High Dose of A Conjugated Linoleic Acid Mixture Increases Insulin Resistance in Rats Fed Either A Low Fat or A High Fat Diet

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-118348

Obesity and related diseases are becoming more prevalent. Conjugated linoleic acid (CLA) might be a useful coadjutant treatment helping to decrease fat mass. However, the precise impact of CLA is unclear because the decreased body fat mass is followed by an increase in insulin resistance. This study aimed to evaluate some of the consequences of a high dose of CLA in rats fed a normal low fat or a high fat diet for 30 days. Male Wistar rats were separated into 4 groups (each n = 10): Control group receiving 7% fat (soybean oil); CLA group receiving 4% soybean oil and 3% CLA mixture; animal fat (AF) group, receiving 45% fat (lard); and animal fat plus CLA (AF+CLA) group, receiving 42% lard and 3% CLA mixture. The CLA mixture contained 39.32 mole% c9,t11-CLA and 40.50 mole% t10,c12-CLA. After 30 days, both CLA groups (CLA and AF+CLA groups) developed insulin resistance, with an increase in glucose in the fasting state and in an insulin tolerance test. The CLA group had increased liver weight and percentage of saturated fatty acids in liver and adipose tissue. Feeding the high fat diet resulted in increased hepatic triacylglycerol accumulation and this was exacerbated by dietary CLA. It is concluded that a high dose of CLA mixture increases insulin resistance and exacerbates hepatic steatosis when combined with a high fat diet.
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© Georg Thieme Verlag KG Stuttgart · New York

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Antral Follicle Diameter Variance Within Each Ovary May Be A Predictor For Poor Response In Cases With Normal Ovarian Reserve

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-125404

Objectives To determine the predictive value of antral follicle diameter variance within each ovary for ovarian response in cases with normal ovarian reserve tests. Methods This is a prospective observational study. One hundred and thirty nine infertile women who underwent ART in IVF-ICSI unit of Zeynep Kamil women and children's Health Training and research hospital between January 2017 to June 2017 were recruited. Blood samples were collected on day 2/day 3 for assessment of serum FSH and estradiol. Trans-vaginal sonography was done for antral follicle count. During antral follicle count, in order to determine antral follicle diameter variance, diameters of the largest and smallest follicles were recorded. Variance was calculated by subtracting the smallest diameter from the largest one. Following ovarian stimulation with antagonist protocol, poor response was determined in cases with total oocyte number≤3. Ovarian reserve tests and antral follicle diameter variance were utilized to predict cases with poor response in women with normal ovarian reserve. Results Antral follicle diameter variance both in right (AUC=0.737, P<0.001) and left (AUC=0.651, P<0.05) ovaries significantly predicted poor ovarian response. Variance>3.5 mm was found to have 75% sensitivity to predict poor response. Basal serum FSH with estradiol levels and AFC failed to predict poor response (P>0.05). Other significant predictors for poor response were day 5 estradiol level and estradiol level at trigger day (P<0.05). In multivariate regression analysis, both AFC and antral follicle diameter variance in the right ovary were found to be significantly associated with clinical pregnancy, on the other hand peak estradiol concentration and antral follicle diameter variance in the right ovary were significantly associated with poor response. Conclusion Antral follicle diameter variance may be utilized to predict poor ovarian response in cases with normal ovarian reserve.
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© Georg Thieme Verlag KG Stuttgart · New York

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Early Stage Graves’ Disease is Uniformly Accompanied by Orbital Immune Activity even in Patients who Fail to Develop Orbithopathy during Follow-up

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-125065

Purpose Graves' orbitopathy (GO) is a complication of Graves' disease (GD), the development of which cannot be predicted at the time of diagnosis of GD. Our aims were (i) to test if orbital 99mTc-labelled diethylenetriamine pentaacetic acid single-photon emission computer tomography (DTPA SPECT) can predict development of GO later during the course of the disease and (ii) to study whether orbital immune activity can be detected in GD patients who do not develop GO during follow-up. Methods Fifty-four orbits of 27 patients with newly diagnosed GD were entered into the case-control study. Individuals showing signs of GO at enrolment were excluded. During the two-year follow-up, eye signs were recorded every 3 months. Orbital DTPA uptakes on SPECT images were measured when entering the study and at the end of the follow-up period, or when clinical signs of GO developed, whichever occurred first. Results During the follow-up, 6 patients (22%) were diagnosed with GO. There was no significant difference between the initial DTPA uptakes of the patients with or without later developing GO (10.45±1.72 MBq/cm3 vs. 9.18±1.18 MBq/cm3 respectively). However, the DTPA uptakes of both GD groups (ie. with and without GO) were higher than that of the control group (7.45±1.36 MBq/cm3, p<0.05). Conclusions We have shown that GD is accompanied by moderate orbital immune activity in GD patients without GO, irrespective of later development of GO. Why this orbital autoimmunity remains subclinical in the majority of the cases, and progresses into clinically detectable GO in others, remains unclear.
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Tanshinone IIA Improves Painful Diabetic Neuropathy by Suppressing the Expression and Activity of Voltage-Gated Sodium Channel in Rat Dorsal Root Ganglia

