Frequency and characteristics of immune-related thyroid adverse events in patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors: a national cohort study.

PURPOSE: Immune-related thyroid adverse events (irTAEs) occur frequently following immune checkpoint inhibitor (ICI) therapy. The purpose of this study is to provide knowledge about the incidence, clinical timeline characteristics, associated factors of irTAEs, and potential impact on treatment efficacy in patients with melanoma receiving adjuvant ICI therapy. METHODS: A national multicenter retrospective cohort study of patients with resected stage III/IV melanoma treated with adjuvant PD-1 inhibitors between November 2018 and December 2020. Data were extracted from the Danish Metastatic Melanoma Database. The irTAEs were defined as two consecutive abnormal TSH values and subdivided into transient or persistent. RESULTS: Of 454 patients, 99 developed an irTAE (21.8%), of these were 46 transient (46.5%) and 53 persistent (53.5%). Median time to transient and persistent irTAE was 55 and 44 days, respectively (p = 0.57). A hyperthyroid phase followed by hypothyroidism was seen in 73.6% of persistent irTAEs, whereas 87% of transient irTAEs developed an isolated hypo- or hyperthyroid phase. Multiple variable analysis demonstrated an association between irTAE and female sex (HR 2.45; 95% CI 1.63-3.70; p < 0.001), but no association with recurrence-free survival (HR 0.86; 95% CI 0.50-1.48; p = 0.587) or overall survival (HR 1.05; 95% CI 0.52-2.12, p = 0.891). CONCLUSIONS: IrTAE is a common side effect to PD-1 inhibitors primarily occurring within the first 3 months, with a high risk of persistency. Female sex is a strong predictive factor. IrTAE was not associated with improved clinical outcome.

Case Report: Rare Case of Staphylococcus pasteuri Endocarditis.

A 45-year-old woman was admitted with severe pain in the right leg and dyspnea. Her medical history included previous Staphylococcus aureus endocarditis, biological aortic valve replacement, and intravenous drug abuse. She was febrile but did not have any focal signs of infection. Blood tests showed raised infectious markers and troponin levels. Electrocardiogram showed sinus rhythm without signs of ischemia. Ultrasound revealed thrombosis of the right popliteal artery. The leg was not critically ischemic, and therefore, treatment with dalteparin was chosen. Transesophageal echocardiography showed an excrescence on the biological aortic valve. Empiric treatment for endocarditis was started with intravenous vancomycin, gentamicin, and oral rifampicin. Blood cultures subsequently grew Staphylococcus pasteuri. On day 2, treatment was changed to intravenous cloxacillin. Due to the comorbidity, the patient was not a candidate for the surgical treatment. On day 10, the patient developed moderate expressive aphasia and weakness in the right upper limb. Magnetic resonance imaging showed micro-embolic lesions scattered across both hemispheres of the brain. Treatment was changed from cloxacillin to cefuroxime. On day 42, infectious markers were normal, and echocardiography showed regression of the excrescence. Antibiotic treatment was stopped. Follow-up on day 52 did not show any signs of active infection. However, on day 143, the patient was readmitted with cardiogenic shock due to aortic root fistulation to the left atrium. She quickly deteriorated and died.

Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study.

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30-40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination therapy with ipilimumab and nivolumab is the first line of treatment for many patients with metastatic melanoma. In this follow-up study, with real-world data from the nationwide DAMMED database, we investigated whether there was a difference in progression-free survival (PFS) and overall survival (OS) for patients who discontinued or did not discontinue treatment within the first four doses of treatment due to irAEs. In total, 448 patients were treated with ipilimumab and nivolumab. Of these, 133 patients discontinued due to irAEs in the induction phase. Using the Cox proportional hazards model, there was no significant difference in PFS when comparing the group that discontinued with the group that did not discontinue. The group that discontinued had a significantly longer OS than the group that received the full length of treatment. Therefore, we conclude that there is no significant negative impact on efficacy for patients who discontinue due to irAEs in the induction phase of combination immunotherapy for metastatic melanoma.

First Danish case of infective endocarditis caused by Enterococcus hirae.

