Quantification of enamel decussation in gracile and robust capuchins (Cebus, Sapajus, Cebidae, Platyrrhini).

Multiple behavioral and biomechanical analyses have demonstrated that capuchin monkeys (Cebus and Sapajus) are specialized for breaking down hard-object foods as compared to other cebid monkeys. In addition to a complex suite of craniodental adaptations, it has specifically been demonstrated that capuchins possess highly complex dental enamel, with extensive Hunter-Schreger banding and other decussation, that likely serve as an adaptation to resist crack propagation during hard-object feeding. Furthermore, it has been demonstrated that robust capuchins (Sapajus spp., formerly Cebus apella) demonstrate further adaptation for hard-object feeding than other capuchins, routinely breaking down extremely mechanically challenging foods. However, there has been no comparison of dental enamel complexity in robust versus gracile capuchins, to assess whether the dental enamel in Sapajus follows this same pattern of further specialization. Therefore, this study compares dental enamel complexity in images of dental thin sections from a sample of robust versus gracile capuchins using image compression ratio (ICR) analysis. ICR is a variable that correlates with enamel complexity, such that higher ICR values are indicative of increased complexity in the form of enamel decussation. We found no significant difference between robust and gracile capuchins when assessing all teeth in our sample together, however, we did find that robust capuchins have significantly higher ICR values than gracile capuchins for canine teeth, specifically. Our results support prior studies suggesting that robust capuchins are specialized to generate increased masticatory loads with their anterior dentition, specifically, as compared to gracile species.

Enamel multidien biological timing and body size variability among individuals of Chinese Han and Tibetan origins.

AIMS: To measure the number of days of enamel formation between periodic striae of Retzius growth lines, the Retzius periodicity (RP), and to compare this multi-day, or multidien rhythm, to body height and weight among people from Beijing, China and Lhasa, Tibet/China. SUBJECTS AND METHODS: Subjects requiring dental extractions from clinics in Beijing, China (N = 338) and Lhasa, Tibet/China (N = 227) provided a tooth and body size information. Multiple observers examined histological sections of the teeth and recorded RP. RP values were statistically compared to body height and weight. RESULTS: In Beijing and Lhasa samples, respectively, average height was 166.38 and 165.70 cm, average weight was 59.53 and 66.53 kg, and average RP was 7.47 and 7.69 d. Statistically significant differences were found between Beijing and Lhasa weight and RP means. Correlations for height and weight against RP were significant, but only comparatively strong for height. CONCLUSIONS: Supporting the negative correlation presented in previous studies, RP is negatively associated with height and weight among a large intraspecific sample of people from Beijing and Lhasa. RP represents a metabolic-mediated multidien biological timing mechanism responsible for the rate of cell proliferation and maintenance of the body.

A comprehensive survey of Retzius periodicities in fossil hominins and great apes.

Recent studies have provided great insight into hominin life history evolution by utilizing incremental lines found in dental tissues to reconstruct and compare the growth records of extant and extinct humans versus other ape taxa. Among the hominins, studies that have examined Retzius periodicity (RP) variation have come to contradictory conclusions in some instances. To clarify RP variation among hominins and better place this variation in its broader evolutionary context, we conduct the most comprehensive analysis of published RP values for hominins and great apes to date. We gathered all available data from the literature on RP data from extant humans, great apes, and fossil hominins and assessed their variation using parametric and nonparametric analyses of variance. We also performed phylogenetic generalized least-squares regressions of RP data for these taxa as well as a larger set of hominoids for which RP data have been published against data for body mass, encephalization, and mean semicircular canal radius (a proxy for metabolic rate). Our results show that modern humans have a mean RP significantly differing from that of other hominins. Pongo also is significantly different from nearly all other taxa in all analyses. Our results also demonstrate that RP variation among hominins scales with respect to body mass, encephalization, and semicircular canal radius similarly to other hominids but that modern humans and Pongo stand out in this regard. Operating within the hypothesis that RP reflects autonomic biorhythms that regulate multiple life history variables, our results reinforce the idea that Homo sapiens has evolved a life history distinct from other hominins, even from other members of Homo, and suggest that many of these life history differences may be driven by hypothalamic output from the brain.