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0044-100722

Painful diabetic neuropathy (PDN) is one of the intractable complications of diabetes mellitus, which manifest as exaggerated pain perception. Previous studies showed that Tanshinone IIA (TIIA), one of the major bioactive extracts of Salvia miltiorrhiza Bunge, have obvious analgesic effect on different types of pain process, and the underlying analgesic mechanisms are not fully understood. The present study combined the behavioral, electrophysiological and biochemical methods to elucidate the analgesic mechanism of TIIA, using streptozotocin (STZ)-induced PDN rat models. Intraperitoneal injection (i.p.) of TIIA for 3 weeks in PDN rats significantly improved mechanical allodynia and thermal hyperalgesia. Patch clamp recordings showed that the excitability of dorsal root ganglion (DRG) nociceptive neuron was increased in diabetic state, and TIIA treatment effectively recovered the subnormality, which was achieved by preventing augments of both Tetrodotoxin-sensitive (TTX-resistant) and Tetrodotoxin-sensitive (TTX-S) sodium currents. Further, the protein expressions of voltage-gated sodium channels (VGSCs) α-subunits Nav1.3, Nav1.7 and Nav1.9 increased in DRG of diabetic rats and were normalized by TIIA application. In conclusion, this study provides evidence that the TIIA attenuated PDN by effecting VGSCs activities and expressions, indicating that the TIIA could be a promising agent for PDN treatment.
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© Georg Thieme Verlag KG Stuttgart · New York

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The PCOS Patients differ in Lipid Profile According to their Phenotypes

Exp Clin Endocrinol Diabetes
DOI: 10.1055/s-0043-121264

Polycystic ovary syndrome (PCOS) affects 4–18% of women of reproductive age. The number of reports exploring the lipid profiles among PCOS patients and number of studied patients are limited. The aim of our study was to assess the lipid profile separately in lean and non-lean women with polycystic ovary syndrome divided according to hyperandrogenemia, defined as free androgen index (FAI)≥5. The second aim was to compare the lipid profiles among lean and non-lean PCOS patients with respect to hyperandrogenemia and regularity of menstruation cycles. We evaluated 232 patients from Department of Endocrinological Gynecology, Jagiellonian University Medical College in Krakow diagnosed with PCOS. The population consisted of 166 lean and 66 non-lean women. We observed higher levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C) in lean patients with FAI<5 than in lean patients with FAI≥5. There were no differences in lipid profile between non-lean patients with FAI≥5 and non-lean patients with FAI<5. Among lean patients higher total cholesterol levels were observed in those with irregular menstruation cycles and FAI<5 than in patients with FAI≥5 and regular cycles. There were no differences in lipid profiles between four phenotypes among non-lean PCOS patients. Conclusions The results of our study showed differences in lipid profile between lean PCOS patients according to their phenotype based on androgens' level. This effect was abandoned by fat tissue mass in non-lean ones. Further studies should be conducted to explore these associations.
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© Georg Thieme Verlag KG Stuttgart · New York

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New findings in non-invasive imaging of cutaneous endometriosis: Dermoscopy, high-frequency ultrasound and reflectance confocal microscopy

Abstract

Background

Cutaneous endometriosis (CE) is rare and its dermoscopic features were reported only in 3 patients. The aim of this study was to examine a case of pigmented CE with multiple non-invasive imaging techniques, to compare the obtained images with histopathology and to define their utility in an early diagnosis of the disease.

Case report

We performed dermoscopy, high-frequency ultrasound (HFUS), in vivo and ex vivo reflectance confocal microscopy (RCM) of a pigmented CE arising on the caesarean scar of a phototype IV patient, along with histologic studies. Dermoscopy showed a greyish background and a brownish pigmentation. HFUS shows well-demarcated anechoic areas corresponding to ectopic endometrial tissue at histopathologic examination. RCM and OCT only showed the alterations of the epidermis.

