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Open access

Jordyn Silverstein, Wesley Kidder, Susan J Fisher, Thomas A. Hope, Samantha Maisel, Dianna Ng, Jessica Van Zifle, Chloe Atreya and Katherine Van Loon

BACKGROUND: Colorectal carcinoma (CRC) during the peri-partum period is challenging to diagnose due to the overlapping symptoms of CRC and pregnancy. This is the first case series to investigate clinicopathologic, hormononal, and molecular features of CRC diagnosed during the peri-partum period. We hypothesized that advanced presentations of CRC could possibly be mitigated by pregnancy-related hormonal factors.

METHODS: We conducted a retrospective review of five women diagnosed with CRC during the peri-partum period and studied the clinical and molecular features of their cancer.

RESULTS: All patients presented with stage IV CRC at diagnosis; three had primary tumors in the rectum, and two had primary tumors in the sigmoid colon. The liver was the most common metastatic site (3 of 5 women). Immunohistochemistry stains were negative for estrogen receptors alpha (ERα) and beta (ERβ), and one tumor demonstrated low-level positivity for PR (1%). Formalin-fixed and paraffin-embedded (FFPE) biopsies from each case were tested with next-generation sequencing and found that all tumors were mismatch repair (MMR) proficient, and three harbored a KRAS mutation. Germline testing showed no predisposition to CRC; however, several somatic variants of undetermined significance (VUS) were identified.

DISCUSSION: CRC in the peri-partum period poses significant risk factors for presentations with advanced disease due to diagnostic challenges. While our study provides no evidence that pathogenesis of CRC during pregnancy is driven by elevated estrogen and/or progesterone levels during pregnancy, additional putative etiologic factors, including placental growth factors, the immunosuppressive state of pregnancy, and other physiologic processes during pregnancy, warrant future study.

Open access

Amarjit Saini, Linda Björkhem-Bergman, Johan Boström, Mats Lilja, Michael Melin, Karl Olsson, Lena Ekström, Peter Bergman, Mikael Altun, Eric Rullman and Thomas Gustafsson

The CC genotype of the vitamin D receptor (VDR) polymorphism TaqI rs731236 has previously been associated with a higher risk of developing myopathy compared to TT carriers. However, the mechanistic role of this polymorphism in skeletal muscle is not well defined. The effects of vitamin D on patients genotyped for the VDR polymorphism TaqI rs731236, comparing CC and TT carriers were evaluated. Primary human myoblasts isolated from 4 CC carriers were compared with myoblasts isolated from four TT carriers and treated with vitamin D in vitro. A dose-dependent inhibitory effect on myoblast proliferation and differentiation was observed concurrent with modifications of key myogenic regulatory factors. RNA sequencing revealed a vitamin D dose–response gene signature enriched with a higher number of VDR-responsive elements (VDREs) per gene. Interestingly, the greater the expression of muscle differentiation markers in myoblasts, the more pronounced was the vitamin D-mediated response to suppress genes associated with myogenic fusion and myotube formation. This novel finding provides a mechanistic explanation to the inconsistency regarding previous reports of the role of vitamin D in myoblast differentiation. No effects in myoblast proliferation, differentiation or gene expression were related to CC vs TT carriers. Our findings suggest that the VDR polymorphism TaqI rs731236 comparing CC vs TT carriers did not influence the effects of vitamin D on primary human myoblasts and that vitamin D inhibits myoblast proliferation and differentiation through key regulators of cell cycle progression. Future studies need to employ strategies to identify the primary responses of vitamin D that drive the cellular response towards quiescence.

Open access

Agnieszka Adamska, Aleksandra Maria Polak, Anna Krentowska, Agnieszka Łebkowska, Justyna Hryniewicka, Monika Leśniewska and Irina Kowalska

Objective: PCOS women are characterized by insulin resistance and have higher tendency to the development of hepatic steatosis. Fetuin-B has been introduced as a hepatokine/adipokine which is increased in hepatic steatosis and may be connected with glucose metabolism disturbances. The aim of the study was to evaluate the relationships between serum fetuin-B concentration and indices of insulin resistance, insulin secretion, and markers of liver steatosis in PCOS women in comparison to the control group.

