Sentinel lymph node (SLN) isolated tumor cells (ITCs) in otherwise stage I/II endometrioid endometrial cancer: To treat or not to treat?

OBJECTIVES: To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC). METHODS: A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS. RESULTS: 175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/- radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11-3.52, and HR = 0.90, 95%CI 0.22-3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS. CONCLUSIONS: Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made.

Endometrial carcinoma recurrence according to race and ethnicity: An NRG Oncology/Gynecologic Oncology Group 210 Study.

Non-Hispanic black (NHB) women are more likely to experience an endometrial carcinoma (EC) recurrence compared to non-Hispanic white (NHW) women. The extent to which tumor characteristics, socioeconomic status (SES) and treatment contribute to this observation is not well defined. In the NRG Oncology/Gynecology Oncology Group (GOG) 210 Study we evaluated associations between race/ethnicity and EC recurrence according to tumor characteristics with adjustment for potential confounders. Our analysis included 3,199 NHW, 532 NHB and 232 Hispanic women with EC. Recurrence was documented during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between race/ethnicity and EC recurrence in models stratified by histologic subtype (low-grade endometrioid, high-grade endometrioid, serous, mixed cell, carcinosarcoma, clear cell) or stage (I, II, III) and adjusted for age, SES, body mass index, smoking status and treatment. In histologic subtype-stratified models, higher EC recurrence was noted in NHB women with low-grade endometrioid (HR = 1.94, 95% CI = 1.21-3.10) or carcinosarcomas (HR = 1.66, 95% CI = 0.99-2.79) compared to NHWs. In stage-stratified models, higher EC recurrence was noted among NHB women with stage I (HR = 1.48, 95% CI = 1.06-2.05) and Hispanic women with stage III disease (HR = 1.81, 95% CI = 1.11-2.95). Our observations of higher EC recurrence risk among NHB and Hispanic women, as compared to NHW women, were not explained by tumor characteristics, SES, treatment or other confounders. Other factors, such as racial differences in tumor biology or other patient factors, should be explored as contributors to racial disparities in EC recurrence.

Cognitive appraisal of environmental stimuli induces emotion-like states in fish.

The occurrence of emotions in non-human animals has been the focus of debate over the years. Recently, an interest in expanding this debate to non-tetrapod vertebrates and to invertebrates has emerged. Within vertebrates, the study of emotion in teleosts is particularly interesting since they represent a divergent evolutionary radiation from that of tetrapods, and thus they provide an insight into the evolution of the biological mechanisms of emotion. We report that Sea Bream exposed to stimuli that vary according to valence (positive, negative) and salience (predictable, unpredictable) exhibit different behavioural, physiological and neuromolecular states. Since according to the dimensional theory of emotion valence and salience define a two-dimensional affective space, our data can be interpreted as evidence for the occurrence of distinctive affective states in fish corresponding to each the four quadrants of the core affective space. Moreover, the fact that the same stimuli presented in a predictable vs. unpredictable way elicited different behavioural, physiological and neuromolecular states, suggests that stimulus appraisal by the individual, rather than an intrinsic characteristic of the stimulus, has triggered the observed responses. Therefore, our data supports the occurrence of emotion-like states in fish that are regulated by the individual's perception of environmental stimuli.

Reproductive and hormonal factors and mortality among women with colorectal cancer in the NIH-AARP Diet and Health Study.

BACKGROUND: Although use of menopausal hormone therapy (MHT) and some reproductive factors have been associated with colorectal cancer (CRC) risk, relations between these factors and survival after CRC diagnosis are unclear. METHODS: Among 2053 post-menopausal women diagnosed with incident CRC in the NIH-AARP Diet and Health Study, we calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards regression to test associations between oral contraceptive (OC) use, menarche age, age at first birth, parity, menopausal age, and MHT use with all-cause and CRC-specific mortality. RESULTS: There were 759 deaths (332 CRC-related deaths) over a median follow-up of 7.7 years. We observed no statistically significant associations between OC use, menarche age, age at first birth, parity, menopausal age, and mortality. Compared with never MHT use, former use was not associated with mortality, but we found an inverse association among baseline current users, for both all-cause (HR=0.79, 95% CI 0.66-0.94) and CRC mortality (0.76, 0.59-0.99). CONCLUSION: Future studies should further focus on the mechanisms by which exogenous oestrogen exposure might affect tumour progression and CRC survival.

Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2).

BACKGROUND: Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes. METHODS: We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided self-reported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR=1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR=1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer. CONCLUSIONS: Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters.

The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium.