Conclusion

High-frequency ultrasound could represent a very useful tool for an early diagnosis of CE and its usefulness could be tested in patients with unusual cyclical pain, even before skin lesion appearance. RCM allowed the visualization of skin surface modification due to underlying endometriosic tissue. Dermoscopy showed a new aspect that was probably related to the mix of blood extravasation (ie, greyish background) and epidermal pigmentation (ie, brown pigmentation).

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Benign and malignant collision tumors of melanocytic skin lesions with hemangioma: Dermoscopic and reflectance confocal microscopy features

Abstract

Background

Though the combination/collision of nevi or lentigo simplex and hemangiomas is frequent, the malignant collision tumor melanoma-hemangioma is exceptional and can sometime clinically simulate a benign collision. To date, a series of collision tumors of hemangiomas associated with either benign or malignant melanocytic skin lesions (MSL) has yet to be studied by non-invasive imaging and clinico-pathologic correlates.

Methods

We present 10 cases of patients with collision tumors of hemangioma with different MSL including: 2 in situ lentigo-maligna melanoma, 1 invasive melanoma, 5 melanocytic nevi, and 2 lentigo simplex. The clinical aspect along with the dermoscopic and reflectance confocal microscopy (RCM) features is described and compared with histopathologic findings.

Results

Dermoscopic examination allows to recognize a dark ring in malignant collision melanoma-hemangioma and a jelly ring sign in benign collision of nevi/lentigo simplex-hemangioma. These peculiar features were confirmed by RCM and histopathologic findings.

Conclusion

Two simple dermoscopic clues confirmed by RCM features can be proposed to help distinguish between benign and malignant collisions tumors.

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Immunohistochemical evaluation of H3K27 trimethylation in malignant peripheral nerve sheath tumors

Publication date: Available online 31 January 2018
Source:Pathology - Research and Practice
Author(s): Hiroshi Otsuka, Kenichi Kohashi, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yuichi Yamada, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda
The histological definitive diagnosis of malignant peripheral nerve sheath tumor (MPNST) is quite difficult because the morphological features are not specific and no useful immunohistochemical marker has been identified. Loss-of-function mutations in EED or SUZ12, which encode the core subunit of polycomb repressive complex 2 (PRC2), were reported in MPNSTs, and the mutations were shown to cause inactivation of PRC2, leading to loss of trimethylation of histone H3 at lysine 27 (H3K27me3). Immunohistochemistry of H3K27me3 is expected to be a specific marker for MPNSTs. We evaluated immunohistochemical expression of H3K27me3 in MPNSTs with heterologous components and metachronous cases of MPNSTs. Among 145 MPNST samples, 50 (34.5%) showed complete loss of staining, and 45 (31.0%) showed partial loss of staining. Regarding the backgrounds of MPNSTs, 74 samples of neurofibromatosis type 1 (NF-1)-associated MPNST demonstrated 26 (35.1%) complete and 26 (35.1%) partial loss of H3K27me3. Among MPNSTs with heterologous component, almost all of MPNSTs with epithelioid differentiation (8/9 samples, 88.9%) retained H3K27me3, and malignant Triton tumors without epithelioid component lacked H3K27me3 at high rate (91.7%). Five of 20 metachronous MPNST cases showed significantly reduced expression of H3K27me3 between primary and later-occurring tumors, but in some cases increased expression of H3K27me3 in the clinical course (such as complete loss to partial loss) was observed. If the tumors are recurrent or metastatic, H3K27me3 expression should be reduced or at least maintained because loss of H3K27me3 is due to genetic mutation of EED or SUZ12. MPNSTs, especially those associated with NF-1, can occur in heterochronous and multiple patterns, and the identification of increased expression of H3K27me3 during a patient's clinical course can be helpful for determining whether the tumors are heterochronous, multiple or not. As heterochronous and multiple tumors may show lower malignancy compared to recurrent or metastatic tumors, favorable prognosis may be expected when H3K27me3 expression is increased.