Patients and methods: The study group included 108 women: 57 women with PCOS and 51 women matched for age and BMI as a control group. Serum concentration of fetuin-B was estimated. Homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment β cell function (HOMA-β) were calculated. Fatty liver index (FLI), lipid accumulation product (LAP) and visceral adiposity index (VAI) were used as markers of liver steatosis.

Results: We found higher serum concentration of fetuin-B and FLI in PCOS women in comparison to the control group (all p<0.05). We observed a positive relationship between serum fetuin-B concentration and HOMA-β (r=0.43,p=0.01), HOMA-IR (r=0.31,p=0.01), FLI (r=0.29, p=0.02), VAI (r=0.29, p=0.02) and LAP (r=0.32, p=0.01) in PCOS women. We also noticed a relationship between HOMA-IR and FLI (r=0.42,p=0.01), VAI (r=0.38,p=0.004) and LAP (r=0.41,p=0.001) in this group. Multiple regression analysis revealed that HOMA-β (β=0.39,p=0.002) and LAP (β=0.27,p=0.02) were independently connected with serum fetuin-B levels in women with PCOS.

Conclusions: Serum fetuin-B levels are higher in women with PCOS and are independently connected with HOMA-β and hepatic steatosis.

Open access

Helle Døssing, Finn Noe Bennedbæk and Laszlo Hegedüs

Objective

Laser therapy (LT) is considered a safe and effective procedure for inducing thyroid nodule necrosis, fibrosis and shrinkage. Little is known about long-term efficacy of LT in benign complex thyroid nodules, which we report here.

Design and methods

One hundred and ten euthyroid outpatients (28 men and 82 women; median age 48 years (range 17–82)) with a recurrent cytologically benign cystic (≥2 mL cyst volume) thyroid nodule causing local discomfort were assigned to LT. LT was performed after complete cyst aspiration and under continuous ultrasound (US) guidance. Nineteen patients (17 within 6 months) had surgery after LT. The median follow-up for the remaining 91 patients was 45 months (range: 12–134).

Results

The overall median nodule volume in the 110 patients decreased from 9.0 mL (range: 2.0–158.0) to 1.2 mL (range: 0.0–85.0) (P < 0.001) at the final evaluation, corresponding to a median reduction of 85% (range: −49 to 100%). Remission of the cystic part (volume ≤1 mL) was obtained in 82 of 110 (75%) patients after LT. The median cyst volume decreased from 6.3 mL (range: 2.0–158.0) to 0.0 mL (range: 0.0–85.0) (P < 000.1), corresponding to a median reduction of 100% (range: −49 to 100%). These results correlated with a significant decrease in pressure as well as cosmetic complaints. Side effects were restricted to mild local pain.

Conclusion

US-guided aspiration and subsequent LT of benign recurrent cystic thyroid nodules results in a satisfactory long-term clinical response in the majority of patients. LT constitutes a clinically relevant alternative to surgery in such patients.

Open access

Jakob Høgild Langdahl, Anja Lisbeth Frederiksen, John Vissing, Morten Frost, Knud Bonnet Yderstræde and Per Heden Andersen

Aim

This case–control study aimed to examine impairments in glucose metabolism in non-diabetic carriers of the mitochondrial mutation m.3243A>G by evaluating insulin secretion capacity and sensitivity.

Methods

Glucose metabolism was investigated in 23 non-diabetic m.3243A>G carriers and age-, sex- and BMI-matched healthy controls with an extended 4-h oral glucose tolerance test (OGTT). Insulin sensitivity index and acute insulin response were estimated on the basis of the OGTT. This was accompanied by examination of body composition by dual-energy X-ray absorptiometry (DXA), maximum aerobic capacity and a Recent Physical Activity Questionnaire (RPAQ).

Results

Fasting p-glucose, s-insulin and s-c-peptide levels did not differ between m.3243A>G carriers and controls. Insulin sensitivity index (BIGTT-S1) was significantly lower in the m.3243A>G carriers, but there was no difference in the acute insulin response between groups. P-lactate levels were higher in carriers throughout the OGTT. VO2max, but not BMI, waist and hip circumferences, lean and fat body mass%, MET or grip strength, was lower in mutation carriers. BIGTT-S1 remained lower in mutation carriers after adjustment for multiple confounding factors including VO2max in regression analyses.