Patterns of surgical care for women with ovarian cancer in New South Wales.

BACKGROUND: Little is known about the delivery of surgical services and outcomes for women with ovarian cancer across New South Wales (NSW). AIM: The study objective was to provide a descriptive analysis of the proportion of women who had surgery for ovarian cancer in NSW in specialist gynaecological oncology hospitals and compare outcomes for women attending specialist and non-specialist services in NSW. MATERIALS AND METHODS: This study is a retrospective analysis of women with primary ovarian, fallopian tube or peritoneal cancer from 2009 to 2012. Data were analysed from the NSW Cancer Registry, NSW Admitted Patient Data Collection and Register of Births Deaths and Marriages. Treating hospitals were characterised as public specialist, public non-specialist and private. Morbidity and mortality outcomes are reported. RESULTS: The study included 1106 women. Fifty-seven hospitals performed surgery: seven public specialist, 27 private and 23 public non-specialist hospitals. The highest proportion of surgery was performed in public specialist hospitals (61%). There was considerable variation in the utilisation of public specialist hospitals between local health districts. There was no significant difference in outcomes related to the type of hospital where surgery was performed. CONCLUSIONS: Although the majority of women are having surgery in a specialist gynaecological oncology public hospital across NSW, many are not. Women living in regional and remote NSW were less likely to have their surgery in a specialist hospital. This is the first step in understanding where women in NSW are currently receiving their surgical care, as well as the outcomes related to this.

Histology of dental long-period biorhythms in Canis familiaris.

Our objective is to assess variation in Havers-Halberg oscillation (HHO) periodicities among domestic dogs (Canis familiaris). The HHO is hypothesized to be a hypothalamic-generated biorhythm coordinating multiple life history variables including body mass and lifespan. Dogs have a broad mass range spanning two orders of magnitude, but this variation has been shown to result from selection on very few genetic loci, and dogs have low variation in other life history traits. Therefore, we predict that HHO variation will not be correlated to body mass among domestic dogs, as it is in anthropoid primates. To test the prediction, we examined dog HHO periodicity via manifestations in tooth enamel and dentine, quantifying HHO rhythm histologically. HHO rhythm is reflected in teeth as the number of days between secretion of successive striae of Retzius (enamel) and Andresen lines (dentine), a value referred to as Retzius periodicity (RP). We counted ca. 24-h growth lines between successive Retzius and Andresen lines to determine RP in histological thin-sections from canine teeth of 19 dogs, representing different breeds and sizes. To test our hypothesis, we regressed RP periodicity against body mass data. Dogs have low RP variation for their body mass range, with a modal periodicity of 5 days and a range of 4-6 days. RP was not significantly correlated with body mass. We conclude that mass variation in dogs does not seem driven by HHO physiology, consistent with findings that IGF1 variants produce dog mass variation. However, low RP (and by extension HHO) variation is consistent with low variation in dog lifespan and gestation, suggesting that dog life history may still be governed by HHO mechanisms even if body mass does not reflect this.

Effect of Total Laparoscopic Hysterectomy vs Total Abdominal Hysterectomy on Disease-Free Survival Among Women With Stage I Endometrial Cancer: A Randomized Clinical Trial.