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Downregulation of SETD8 by MiR-382 is involved in glioma progression

Publication date: Available online 31 January 2018
Source:Pathology - Research and Practice
Author(s): Zhiming Ma
BackgroundSETD8 (named PR-SET7 or KMT5a) has been reported to regulate various biological processes including carcinogenesis. However, the role of SETD8 in glioma progression has not been investigated.MethodqPCR and western blot were used to detect the expression levels of miR-382 and SETD8. MTT and wound healing assay used to detect the cell proliferation and migratory capability. A predicted target of miR-382 (SETD8) was first validated using a luciferase assay.ResultsIn this study, we found that SETD8 expression was evidently upregulated in glioma tissues and glioma cells, compared with the adjacent normal tissues and normal human astrocytes (NHA). Next, we showed that SETD8 evidently induced cell proliferation and migration in vitro and in vivo. In addition,dual-luciferase assays revealed that miR-382 directly regulates oncogenic SETD8 expression in U87 and U251 cells. Finally a statistically significant inverse correlation of miR-382 and SETD8 expression was observed in 30 glioma patients.ConclusionThese data indicated that oncogenic SETD8 was regulated by miR-382 and involved glioma progression, .revealing new therapeutic targets for glioma cancer.



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Knowledge of resting heart rate mediates the relationship between intelligence and the heartbeat counting task

Publication date: Available online 31 January 2018
Source:Biological Psychology
Author(s): Jennifer Murphy, Edward Millgate, Hayley Geary, Eri Ichijo, Michel-Pierre Coll, Rebecca Brewer, Caroline Catmur, Geoffrey Bird
Evidence suggests that intelligence is positively associated with performance on the heartbeat counting task (HCT). The HCT is often employed as measure of interoception – the ability to perceive the internal state of one's body – however it's use remains controversial as performance on the HCT is strongly influenced by knowledge of resting heart rate. This raises the possibility that heart rate knowledge may mediate the previously-observed association between intelligence and HCT performance. Study One demonstrates an association between intelligence and HCT performance (N = 94), and Study Two demonstrates that this relationship is mediated by knowledge of the average resting heart rate (N = 134). These data underscore the need to account for the influence of prior knowledge and beliefs when examining individual differences in cardiac interoceptive accuracy using the HCT.



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Electrophysiological individual face adaptation effects with fast periodic visual stimulation resist long interruptions in adaptation

Publication date: Available online 31 January 2018
Source:Biological Psychology
Author(s): Segolene Lithfous, Bruno Rossion
This study used fast periodic visual stimulation (FPVS) and electroencephalography (EEG) to investigate whether the reduction of face adaptation effects over time is due to the introduction of a novel stimulus. In adapting sequences, one individual face was presented at a rate of 6 Hz over 60 sec. In testing sequences this adapted face was alternated with a novel individual face at the same rate for 20 sec, so that face identity was repeated at a frequency of 3 Hz (i.e. 6 Hz/2). Testing sequences started immediately or 9–15 sec after adapting sequences. Identity adaptation produced a selective response at 3 Hz over the right occipito-temporal cortex both with and without delay after adapting sequences. These results suggest that the adaptation effect persists for several seconds, and that the decay of the adaptation effect is due to the introduction of a novel face stimulus.



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The Late Posterior Negativity in Episodic Memory: A Correlate of Stimulus Retrieval?

Publication date: Available online 31 January 2018
Source:Biological Psychology
Author(s): Kathrin Sommer, Salvatore Vita, Vilfredo De Pascalis
We investigated whether the late posterior negativity (LPN) is a component linked to stimulus retrieval or rather to complex, higher-order stimulus evaluation processes or response preparation processes. Participants performed three separate tasks across separate sessions: an encoding task, a memory recognition task, and a visual discrimination task. In the visual discrimination task, the difficulty of stimulus evaluation was manipulated via stimuli varying in complexity (easy vs. moderately difficult) and duration of stimulus presentation (short vs. long). Three indices of the LPN peak were examined: amplitude, latency, and width. The LPN was present in all three tasks, with maximum amplitudes at occipital sites. Results of the visual discrimination task showed that the LPN amplitude is modulated by task difficulty. No latency differences were observed between short and long presentations, suggesting that the LPN is not related to response preparation. Consequently, we compared the LPN associated with short presentations of easy and difficult stimuli with the LPN of the encoding and memory task. The LPN amplitude was more negative in the memory task compared to the other tasks. Latency and width of the LPN were modulated by stimulus complexity, with increased latency and width in the encoding and memory task relative to the visual discrimination task. Overall, these findings suggest that the LPN is not a component linked to stimulus retrieval and response preparation, but rather to complex, higher-order stimulus evaluation processes, which are modulated by task difficulty.