BACKGROUND: Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes. METHODS: We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28,829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma. RESULTS: Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)≥30 vs BMI<25 kg m(-2) (OR: 1.73, 95% CI: 1.22-2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41-3.83). Older age at menarche was inversely associated with uterine sarcoma risk (≥15 years vs <11 years (OR: 0.70, 95% CI: 0.34-1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82-3.26) or MMMTs (OR: 2.25, 95% CI: 1.60-3.15, P-heterogeneity=0.01). CONCLUSION: In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed.

Associations between hepatocyte growth factor, c-Met, and basic fibroblast growth factor and survival in endometrial cancer patients.

BACKGROUND: Hepatocyte growth factor (HGF), c-Met, and basic fibroblast growth factor (bFGF) are molecular markers that contribute to angiogenesis and proliferation in numerous cancers. We assessed the prognostic significance of these factors in tumour and stroma of endometrial cancer (EC) patients (n=211). METHODS: Immunohistochemistry (IHC) was used to detect tumour and stromal protein expression of the biomarkers. Associations between expression and clinicopathological factors were assessed using Chi-square tests. Kaplan-Meier curves, log-rank tests, and Cox regression were used to summarise associations between biomarker expression and overall survival (OS) and recurrence-free survival (RFS). RESULTS: Tumour bFGF was significantly associated with high-grade endometrioid and clear cell histology (P<0.001), advanced stage (P=0.008), positive lymph-node involvement (P=0.002), poor OS (log-rank test, P=0.009), and poor RFS (P<0.001). In multivariable analyses, cases with HGF-positive, stromal bFGF-positive tumours had a lower risk of death compared with cases with HGF-positive, stromal bFGF-negative tumours (hazard ratio (HR): 0.14, 95% CI: 0.03, 0.60). Cases with HGF-positive, bFGF-positive tumours had a higher risk of recurrence compared with cases with negative expression of both markers (HR: 9.88, 95% CI: 2.63, 37.16). CONCLUSION: These IHC data show that tumour and stromal bFGF expression have opposite associations with survival outcomes in EC patients. If confirmed in larger studies, tumour-derived bFGF could be an attractive target in EC therapy.

Carotid body remodelling in l-NAME-induced hypertension in the rat.

The carotid body (CB) is a chemoreceptor organ located at the bifurcation of the common carotid artery. It is made up of the carotid glomus, a structure containing type 1 cells surrounded by type 2 cells. The aim of this study was to evaluate the morphological changes of the CB and carotid glomus in the rat model of l-NAME-induced hypertension. Male Wistar rats were divided in two groups: control untreated rats (C) and rats receiving l-NAME 40 mg/kg/day (LN) for 6 weeks. At the end of the experiment, the systolic blood pressure was 63% higher in the LN group compared with the C group. Morphometric analysis showed that the area of the CB was 29% greater in the LN group compared with the C group. The density of nuclei in the CB was similar between groups, but it was 31% less in the carotid glomus of the LN group. Cells in the CB of the LN group displayed cytoplasmic vacuolation and expressed several biogenic amines. There were more elastic fibres, proteoglycans and collagen fibres in the LN group compared with the C group. Immunohistochemistry showed increased expression of nuclear factor kB, substance P, vascular endothelial growth factor and neuronal nitric oxide synthase in the LN group, while expression of the protein gene product 9.5 was decreased. l-NAME alters cell morphology and the expression of extracellular matrix molecules in the CB and carotid glomus in rats with l-NAME-induced hypertension.

Primary implant stability after maxillary sinus augmentation with autogenous mesenchymal stem cells: a biomechanical evaluation in rabbits.

OBJECTIVES: To mechanically evaluate the effect of transplantation of precultured preosteoblasts derived from autogenic adult mesenchymal stem cells (aMSC) for experimental sinus floor augmentation on primary dental implant stability in comparison with conventional augmentation procedures in rabbits. MATERIAL AND METHODS: After experimental sinus floor augmentation with a synthetic bone substitute, autogenous bone transplantation or osteoblast precursor cells, the primary stability of implants inserted in the edentulous part of the upper jaw of New Zealand White Rabbits was examined. Mechanical evaluation was performed by determination of insertion torque values (Osseocare(™) ), percussion testing (Periotest(™) ), resonance frequency analysis (Osstell(™) and scanning laser Doppler vibrometer) and measurement of extraction forces. RESULTS: Evaluation of mechanical properties with percussion testing and resonance frequency analysis with Osstell(™) revealed slightly higher primary stability of the stem cell group whereas the scanning laser Doppler vibrometer and measurement of pull-out forces showed no significant difference to the bone substitute group. Transplantation of autogenous bone graft resulted in the highest primary implant stability. CONCLUSIONS: The three examination modalities proved suitable for the determination of primary implant stability. The experimental maxillary sinus floor augmentation with precultured osteoblast precursor cells from autogenic stems cells clearly enhanced the primary stability of implants compared with the unaugmented sinus and lead to comparable primary mechanical properties to bone substitutes in rabbits. In comparison with the autogenous bone graft stability enhancement by stem cell transplantation declined.