Importance: Standard treatment for endometrial cancer involves removal of the uterus, tubes, ovaries, and lymph nodes. Few randomized trials have compared disease-free survival outcomes for surgical approaches. Objective: To investigate whether total laparoscopic hysterectomy (TLH) is equivalent to total abdominal hysterectomy (TAH) in women with treatment-naive endometrial cancer. Design, Setting, and Participants: The Laparoscopic Approach to Cancer of the Endometrium (LACE) trial was a multinational, randomized equivalence trial conducted between October 7, 2005, and June 30, 2010, in which 27 surgeons from 20 tertiary gynecological cancer centers in Australia, New Zealand, and Hong Kong randomized 760 women with stage I endometrioid endometrial cancer to either TLH or TAH. Follow-up ended on March 3, 2016. Interventions: Patients were randomly assigned to undergo TAH (n = 353) or TLH (n = 407). Main Outcomes and Measures: The primary outcome was disease-free survival, which was measured as the interval between surgery and the date of first recurrence, including disease progression or the development of a new primary cancer or death assessed at 4.5 years after randomization. The prespecified equivalence margin was 7% or less. Secondary outcomes included recurrence of endometrial cancer and overall survival. Results: Patients were followed up for a median of 4.5 years. Of 760 patients who were randomized (mean age, 63 years), 679 (89%) completed the trial. At 4.5 years of follow-up, disease-free survival was 81.3% in the TAH group and 81.6% in the TLH group. The disease-free survival rate difference was 0.3% (favoring TLH; 95% CI, -5.5% to 6.1%; P = .007), meeting criteria for equivalence. There was no statistically significant between-group difference in recurrence of endometrial cancer (28/353 in TAH group [7.9%] vs 33/407 in TLH group [8.1%]; risk difference, 0.2% [95% CI, -3.7% to 4.0%]; P = .93) or in overall survival (24/353 in TAH group [6.8%] vs 30/407 in TLH group [7.4%]; risk difference, 0.6% [95% CI, -3.0% to 4.2%]; P = .76). Conclusions and Relevance: Among women with stage I endometrial cancer, the use of total abdominal hysterectomy compared with total laparoscopic hysterectomy resulted in equivalent disease-free survival at 4.5 years and no difference in overall survival. These findings support the use of laparoscopic hysterectomy for women with stage I endometrial cancer. Trial Registration: clinicaltrials.gov Identifier: NCT00096408; Australian New Zealand Clinical Trials Registry: CTRN12606000261516.

Lower preoperative quality of life increases postoperative risk of adverse events in women with endometrial cancer: results from the LACE trial.

OBJECTIVE: To examine the association between preoperative quality of life (QoL) and postoperative adverse events in women treated for endometrial cancer. METHODS: 760 women with apparent Stage I endometrial cancer were randomised into a clinical trial evaluating laparoscopic versus open surgery. This analysis includes women with preoperative QoL measurements, from the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, and who were followed up for at least 6 weeks after surgery (n=684). The outcomes for this study were defined as (1) the occurrence of moderate to severe adverse events within 6 months (Common Toxicology Criteria (CTC) grade≥3); and (2) any serious adverse event (SAE). The association between preoperative QoL and the occurrence of AE was examined, after controlling for baseline comorbidity and other factors. RESULTS: After adjusting for other factors, odds of occurrence of AE of CTC grade≥3 were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.00-1.03, p=0.030), which was driven by physical well-being (PWB) (OR=1.09, 95% CI 1.04-1.13, p=0.0002) and functional well-being subscales (FWB) (OR=1.04, 95% CI 1.00-1.07, p=0.035). Similarly, odds of SAE occurrence were significantly increased with each unit decrease in baseline FACT-G score (OR=1.02, 95% CI 1.01-1.04, p=0.011), baseline PWB (OR=1.11, 95% CI 1.06-1.16, p<0.0001) or baseline FWB subscales (OR=1.05, 95% CI 1.01-1.10, p=0.0077). CONCLUSION: Women with early endometrial cancer presenting with lower QoL prior to surgery are at higher risk of developing a serious adverse event following surgery. FUNDING: Cancer Council Queensland, Cancer Council New South Wales, Cancer Council Victoria, Cancer Council, Western Australia; NHMRC project grant 456110; Cancer Australia project grant 631523; The Women and Infants Research Foundation, Western Australia; Royal Brisbane and Women's Hospital Foundation; Wesley Research Institute; Gallipoli Research Foundation; Gynetech; TYCO Healthcare, Australia; Johnson and Johnson Medical, Australia; Hunter New England Centre for Gynaecological Cancer; Genesis Oncology Trust; and Smart Health Research Grant QLD Health.