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Haptic recognition memory following short-terrm visual deprivation: Behavioral and neural correlates from ERPs and alpha band oscillations

Publication date: Available online 31 January 2018
Source:Biological Psychology
Author(s): Gerardo Santaniello, Manuel Sebastián, Luis Carretié, Uxia Fernández-Folgueiras, José Antonio Hinojosa
In the current study, we investigated the effects of short-term visual deprivation (2 hours) on a haptic recognition memory task with familiar objects. Behavioral data, as well as event-related potentials (ERPs) and induced event-related oscillations (EROs) were analyzed. At the behavioral level, deprived participants showed speeded reaction times to new stimuli. Analyses of ERPs indicated that starting from 1000 ms the recognition of old objects elicited enhanced positive amplitudes only for the visually deprived group. Visual deprivation also influenced EROs. In this sense, we observed reduced power in the lower-1 alpha band for the processing of new compared to old stimuli between 500 and 750 ms. Overall, our data showed improved haptic recognition memory after a short period of visual deprivation. These effects were thought to reflect a compensatory mechanism that might have developed as an adaptive strategy for dealing with the environment when visual information is not available.



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Coupling and Segregation of Large-scale Brain Networks Predict Individual Differences in Delay Discounting

Publication date: Available online 31 January 2018
Source:Biological Psychology
Author(s): Zhiyi Chen, Yiqun Guo, Tingyong Feng
Decision-making about rewards, which requires us to choose between different time points, generally refers to intertemporal choice. Converging evidence suggests that some of the brain networks recruited in the delay discounting task have been well characterized for intertemporal choice. However, little is known about how the connectivity patterns of these large-scale brain networks are associated with delay discounting. Here, we use a resting-state functional connectivity MRI (rs-fcMRI) and a graph theoretical analysis to address this question. We found that the delay discounting rates showed a positive correlation with the functional network connectivity (FNC) between the cingulo-opercular network (CON) and the default mode network (DMN), while they showed a negative correlation with the FNC of both the CON-SAN (salience network) and the SAN-FPN (fronto-parietal network). Our results showed the association of both coupling and segregating processes with large-scale brain networks in delay discounting. Thus, the present study highlights the pivotal role of the functional connectivity patterns of intrinsic large-scale brain networks in delay discounting and extends our perspective on the neural mechanism of delay discounting.



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The role of emotions and physiological arousal in modulating impulsive behaviour

Publication date: Available online 31 January 2018
Source:Biological Psychology
Author(s): Aleksandra M. Herman, Hugo D. Critchley, Theodora Duka
Impulsivity received considerable attention in the context of drug misuse and certain neuropsychiatric conditions. Because of its great health and well-being importance, it is crucial to understand factors which modulate impulsive behaviour. As a growing body of literature indicates the role of emotional and physiological states in guiding our actions and decisions, we argue that current affective state and physiological arousal exert a significant influence on behavioural impulsivity. As 'impulsivity' is a heterogeneous concept, in this paper, we review key theories of the topic and summarise information about distinct impulsivity subtypes and their methods of assessment, pointing out to the differences between the various components of the construct. Moreover, we review existing literature on the relationship between emotional states, arousal and impulsive behaviour and suggest directions for future research.

Graphical abstract

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Measurement of attentional reserve and mental effort for cognitive workload assessment under various task demands during dual-task walking

Publication date: Available online 31 January 2018
Source:Biological Psychology
Author(s): Emma P. Shaw, Jeremy C. Rietschel, Brad D. Hendershot, Alison L. Pruziner, Matthew W. Miller, Bradley D. Hatfield, Rodolphe J. Gentili
Previous work focused on assessing cognitive workload has suggested EEG spectral content and component amplitudes of the event-related potential (ERP) waveform may index mental effort and attentional reserve, respectively. Although few studies have assessed attentional reserve and mental effort during upper-extremity performance, none employed a combined approach to measure cognitive workload during locomotion. Therefore, by systematically considering ERPs, spectral content, and importantly, their combinations this study aimed to examine whether concurrent changes in spectral content and ERPs could collectively index cognitive workload during locomotion. Specifically, ERP and EEG markers were assessed as participants performed a cognitive task under two levels of difficulty (easy or hard) and two conditions (seated or walking). Changes in attentional reserve and mental effort appeared to collectively index cognitive workload under varying demands due to changes in task difficulty or performance conditions. This work can inform cognitive workload assessment in patient populations with gait deficiencies for future applications.