Conclusions

Glucose metabolism in m.3243A>G carriers was characterized by reduced insulin sensitivity, which could represent the earliest phase in the pathogenesis of m.3243A>G-associated diabetes.

Open access

K G Samsom, L M van Veenendaal, G D Valk, M R Vriens, M E T Tesselaar and J G van den Berg

Background

Small-intestinal neuroendocrine tumours (SI-NETs) represent a heterogeneous group of rare tumours. In recent years, basic research in SI-NETs has attempted to unravel the molecular events underlying SI-NET tumorigenesis.

Aim

We aim to provide an overview of the current literature regarding prognostic and predictive molecular factors in patients with SI-NETs.

Method

A PubMed search was conducted on (epi)genetic prognostic factors in SI-NETs from 2000 until 2019.

Results

The search yielded 1522 articles of which 20 reviews and 35 original studies were selected for further evaluation. SI-NETs are mutationally quiet tumours with a different genetic make-up compared to pancreatic NETs. Loss of heterozygosity at chromosome 18 is the most frequent genomic aberration (44–100%) followed by mutations of CDKN1B in 8%. Prognostic analyses were performed in 16 studies, of which 8 found a significant (epi)genetic association for survival or progression. Loss of heterozygosity at chromosome 18, gains of chromosome 4, 5, 7, 14 and 20p, copy gain of the SRC gene and low expression of RASSF1A and P16 were associated with poorer survival. In comparison with genetic mutations, epigenetic alterations are significantly more common in SI-NETs and may represent more promising targets in the treatment of SI-NETs.

Conclusion

SI-NETs are mutationally silent tumours. No biomarkers have been identified yet that can easily be adopted into current clinical decision making. SI-NETs may represent a heterogeneous disease and larger international studies are warranted to translate molecular findings into precision oncology.

Open access

Lesley Hill, Zeynep Sumer-Bayraktar, John G Lewis, Eva Morava, Morten Thaysen-Andersen and Geoffrey L Hammond

Objective: Discrepancies in enzyme-linked immunosorbent assay (ELISA) measurements of human corticosteroid-binding globulin (CBG) using detection monoclonal antibodies that recognize an epitope (9G12) within its reactive center loop (RCL), versus an epitope (12G2) in a different location, have suggested that CBG with a proteolytically-cleaved RCL exists in blood samples. We have previously been unable to verify this biochemically, and sought to determine if N-glycosylation differences account for discrepancies in ELISA measurements of CBG.

Methods and Subjects: Molecular biological, biochemical and glycopeptide analyses were used to examine how N-glycosylation at specific sites, including at N347 within the RCL, affect CBG ELISA or steroid-binding capacity assay (BCA) measurements. Plasma from patients with congenital disorders of glycosylation (CDG) was also examined in these assays as examples of N-glycosylation defects.

Results: We demonstrate that an N-glycan at N347 within the CBG RCL limits the 9G12 antibody from recognising its epitope, whereas the 12G2 antibody reactivity is unaffected, thereby contributing to discrepancies in ELISA measurements using these two antibodies. Qualitative differences in N-glycosylation at N238 also negatively affect the steroid-binding of CBG in the absence of an N-glycan at N347 caused by a T349A substitution. Desialylation increased both ELISA measurements relative to BCA values. Similarly, plasma CBG levels in both ELISAs were much higher than BCA values in several CDG patients.

Conclusions: Plasma CBG measurements are influenced by variations in N-glycosylation. This is important given the increasing number of CDG defects identified recently, and because N-glycosylation abnormalities are common in patients with metabolic and liver diseases.

Open access

Gaëtan Prévost, Marie Picot, Marie-Anne Le Solliec, Arnaud Arabo, Hind Berrahmoune, Mouna El Mehdi, Saloua Cherifi, Alexandre Benani, Emmanuelle Nédélec, Françoise Gobet, Valéry Brunel, Jérôme Leprince, Hervé Lefebvre, Youssef Anouar and Nicolas Chartrel

Objective

Recent studies performed in mice revealed that the neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and by increasing insulin sensitivity. However, in humans, an association between 26RFa and the regulation of glucose homeostasis is poorly documented. In this study, we have thus investigated in detail the distribution of 26RFa and its receptor, GPR103, in the gut and the pancreas, and determined the response of this peptidergic system to an oral glucose challenge in obese patients.