Opportunistic bilateral salpingectomy during gynaecological surgery for benign disease: A survey of current Australian practice.

BACKGROUND: Recent evidence supports the fallopian tube as the site of origin for many pelvic serous cancers (PSC) including epithelial ovarian cancers (EOC). As a result, a change in practice with opportunistic bilateral salpingectomy (OBS) at the time of hysterectomy has been advocated as a preventative strategy for PSC in a low-risk population. AIMS: The aim of this study was to assess current clinical practice in Australia with respect to OBS during gynaecological surgery for benign indications. MATERIALS AND METHODS: An anonymous online survey was sent to all active Royal Australian and New Zealand College of Obstetrics and Gynaecology (RANZCOG) Fellows in Australia. Data regarding clinician demographics and the proportion of clinicians offering OBS were collected. Reasons for and against offering or discussing OBS were sought. A descriptive analysis was performed. RESULTS: The response rate was 26% (280/1490) with 70% of respondents offering or discussing OBS to women undergoing gynaecological surgery for benign indications, usually at the time of abdominal (96%) or laparoscopic (76%) hysterectomy. The main reason for offering or discussing OBS was current evidence to suggest the fallopian tubes as the site of origin for most EOC. Main reasons for not offering OBS were insufficient evidence to benefit the woman (36%) or being unaware of recent evidence (33%). CONCLUSIONS: The survey responses indicate that OBS is frequently discussed or offered in Australia, usually at the time of hysterectomy. Given the lack of robust evidence to suggest a benefit at a population-based level, a national registry is recommended to monitor outcomes.

Space invaders: Reassessing the histology of hyperostosis frontalis interna.

Hyperostosis frontalis interna (HFI) is a human skeletal lesion characterized by nodules of hyperplastic bone and thickening of the frontal bone's inner surface. Despite its prevalence in the general population and its long history of observation-it is one of the most frequently observed pathologies in gross anatomy laboratories-HFI's etiology and pathogenesis remain poorly understood. This is largely due to the lack of a thorough survey of its histology across the various stages of its development. Our study has three major aims: (1) assess HFI histology from incipient to advanced lesions; (2) elucidate lamellar and trabecular structure in HFI; and (3) clarify impacts/roles of the dura mater in HFI. Sections of nondecalcified bone provide evidence for two different categories of lesions: (1) stratum lesions, characterized by lamellar-based overall thickening of the internal table, and (2) eruptive lesions, characterized by nodular formations of initially lamellar bone that appear to form the bulk of bone mass in advanced stages. Sections of nondecalcified bone also suggest that for both lesion types, HFI growths begin as deposits of lamellar bone, which are later remodeled into woven bone deposits; our data do not support the hypothesis that lesions begin as a "diploization" of cortical bone as suggested by prior studies. Trichrome-stained sections provide evidence that growing lesions erode through and engulf the dura mater, effectively destroying this tissue layer as they grow laterally and inwardly. Our results indicate possible avenues of research to better understand the root causes of this disorder.

Primate enamel evinces long period biological timing and regulation of life history.