Enterococcus hirae, a member of the Enterococcus genus, is known to cause infections, including infective endocarditis (IE), in animal species. In humans, E. hirae is an uncommon pathogen, but has been associated with severe and recurrent disease. Here, we report the first Danish case of E. hirae native aortic valve IE in a 62-year-old woman with no history of heart disease. She presented to the hospital with symptoms of gastroenteritis but no signs of heart disease. Nevertheless, blood culture revealed growth of E. hirae, and a transoesophageal echocardiography demonstrated a mobile mass adherent to the aortic valve, compatible with a vegetation. The patient was successfully treated for E. hirae native aortic valve IE with 4 weeks of intravenous benzylpenicillin in combination with gentamicin for the initial 2 weeks. To the best of our knowledge, this is the first documented case of E. hirae IE in Denmark and the sixth documented case worldwide.

Case report: A fatal case of aortic and mitral valve endocarditis caused by Streptobacillus moniliformis.

BACKGROUND: Infective endocarditis (IE) secondary to rat-bite fever (RBF) is rare but potentially lethal. Rapid diagnosis is of utmost prognostic importance. However, the diagnosis of RBF is challenging because Streptobacillus moniliformis does not grow under conventional culture conditions. CASE SUMMARY: A 65-year-old male without previous cardiac history presented with sudden onset of balance problems and facial palsy. For 2 weeks, he had experienced intermittent fever and myalgia. Transoesophageal echocardiography (TOE) revealed severe mitral and aortic valve IE with aortic root abscess. The patient underwent a double biological valve replacement. Blood cultures remained negative after 9 days of incubation. However, sub-cultivation on solid media demonstrated the growth of pleomorphic Gram-negative rods, identified as S. moniliformis. After 4 weeks of antibiotic therapy, he was discharged. One month later, control TOE showed valve excrescences and aortic annular aneurysm. Despite comprehensive surgery, antibiotic treatment, and intensive care, the patient died 1 week after reoperation. DISCUSSION: A fatal outcome of S. moniliformis IE is rare. The majority of previous cases describe underlying valvular abnormalities or death due to insufficient antimicrobial therapy. Here, the patient had no prehistory of valvular heart disease and despite appropriate antibiotics, the outcome was fatal. Rapid diagnosis of RBF IE has prognostic implications. Identification of S. moniliformis is, however, difficult, because the bacterium is fastidious and does not grow under standard laboratory conditions. Therefore, diagnosis often relies on clinical symptoms or a history of rodent exposure. Close attention to this disease by clinicians, in addition to, dialogue with clinical microbiologists is essential.

Limited factor VIIa surface localization requirement of the factor VIIa-induced overall thrombin generation in platelet-rich hemophilia A plasma.

BACKGROUND: Thrombin generation assay (TGA) and thrombelastography (TEG) are increasingly employed, global, in vitro methods for assessment of the procoagulant potential of plasma/blood and possibly ideally suited tools to monitor, for example, therapy with recombinant factor VIIa (FVIIa). It remains controversial to what extent results obtained with spiked and postinfusion samples reflect the outcome in patients. OBJECTIVE: To characterize the TGA response to FVIIa in hemophilic plasma and compare with TEG data. METHODS: Hemophilia A (HA) was induced in platelet-rich plasma (PRP) from healthy volunteers, followed by spiking with FVIIa, γ-carboxyglutamic acid (Gla)-domainless FVIIa or V158D/E296V/M298Q-FVIIa (FVIIaDVQ). Samples were triggered with tissue factor and analyzed by TGA and TEG in parallel. RESULTS: Addition of 25 nmol L-1 FVIIa to HA PRP normalized TEG parameters angle and R time, as well as TGA lag time, but had poor effects on the thrombin peak height and velocity index. All parameters (at least) returned to normal levels either upon adding a much higher concentration of FVIIa (~1500 nmol L-1) or by using the superactive variant FVIIaDVQ. Surprisingly, Gla-domainless derivatives of FVIIa and FVIIaDVQ also yielded considerable effects in HA PRP. CONCLUSIONS: The good general responses to clinically effective concentrations of FVIIa (25 and 75 nmol L-1) seen in TEG analyses, as well as for TGA lag time, were accompanied by far-from-normal thrombin peaks. A near-normal thrombin peak response required the presence of considerably higher FVIIa activity but, intriguingly, relied only marginally on a functional Gla domain (ie, on platelet surface localization).

Clinical Impact of a Novel MicroRNA Chemo-Sensitivity Predictor in Gastrooesophageal Cancer.