Design and methods

Distribution of 26RFa and GPR103 was examined by immunohistochemistry using gut and pancreas tissue sections. Circulating 26RFa was determined using a specific radioimmunoassay in plasma samples collected during an oral glucose tolerance test.

Results

26RFa and GPR103 are present all along the gut but are more abundant in the stomach and duodenum. In the stomach, the peptide and its receptor are highly expressed in the gastric glands, whereas in the duodenum, ileum and colon they are present in the enterocytes and the goblet cells. In the pancreatic islets, the 26RFa/GPR103 system is mostly present in the β cells. During an oral glucose tolerance test, plasma 26RFa profile is different between obese patients and healthy volunteers, and we found strong positive correlations between 26RFa blood levels and the BMI, and with various parameters of insulin secretion and insulin resistance.

Conclusion

The present data suggest an involvement of the 26RFa/GPR103 peptidergic system in the control of human glucose homeostasis.

Open access

Tiina Vesterinen, Teijo Kuopio, Maarit Ahtiainen, Aija Knuuttila, Harri Mustonen, Kaisa Salmenkivi, Johanna Arola and Caj Haglund

Pulmonary carcinoid (PC) tumors are rare tumors that account for approximately 1% of all lung cancers. The primary treatment option is surgery, while there is no standard treatment for metastatic disease. As the number of PCs diagnosed yearly is increasing, there is a need to establish novel therapeutic options. This study aimed to investigate programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression in PC tumors since blocking of the PD-1/PD-L1 pathway is a promising therapeutic option in various other malignancies. A total of 168 PC patients treated between 1990 and 2013 were collected from the Finnish biobanks. After re-evaluation of the tumors, 131 (78%) were classified as typical carcinoid (TC) and 37 (22%) as atypical carcinoid (AC) tumors. Primary tumor samples were immunohistochemically labeled for PD-1, PD-L1, and CD8. High PD-1 expression was detected in 16% of the tumors. PD-L1 expression was detected in 7% of TC tumors; all AC tumors were PD-L1 negative. PD-L1 expression was associated with mediastinal lymph-node metastasis at the time of diagnosis (P=0.021) as well as overall metastatic potential of the tumor (P=0.010). Neither PD-1 expression, PD-L1 expression nor CD8+ T cell density was associated with survival. In conclusion, PD-1 and PD-L1 were expressed in a small proportion of PC tumors and PD-L1 expression was associated with metastatic disease. Targeting of the PD-1/PD-L1 pathway with immune checkpoint inhibitors may thus offer a treatment option for a subset of PC patients.

Open access

Eva Jakobsson Ung, Ann-Charlotte Olofsson, Ida Björkman, Tobias Hallén, Daniel S Olsson, Oskar Ragnarsson, Thomas Skoglund, Sofie Jakobsson and Gudmundur Johannsson

Objective

Experiences and need of support during surgery and start of replacement therapy in patients with pituitary tumours are highly unknown. This study aimed at exploring patient experiences during pre- and postoperative care and recovery after pituitary surgery in patients with a pituitary tumour.

Methods

Within a qualitative study design, 16 consecutive patients who underwent surgery for pituitary tumours were repeatedly interviewed. In total, 42 interviews were performed before and after surgery. Analysis was performed using qualitative interpretation.

Results

Suffering a pituitary tumour was overwhelming for many patients and struggling with existential issues was common. Patients expressed loneliness and vulnerability before and after surgery. How professionals handled information in connection with diagnosis greatly affected the patients. Other patients with the same diagnosis were experienced as the greatest support. Normalisation of bodily symptoms and relationships with others were reported during postoperative recovery. However, a fear that the tumour would return was present.

Conclusions

Patients with pituitary tumours need structured support, including peer support, which acknowledges physical, cognitive as well as emotional and existential concerns. Information related to diagnosis and surgery should be adapted in relation to the loneliness and the existential seriousness of the situation. Care and support for patients with pituitary tumours should preferably be organised based on continuity and an unbroken care pathway from the first pre-operative evaluation through to postoperative care and the start of a life-long endocrine treatment and tumour surveillance.