The factor(s) regulating the combination of traits that define the overall life history matrix of mammalian species, comprising attributes such as brain and body weight, age at sexual maturity, lifespan and others, remains a complete mystery. The principal objectives of the present research are (1) to provide evidence for a key variable effecting life history integration and (2) to provide a model for how one would go about investigating the metabolic mechanisms responsible for this rhythm. We suggest here that a biological rhythm with a period greater than the circadian rhythm is responsible for observed variation in primate life history. Evidence for this rhythm derives from studies of tooth enamel formation. Enamel contains an enigmatic periodicity in its microstructure called the striae of Retzius, which develops at species specific intervals in units of whole days. We refer to this enamel rhythm as the repeat interval (RI). For primates, we identify statistically significant relationships between RI and all common life history traits. Importantly, RI also correlates with basal and specific metabolic rates. With the exception of estrous cyclicity, all relationships share a dependence upon body mass. This dependence on body mass informs us that some aspect of metabolism is responsible for periodic energy allocations at RI timescales, regulating cell proliferation rates and growth, thus controlling the pace, patterning, and co-variation of life history traits. Estrous cyclicity relates to the long period rhythm in a body mass-independent manner. The mass-dependency and -independency of life history relationships with RI periodicity align with hypothalamic-mediated neurosecretory anterior and posterior pituitary outputs. We term this period the Havers-Halberg Oscillation (HHO), in reference to Clopton Havers, a 17th Century hard tissue anatomist, and Franz Halberg, a long-time explorer of long-period rhythms. We propose a mathematical model that may help elucidate the underlying physiological mechanism responsible for the HHO.

Anatomy and clinical relevance of sub occipital soft tissue connections with the dura mater in the upper cervical spine.

BACKGROUND: The upper cervical region is a complex anatomical structure. Myodural bridges between posterior suboccipital muscles and the dura might be important explaining conditions associated with the upper cervical spine dysfunction such as cervicogenic headache. This cadaver study explored the upper cervical spine and evaluated the myodural bridges along with position of spinal cord in response to passive motion of upper cervical spine. METHODS: A total of seven adult cadavers were used in this exploratory study. The suboccipital muscles and nuchal ligament were exposed. Connections between the Rectus Capitis Posterior major/minor and the Obliquus Capitis minor, the nuchal ligament, posterior aspect of the cervical spine, flavum ligament and the dura were explored and confirmed with histology. The position of the spinal cord was evaluated with passive motions of the upper cervical spine. OUTCOMES: In all cadavers connective tissues attaching the Rectus Capitis Posterior Major to the posterior atlanto-occipital membrane were identified. In the sagittal dissection we observed connection between the nuchal ligament and the dura. Histology revealed that the connection is collagenous in nature. The spinal cord moves within the spinal canal during passive movement. DISCUSSION: The presence of tissue connections between ligament, bone and muscles in the suboccipital region was confirmed. The nuchal ligament was continuous with the menigiovertebral ligament and the dura. Passive upper cervical motion results in spinal cord motion within the canal and possible tensioning of nerve and ligamentous connections.

Comparative dental anatomy in newborn primates: Cusp mineralization.

Previous descriptive work on deciduous dentition of primates has focused disproportionately on great apes and humans. To address this bias in the literature, we studied 131 subadult nonhominoid specimens (including 110 newborns) describing deciduous tooth morphology and assessing maximum hydroxyapatite density (MHD). All specimens were CT scanned at 70 kVp and reconstructed at 20.5-39 µm voxels. Grayscale intensity from scans was converted to hydroxyapatite (HA) density (mg HA/cm3 ) using a linear conversion of grayscale values to calibration standards of known HA density (R2 = .99). Using Amira software, mineralized dental tissues were captured by segmenting the tooth cusps first and then capturing the remainder of the teeth at descending thresholds of gray levels. We assessed the relationship of MHD of selected teeth to cranial length using Pearson correlation coefficients. In monkeys, anterior teeth are more mineralized than postcanine teeth. In tarsiers and most lemurs and lorises, postcanine teeth are the most highly mineralized. This suggests that monkeys have a more prolonged process of dental mineralization that begins with incisors and canines, while mineralization of postcanine teeth is delayed. This may in part be a result of relatively late weaning in most anthropoid primates. Results also reveal that in lemurs and lorises, MHD of the mandibular first permanent molar (M1 ) negatively correlates with cranial length. In contrast, the MHD of M1 positively correlates with cranial length in monkeys. This supports the hypothesis that natural selection acts independently on dental growth as opposed to mineralization and indicates clear phylogenetic differences among primates.

