RBCs parameters on GBM prognosis and its possible causes is discussed.

INTRAMEDULLARY SPINAL CORD METASTASIS AS THE PRESENTING FEATURE OF PAPILLARY THYROID CARCINOMA.

OBJECTIVE: The objective of this report is to present an unusual case of intramedullary spinal cord metastasis (ISCM) as the presenting feature of papillary thyroid carcinoma (PTC). METHODS: The presented case includes clinical, biochemical, and imaging findings as well as surgical and pathology reports. Treatment with radioactive iodine (RAI) and the response to this treatment are presented. RESULTS: A 71-year-old woman was evaluated for debilitating low back pain and walking disability. Magnetic resonance imaging demonstrated an oval, lumbar, intramedullary mass with benign features and surgery was scheduled. On preoperative evaluation for the lumbar mass, a multinodular thyroid goiter (unfortunately overlooked previously) was noticed, causing severe narrowing of the trachea. Total thyroidectomy was performed with a pathology diagnosis of PTC. In a second operation, the lumbar lesion was removed and proved to represent metastatic PTC. External beam radiation was subsequently administered to the thyroid bed, lumbar spine, and other skeletal metastases, followed by 150 milliCurie of RAI. A post-treatment scan showed high uptake over the lumbar spine, and skeletal and lung lesions. Clinically, the patient restored her walking ability and back pain improved. CONCLUSION: ISCM rarely is the presenting feature of PTC. Our patient presented with back pain which is the typical, though non-specific symptom, of ISCM. She showed good clinical response to multimodal treatment which is in line with the few other differentiated thyroid cancer patients with ISCM reported in the literature. Prompt surgical resection, followed by external beam radiation and RAI, may improve neurological signs, alleviate pain, and improve quality of life.

Distinct expression and localization of TNF system in ovarian carcinoma tissues: possible involvement of TNF-α in morphological changes of ovarian cancerous cells.

BACKGROUND/AIM: It has been previously shown that epithelial ovarian carcinoma tissues express high levels of tumor necrosis alpha (TNF-α), interleukin (IL)-6, IL-1α and IL-1ß. The aim of the present study was to evaluate the localization of TNF-α and its receptors (TNFR1 and TNFR2) in different types of ovarian carcinoma tissues and the possible role of TNF in the pathogenesis of epithelial ovarian carcinoma. MATERIALS AND METHODS: Total RNA was extracted from normal and cancerous ovarian tissues and mRNA was analyzed with semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). Immunohistochemical staining was performed with use of antibodies against human (ah)TNFR1 and TNF2. RESULTS: TNF-α mRNA and TNFR2 mRNA levels were significantly higher in ovarian carcinoma tissues than in normal ovarian tissues, whereas TNFR1 mRNA levels were similar. TNFR1 and TNFR2 were mainly localized in the epithelial neoplastic cells of the tumor. Knocking-down TNF-α activity with αhTNF-a altered ovarian carcinoma cell morphology (with more branches) in vitro. CONCLUSION: Our study indicates a possible role of TNF-α in epithelial ovarian carcinoma pathogenesis through TNFR2, which affects morphological changes, which may be involved ovarian cancer pathogenesis.

Thalidomide distinctly affected TNF-α, IL-6 and MMP secretion by an ovarian cancer cell line (SKOV-3) and primary ovarian cancer cells.

BACKGROUND: Thalidomide inhibits TNF-α production in lipopolysaccharide-stimulated monocytes. The aim of this study was to evaluate the effect of thalidomide on TNF-α, IL-6 and MMP secretion in epithelial ovarian carcinoma cells. MATERIALS AND METHODS: SKOV-3 cells and primary epithelial ovarian carcinoma cells were cultured in the presence of various concentrations of thalidomide. Cell proliferation was examined by MTT proliferation assay. TNF-α and IL-6 levels were determined in the supernatants of the cell cultures by ELISA, and MMP activity was examined by gelatin zymography. RESULTS: Thalidomide did not significantly affect the proliferation and growth of SKOV-3 cells. However, it decreased significantly the capacity of SKOV-3 cells and primary epithelial ovarian carcinoma cells to secrete TNF-α. Thalidomide also significantly decreased the capacity of SKOV-3 cells, but not primary epithelial ovarian carcinoma cells, to secrete MMP-9 and MMP-2. However, thalidomide did not affect IL-6 secretion in SKOV-3 cells or primary epithelial ovarian carcinoma cells. CONCLUSION: Our study suggests that thalidomide distinctly affected TNF-α, IL-6 and MMPs secretion by an ovarian carcinoma cell line (SKOV-3) and primary ovarian cancer cells. This might suggest a different susceptibility of these two types of cells to thalidomide, and/or that the mechanisms of secretion of the factors examined are differently regulated in these cells. Our results may deepen our understanding the mechanism/s of action of thalidomide in ovarian carcinoma cells. The results might have important implications in future therapeutic strategies that will incorporate thalidomide and other cytokine inhibitors in the treatment of epithelial ovarian carcinoma.

Differential optical spectropolarimetric imaging system assisted by liquid crystal devices for skin imaging.

Skin cancer diagnosis depends not only on histopathological examination but also on visual inspection before and after the excision of suspected lesion. Neoplasm is accompanied with changes in birefringence of collagen, pleomorphicity, and hyperchromatic state of epithelial nuclei. These phenomena can be measured by spectral and polarization changes of light backscattered by the examined tissue. A new differential spectropolarimetric system is proposed using liquid crystal devices, one as a tunable filter and the other as a polarization rotator, both operating at wide spectral ranges from the visible to the near-infrared. Since collagen's fibrils texture orientation depends on its location in the skin and since it is not well organized, our system scans the bipolarization states by continuously rotating the linearly polarized light incident on a skin lesion, and collecting differential contrasts between sequenced images when simultaneously averaging the statistical readout of a video camera. This noninvasive method emphasizes areas on skin where the neoplasm, or tumor, minimizes the statistical polarization change of the scattered light from the lesion. The module can be considered as an assistant tool for epiluminescence microscopy. Images of skin tumors were captured in vivo before the patients having their surgery and compared to histopathological results.

Distinct expression of interleukin-1α, interleukin-1ß, and interleukin-1 receptor antagonist in testicular tissues and cells from human biopsies with normal and abnormal histology.

Cytokines are paracrine/autocrine growth factors known to affect testicular cell functions. The cellular origin and expression levels of interleukin-1 (IL-1) in human normal and pathological testicular biopsies are not yet clear. In the present study, we have investigated the levels and cellular origin of IL-1 family members [IL-1α, IL-ß, and IL-1 receptor antagonist (IL-1ra)] in human testicular normal and abnormal biopsies with incomplete maturation arrest (IMA) or Sertoli only syndrome (SOS), using real-time polymerase chain reaction and immunohistochemical staining analysis. Our results show that the levels of IL-1α were higher in Leydig/interstitial cells of biopsies with IMA and SOS compared with normal. The levels of IL-1α in Sertoli cells of normal biopsies were higher than IMA and SOS. The mRNA levels of IL-1α were similar in all biopsies. IL-1ß levels were higher in Leydig/interstitial cells of normal biopsies compared with Sertoli and germ cells. The levels of IL-1ß were similar in testicular cells of all biopsies. However, the mRNA levels of IL-1ß were significantly lower in SOS and IMA biopsies compared with normal. IL-1ra was expressed only in Leydig/interstitial cells, and their expression in normal biopsies was higher than in biopsies with IMA and SOS. The mRNA levels of IL-1ra were similar in all biopsies. Thus, it is possible to suggest the involvement of IL-1 system in the regulation of spermatogenesis and male infertility.