Future directions in the field of endometrial cancer research: the need to investigate the tumor microenvironment.

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. In 2008, approximately 40,000 cases were newly diagnosed. Although the majority of these cancers are curable by means of hysterectomy and radiotherapy, a subset of endometrial tumors exhibits an aggressive phenotype characterized by lymphovascular invasion, high histological grade, and myometrial invasion, leading to poor prognosis. The mechanisms involved in this aggressive transformation are largely unknown, however, interactions between the primary tumor mass and the surrounding stroma likely play a role in this transformation. Despite the fact that research in other common malignancies has elucidated important associations between stromal protein expression and invasion, these mechanisms have been poorly explored in the area of endometrial cancer. In fact, few investigations have been conducted in the area of tumor microenvironment for endometrial tumors. Invasion and metastasis are two primary reasons for treatment failure related to endometrial cancer. Expression of stromal-derived proteins can potentially serve as biomarkers of aggressive disease as well as biomarkers for remission monitoring. In order to study how expression of these proteins relates to the prognosis of endometrial cancer, these proteins need to be explored in large sets of existing data and/or tissue banks. In this paper, we briefly review the role of three stromal related pathways, SDF-1alpha/CXCR4, HGF/c-Met, and VEGF-A in endometrial cancer prognosis as an overview of the literature. We report that the role of SDF-1alpha/CXCR4 and HGF/c-Met in endometrial cancer prognosis remains unclear, whereas the evidence pertaining to VEGF indicates that overexpression is involved in tumor growth and metastasis. Finally, we would like to highlight the need to explore stromal proteins as a potential tool for the detection of aggressive endometrial tumors and explore some of the molecular approaches that can be utilized in the exploration of the tumor environment.

Primary osteoplasty using calvarian bone in patients with cleft lip, alveolus and palate.

PURPOSE: The results of primary bone grafting in terms of initial cleft width, existence or absence of a lateral incisor and scar formation in the donor area are compared. METHODS: After primary osteoplasty with calvarian bone at an average age of 24 months (4-56 months) radiographic assessment was carried out in 31 patients with 40 alveolar clefts. The bone formation in the grafted area was assessed using dental radiographs taken at 66 months on average (13-114 months) after primary bone grafting. According to the Abyholm classification patients were assigned to 4 groups (indices I-IV) with indices I and II being rated as a success. RESULTS: We observed success (indices I and II) in 76% and poor results (index IV) in 14%. The causes for the poor results were an alveolar cleft width of 11-12 mm in three cases, an extraction of a decayed deciduous tooth 17 months after bone grafting in one case and a traumatic transplant loss in another case. The non-existence of a lateral incisor and a broad cleft are related to poor results. CONCLUSION: Based on the results presented, primary bone grafting using calvarial bone seems to be a promising alternative in bridging narrow alveolar defects. This method allows early intervention at an age in which children do not recognize themselves as cleft patients. The preservation of the deciduous teeth is equally important regarding their functional stimulus for bone development.

Conditioning of myocutaneous flaps.

PURPOSE: The improvement of the ischaemic tolerance of myocutaneous flaps is of clinical importance and hence the subject of numerous investigations. METHODS: In an attempt to increase the ischaemic tolerance, 20 myocutaneous flaps (rectus abdominis muscle) in pigs were elevated and perfused with various, established solutions prior to the onset of ischaemia. The flaps were elevated, utilizing the superior epigastric vessels as the pedicle. Ten flaps were flushed with the University of Wisconsin solution, five with the Euro-Collins solution and the last five with a Ringer-Lactate solution, prior to the 6h long, normothermic ischaemia. On the day of operation, the first, third, fifth, seventh and tenth postoperative day clinical examinations and thermography were performed as well as biopsies. Additionally, on the tenth postoperative day, the rate of necrosis was determined morphometrically as the average of three measurements. RESULTS: Ten days after surgery, the flaps pretreated with the University of Wisconsin solution displayed a vital surface area of 89%, the Euro-Collins solution 23% and the Ringer-Lactate solution 14%. Histologically, muscle tissue proved to be more susceptible to ischaemia than skin. CONCLUSION: Regarding the rectus abdominis flap in a pig model, the University of Wisconsin solution proved superior in the prevention of ischaemic injury compared with the Euro-Collins solution and Ringer Lactate. In accordance with the literature, muscle tissue proved to be more susceptible to ischaemia than skin in our study.