Lamellar bone is an incremental tissue reconciling enamel rhythms, body size, and organismal life history.

Mammalian enamel formation is periodic, including fluctuations attributable to the daily biological clock as well as longer-period oscillations that enigmatically correlate with body mass. Because the scaling of bone mass to body mass is an axiom of vertebrate hard tissue biology, we consider that long-period enamel formation rhythms may reflect corresponding and heretofore unrecognized rhythms in bone growth. The principal aim of this study is to seek a rhythm in bone growth demonstrably related to enamel oscillatory development. Our analytical approach is based in morphology, using a variety of hard tissue microscopy techniques. We first ascertain the relationship among long-period enamel rhythms, the striae of Retzius, and body mass using a large sample of mammalian taxa. In addition, we test whether osteocyte lacuna density (a surrogate for rates of cell proliferation) in bone is correlated with mammalian body mass. Finally, using fluorescently labeled developing bone tissues, we investigate whether the bone lamella, a fundamental microanatomical unit of bone, relates to rhythmic enamel growth increments. Our results confirm a positive correlation between long-period enamel rhythms and body mass and a negative correlation between osteocyte density and body mass. We also confirm that lamellar bone is an incremental tissue, one lamella formed in the species-specific time dependency of striae of Retzius formation. We conclude by contextualizing our morphological research with a current understanding of autonomic regulatory control of the skeleton and body mass, suggesting a central contribution to the coordination of organismal life history and body mass.

Uterine papillary serous carcinoma: patterns of failure and survival.

OBJECTIVE: To evaluate the outcome in patients with uterine papillary serous carcinoma (UPSC). METHODS: A retrospective review of women treated for UPSC between 1995 and 2006 in Westmead Hospital, Sydney. The patients were treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy and surgical staging. The majority of the patients had platinum-based adjuvant chemotherapy and radiotherapy. Sites of initial recurrence were documented. Overall survival (OS) and progression free survival (PFS) were estimated using Kaplan-Meier method. Univariate and multivariate analysis was performed using Cox regression analysis to test the effects of multiple prognostic factors on survival. RESULTS: Two-year and five-year OS was 65% and 43%. The median OS was 39 months. Two-year and five-year PFS was 60% and 35%. Macroscopic residual disease at the completion of surgery was the only significant prognostic factor associated with worse OS on both univariate and multivariate analysis (P < 0.001). The median OS was only 11 months if patients had macroscopic residual disease, and all patients died within 18 months despite adjuvant therapies. Twenty-one patients relapsed. The site(s) of initial recurrence were: vagina (five patients), pelvic lymph nodes (four patients), abdomen (11 patients), para-aortic lymph nodes (six patients), inguinal lymph nodes (two patients) and distant metastases in seven patients. Only one of 16 patients who received vaginal brachytherapy failed in the vagina, but three of seven patients who received external beam pelvic radiotherapy failed in the vagina. CONCLUSION: We recommend optimal cytoreduction surgery with the aim of leaving no macroscopic disease at the end of the operation. Vaginal brachytherapy should be considered as a component of adjuvant radiotherapy. Abdominal failure was the commonest mode of failure in our cohort of patients.

Application of Image Compression Ratio Analysis as a Method for Quantifying Complexity of Dental Enamel Microstructure.