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The Power to Choose

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Benefit‐Risk Summary of Regorafenib for the Treatment of Patients with Advanced Hepatocellular Carcinoma That Has Progressed on Sorafenib

AbstractOn April 27, 2017, the U.S. Food and Drug Administration approved regorafenib for the treatment of patients with advanced hepatocellular carcinoma (HCC) who had previously been treated with sorafenib. Approval was based on the results of a single, randomized, placebo‐controlled trial (RESORCE) that demonstrated an improvement in overall survival (OS). Patients were randomly allocated to receive regorafenib160 mg orally once daily or matching placebo for the first 21 days of each 28‐day cycle. The trial demonstrated a significant improvement in OS (hazard ratio [HR] = 0.63; 95% confidence interval [CI], 0.50–0.79, p < .0001) with an estimated median OS of 10.6 months in the regorafenib arm and 7.8 months in the placebo arm. A statistically significant improvement in progression‐free survival (PFS) based on modified RECIST for HCC [Semin Liver Dis 2010;30:52–60] (HR = 0.46; 95% CI, 0.37–0.56, p < .0001) was also demonstrated; the estimated median PFS was 3.1 and 1.5 months in the regorafenib and placebo arms, respectively. The overall response rate, based on modified RECIST for HCC, was 11% in the regorafenib arm and 4% in the placebo arm. The toxicity profile was consistent with that observed in other indications; the most clinically significant adverse reactions were palmar‐plantar erythrodysesthesia, diarrhea, and hypertension. Based on the improvement in survival and acceptable toxicity, a favorable benefit‐to‐risk evaluation led to approval for treatment of patients with advanced HCC.Implications for Practice.Regorafenib is the first drug approved by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma that has progressed on sorafenib and is expected to become a standard of care for these patients.

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Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE‐Mutant Uterine Carcinosarcoma

AbstractGynecologic carcinosarcomas, previously known as malignant mixed Müllerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase ɛ (POLE), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE‐endometrioid cases, our patient harbored alterations in PIK3CA, ARID1A, and PTEN and was microsatellite stable, with appreciable tumor‐infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma.Key Points. Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis. Inactivating DNA polymerase ɛ (POLE) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition. To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma. This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB‐high tumors.

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Early Gastric Cancer: Clinical Behavior and Treatment Options. Results of an Italian Multicenter Study on Behalf of the Italian Gastric Cancer Research Group (GIRCG)

AbstractBackground.Early gastric cancer (EGC) generally has a good prognosis. However, the current definition of EGC includes various subgroups of patients with different pathological characteristics and different prognoses, some of whom have aggressive disease with a biological behavior similar to that of advanced carcinoma.Materials and Methods.We retrospectively evaluated 1,074 patients with EGC who had undergone surgery between 1982 and 2009. The cumulative incidence function of cancer‐specific mortality and competing mortality were estimated using the Fine and Gray method.Results.The median follow‐up period was 193 months (range 1–324). Five hundred and sixty‐two (52.3%) patients died, 96 (8.9%) from EGC. The 5‐, 10‐, and 15‐year cumulative incidence rates for mortality of all causes were 20.5% (95% confidence interval [CI] 18.0–22.9), 37.1% (95% CI 34.7–40.7), and 52.6% (95% CI 49.1–56.0), respectively; for cancer‐specific mortality, 6.0% (95% CI 4.5–7.6), 9.9% (95% CI 7.9–11.9), and 11.1% (95% CI 8.8–13.3), respectively; and for mortality of other causes, 14.4% (95% CI 12.1–16.6), 27.2% (95% CI 24.2–30.2), and 41.5% (95% CI 38.1–43.3), respectively. A significant increase in the risk of cancer‐specific mortality was observed for lesions >2 cm (adjusted hazard ratio [HR] = 1.44, 95% CI 1.07–1.94), Pen A‐type disease (adjusted HR = 1.73, 95% CI 1.15–2.61), and node‐positive cancers (adjusted HR = 2.28, 95% CI 1.61–3.21).Conclusion.Patients with EGC with tumors >2 cm, Pen A‐type disease according to Kodama, or lymph node metastases show a poorer prognosis and an increased risk of cancer‐specific mortality.Implications for Practice.Early gastric cancer generally has a good prognosis, and some patients can be treated radically by endoscopic resection. However, the current definition of early gastric cancer includes subgroups of patients with an aggressive disease. In particular, patients with lymph node metastases and Pen A‐type tumors according to Kodama's classification need a more invasive treatment, such as subtotal or total gastrectomy with an extended D2 lymphadenectomy, plus eventual adjuvant chemotherapy.

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