Cancer screening and cancer mortality in Nevis, West Indies.

OBJECTIVE: Cancer screening is one approach that can reduce morbidity and mortality through early detection of pre-cancers; however anxiety, fear, and lack of information are important barriers to universal cancer screening in the Caribbean. Nevis is a small island located in the Eastern Caribbean. We report available data on screening prevalence and cancer mortality for four common cancers: cervical, breast, colon and prostate. METHODS: Demographic information, screening utilization (when available) and cancer mortality statistics were obtained from the Charlestown Health Clinic and the annual reports from the Ministry of Health. Moreover physicians and key stakeholders were interviewed to assess current guidelines for cancer screening as well as to indicate areas of need. RESULTS: Cervical cancer screening is under-utilized in Nevis. Between 2001 and 2007, the overall prevalence of Pap testing fluctuated minutely (mean: 6.87%, range: 6.06-7.41%). Systematic screening for breast, colon, and prostate cancer is not routinely performed, thus utilization rates are not available. Cancer mortality varied slightly between 2002 and 2006; prostate cancer had the highest overall crude mortality rate (30.6 deaths/100,000 persons). Physician interviews revealed that adherence to US and European cancer screening guidelines are inappropriate for their population of patients. Breast and prostate cancers are frequently diagnosed in these geographic areas before the age when cancer screening is currently recommended. CONCLUSION: Cancer is perceived as an important health problem by physicians, key stakeholders and citizens, however cancer screening is under-utilized in Nevis. Future research should focus on generating screening guidelines that are relevant for this population, as well as methods to promote screening.

The biosurgical wound debridement: experimental investigation of efficiency and practicability.

The use of maggot therapy is experiencing a revival in the treatment of problem wounds. Although this alternative therapy is ancient, little scientific research has been aimed at standardizing this therapy. The purpose of our investigation was to determine the debridement efficiency of this therapy, i.e., to compare the use of freely crawling maggots with maggots in a Biobag and to estimate the amount of maggots needed for debridement. We designed an artificial wound model and investigated the rate of decomposition of porcine tissue. Two application alternatives were compared, each being carried out either for 3 or for 4 days, (1) maggots that were allowed to crawl freely over the substrate and (2) maggots confined to a Biobag with no direct contact with the wound. We found that a single maggot was capable of debriding approximately 0.15 g of dead tissue per day. Assuming an absolute difference of <0.05 g per day and maggot as clinically irrelevant, the debridement efficiency of free maggots appears to be similar to those in a Biobag. We were able to determine for the first time the average debriding ability of maggots and thus provide the clinician with data that may help to optimize the maggot therapy by facilitating more exact approximations of the number of maggots needed. Furthermore, the result that the maggots in the Biobag are equal to free maggots in their debriding efficiency will promote its use, especially with respect to the time saved for changing of the dressings. Also, we were able to show that no direct contact is necessary between the maggots and the wound surface, proving that the mechanical crawling effect appears to be neglectable. Because significantly more tissue was metabolized after 4 than after 3 days, application intervals of 4 days appear more appropriate than those of 3 days.

Cervical soft tissue imaging using a mobile CBCT scanner with a flat panel detector in comparison with corresponding CT and MRI data sets.

OBJECTIVE: The aim of this study was to evaluate soft tissue image quality of a mobile cone-beam computed tomography (CBCT) scanner with an integrated flat-panel detector. STUDY DESIGN: Eight fresh human cadavers were used in this study. For evaluation of soft tissue visualization, CBCT data sets and corresponding computed tomography (CT) and magnetic resonance imaging (MRI) data sets were acquired. Evaluation was performed with the help of 10 defined cervical anatomical structures. RESULTS: The statistical analysis of the scoring results of 3 examiners revealed the CBCT images to be of inferior quality regarding the visualization of most of the predefined structures. Visualization without a significant difference was found regarding the demarcation of the vertebral bodies and the pyramidal cartilages, the arteriosclerosis of the carotids (compared with CT), and the laryngeal skeleton (compared with MRI). Regarding arteriosclerosis of the carotids compared with MRI, CBCT proved to be superior. CONCLUSIONS: The integration of a flat-panel detector improves soft tissue visualization using a mobile CBCT scanner.