It is well recognized that enamel microanatomy in mammals reflects biomechanical demands placed upon teeth, as determined by mechanical properties of species' diets, use of teeth as weapons, and so forth. However, there are limited options for researchers wishing to perform large-scale comparisons of enamel microstructure with adaptive questions in mind. This is because to date there has been no efficient method for quantification and statistical analysis of enamel complexity. Our study proposes to apply a method previously developed for quantification of 3D tooth cusp morphology to the problem of quantifying microstructural enamel complexity. Here, we use image compression ratio (ICR) as a proxy variable for enamel complexity in 2D enamel photomicrographs taken using circularly polarized transmitted light microscopy. ICR describes the relationship between a digital image captured in an uncompressed file format and the identical image that has had its file size compressed using computer algorithms; more complex images receive less compression. In our analyses, ICR analysis is able to distinguish between images of teeth with simple, radial enamel and teeth with complex decussating enamel. Moreover, our results show a significant correlation between ICR and enamel complexity ranks assigned via visual assessment. Therefore, our results demonstrate that ICR analysis provides a viable methodology for efficient comparison of overall enamel complexity among dental samples. Anat Rec, 302:2279-2286, 2019. © 2019 American Association for Anatomy.

Craniofacial architectural constraints and their importance for reconstructing the early Homo skull KNM-ER 1470.

OBJECTIVE: Our objective is to exploit architectural constraint for the analysis and interpretation of craniofacial form, which we apply here to the reconstruction of the early Homo cranium KNM-ER 1470. We are motivated to perform this study because in the absence of biological criteria our preconceptions are likely to govern our concept of craniofacial form. STUDY DESIGN: We reassembled the fragmented parts--left and right halves of the calvaria and the face--according to mammalian craniofacial architectural constraints described by Donald H. Enlow and colleagues. RESULTS: When evaluated on a biological premise, KNM-ER 1470 is found to have a more prognathic midface than commonly appreciated. The relationship between facial prognathism and cranial capacity also provides an estimate downward for this specimen, from 752cc to ca. 700cc. CONCLUSION: Awareness of our preconceptions is critical to the performance of relatively unbiased research in fields characterized by interpretations of morphology. When perceptual bias is relatively minimized, applied here as an architecturally constrained of KNM-ER 1470 craniofacial skeleton, we are able to provide the scientific community with a more tractable Gestalt perspective of form.

BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition.

PURPOSE: Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. PATIENTS AND METHODS: Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. RESULTS: Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation-positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. CONCLUSION: BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.

Lessons learnt from implementation of a Lynch syndrome screening program for patients with gynaecological malignancy.

Despite a trend towards universal testing, best practice to screen patients presenting with gynaecological malignancy for Lynch syndrome (LS) is uncertain. We report our institutional experience of a co-ordinated gynaecological LS screening program. All patients with endometrial carcinoma or carcinosarcoma, or gynaecological endometrioid or clear cell carcinomas undergo reflex four panel immunohistochemistry (IHC) for MLH1, PMS2, MSH2 and MSH6 followed by cascade somatic hypermethylation analysis of the MLH1 promoter locus for dual MLH1/PMS2 negative tumours. On the basis of these results, genetic counselling and targeted germline mutation testing is then offered to patients considered at high risk of LS. From 1 August 2013 to 31 December 2015, 124 patients were screened (mean age 64.6 years). Thirty-six (29.0%) demonstrated abnormal MMR IHC: 26 (72.2%) showed dual loss of MLH1/PMS2, five (13.9%) dual loss of MSH2/MSH6, three (8.3%) isolated loss of MSH6, and two (5.6%) isolated loss of PMS2. Twenty-five of 26 (96.1%) patients with dual MLH1/PMS2 loss demonstrated MLH1 promoter methylation. Therefore, 11 (8.9%) patients screened were classified as high risk for LS, of whom nine (81.8%) accepted germline mutation testing. Three (2.4% of total screened) were confirmed to have LS, two with germline PMS2 and one with germline MSH2 mutation. Massive parallel sequencing of tumour tissue demonstrated somatic mutations which were concordant with the IHC results in the remainder. Interestingly, the one MLH1/PMS2 IHC negative but not hypermethylated tumour harboured only somatic MLH1 mutations, indicating that universal cascade methylation testing in MLH1/PMS2 IHC negative tumours is very low yield and could be reconsidered in a resource-poor setting. In conclusion, universal screening for LS in patients presenting with gynaecological malignancy using the algorithm described above identified LS in three of 124 (2.4%) of our population. Only three of nine (33.3%) patients considered at high risk for LS by combined IHC and hypermethylation analysis were proven to have LS. Only one of the LS patients was less than 50 years of age and none of these patients would have been identified had more restrictive Amsterdam or Bethesda criteria been applied.

Inflammatory Myofibroblastic Tumors of the Female Genital Tract Are Under-recognized: A Low Threshold for ALK Immunohistochemistry Is Required.

Inflammatory myofibroblastic tumor (IMT) of the female genital tract is under-recognized. We investigated the prevalence of ALK-positive IMT in lesions previously diagnosed as gynecologic smooth muscle tumors. Immunohistochemistry (IHC) for ALK was performed on tissue microarrays of unselected tumors resected from 2009 to 2013. Three of 1176 (0.26%) "leiomyomas" and 1 of 44 (2.3%) "leiomyosarcomas" were ALK IHC positive, confirmed translocated by fluorescence in situ hybridization (FISH) and therefore more appropriately classified as IMT. On review significant areas of all 4 tumors closely mimicked smooth muscle tumors morphologically, but all showed at least subtle/focal features suggesting IMT. Recognizing that the distinction between IMT and leiomyoma/leiomyosarcoma can be subtle, we then reviewed 1 hematoxylin and eosin slide from each patient undergoing surgery for "leiomyoma" from 2014 to 2017 and selected cases for ALK IHC with a low threshold. Of these, 30 of 571 (5.3%) underwent IHC. Two were confirmed to be IHC positive and FISH rearranged. Of the 6 IMTs, only 1 tumor with a previous diagnosis of leiomyosarcoma, an infiltrative margin and equivocal necrosis, metastasized. Of note it demonstrated a less aggressive clinical course compared with most metastatic leiomyosarcomas (alive with disease at 6 y). The patient was subsequently offered crizotinib to which she responded rapidly. In conclusion, IMTs may closely mimic gynecologic smooth muscle tumors. IMTs account for at least 5 of 1747 (0.3%) tumors previously diagnosed as leiomyoma and 1 of 44 (2.3%) as leiomyosarcoma. These tumors may be recognized prospectively with awareness of subtle/focal histologic clues, coupled with a low threshold for ALK IHC.

Biology of epithelial ovarian cancer: implications for screening women at high genetic risk.

PURPOSE: Our aim was to analyze the clinicopathologic features of screen-detected ovarian cancers identified in women, either at general population risk or high genetic risk of ovarian cancer, who have participated in screening studies. METHODS: Studies published between 1988 and April 2003 were categorized by the population screened and the primary screening modalities used. Each report was examined with reference to the histologic type, stage, and grade of screen-detected cancers. Reports of studies of prophylactically removed ovaries from women at high risk of ovarian cancer were also reviewed. RESULTS: Of the stage I tumors detected by screening women at population risk, almost half were borderline ovarian tumors, granulosa-cell tumors, or germ-cell tumors, which is disproportionate to their frequency. Furthermore, of the stage I invasive epithelial cancers diagnosed in women at population risk, the majority were endometrioid, clear-cell, and mucinous histologic subtypes. Most ovarian cancers that occur in women at high genetic risk are high-grade serous cancers, and these are infrequently screen detected at an early stage. CONCLUSION: The clinicopathologic features of screen-detected ovarian cancers suggest that screening may not reduce mortality in women at increased genetic risk. Prospective screening studies are required in genetically high-risk populations to answer this important question. Women electing surveillance should be aware of the lack of proven benefit and the low likelihood of detecting early stage serous cancers. Bilateral salpingo-oophorectomy appears to be the most effective approach to decrease the risk of ovarian cancer and thereby reduce mortality in high-risk women.