BACKGROUND: miRNAs might be potentially useful biomarkers for prediction of response to chemotherapeutic agents, radiotherapy and survival. The aim of this retrospective study was to validate miRNA response predictors in a cohort of patients with gastrooesophageal cancer in order to predict overall survival (OS) and disease-specific survival (DSS). MATERIAL AND METHODS: The study population encompassed 53 patients treated with curative intend for loco-regional gastrooesophageal cancer. miRNA expression was quantified from pre-therapeutic and diagnostic, formalin-fixed, paraffin embedded tumour specimens using Affymetrix GeneChip miRNA 1.0 Array. Based on growth inhibition of the NCI60 panel in the presence of cisplatin, epirubicine and capecitabine, a miRNA based response predictor was developed. The Cox proportional hazards model was applied to assess the correlations of the response predictor with OS and DSS. RESULTS: A univariate analysis demonstrated a statistical significant improvement of OS for patients who had undergone surgical resection with prediction scores above the median prediction score (HR: 0.41 (95% CI: 0.17-0.96). Adjusting for surgery and stage, this predictor was identified to be independently associated with both OS (HR: 0.37 (95% CI: 0.16-0.87)) and DSS (HR: 0.32 (0.12-0.87)). CONCLUSION: The miRNA profile predictive for sensitivity to cisplatin, epirubicine and capecitabine was shown to be independently associated with OS and DSS in patients with gastrooesophageal cancer.

Hypoxia-regulated MicroRNAs in Gastroesophageal Cancer.

BACKGROUND/AIM: The present study aimed to identify hypoxia-regulated microRNAs (HRMs) in vitro and investigate the clinical role of candidate HRMs in patients with gastroesophageal cancer (GEC). MATERIALS AND METHODS: microRNA expression changes induced by hypoxia in human GEC cell lines were measured with microarrays and validated by quantitative real-time polymerase chain reaction. Candidate HRMs were measured in pre-therapeutic tumor samples from 195 patients with GEC. RESULTS: Expression of miR-210 was shown to be significantly induced in esophageal squamous cell carcinoma (9.26-fold, p<0.001) and adenocarcinoma cell lines (4.95-fold, p<0.001) and miR-27a-star was significantly up-regulated in adenocarcinoma cell lines (4.79-fold, p=0.04). A weak but significant correlation between miR-210 expression and a 15-gene hypoxia signature was observed (Pearson r correlation: r=0.38, p<0.001). No significant associations of HRMs and clinical outcome in patients with GEC were identified. CONCLUSION: This study supports the involvement of hypoxia on miRNAs in vitro and confirms the role of miR-210 as being a universal HRM.

Evaluation of miR-21 and miR-375 as prognostic biomarkers in esophageal cancer.

BACKGROUND: MicroRNAs (miRNAs) have been associated with prognosis in esophageal cancer, suggesting a role for miRNAs to help guide treatment decisions. Especially, miR-21 and miR-375 have been investigated as prognostic biomarkers. The aim of this study was to evaluate the prognostic potential of miR-21 and miR-375 in primary esophageal squamous cell carcinomas (ESCC) and esophagogastric adenocarcinomas (EAC). MATERIAL AND METHODS: Pre-therapeutic tumor specimens from 195 patients with loco-regional esophageal cancer treated with neoadjuvant or definitive chemoradiotherapy or perioperative chemotherapy were analyzed. Expression levels of miR-21 and miR-375 were quantified using Affymetrix GeneChip miRNA 1.0 Array. The Cox proportional hazards model was used to assess the correlation of miR-21 and miR-375 with disease-specific survival (DSS) and overall survival (OS). Forest plots were performed to evaluate the prognostic impact of miR-21 and miR-375 in the present study and previously published reports. RESULTS: In ESCC, patients with miR-21 expression levels above median showed a trend towards poorer DSS and OS. When dividing miR-21 expression by tertiles, high levels of miR-21 significantly correlated with shortened DSS [HR 1.76 (95% CI 1.05-2.97) but not OS. Similarly for EAC, a significant association between miR-21 expression above median and DSS was observed [HR 3.37 (95% CI 1.41-8.05)], in addition to a trend towards poorer OS for patients with miR-21 expression above median. Multivariate analyses identified miR-21 as an independent prognostic marker for DSS in EAC [HR 3.52 (95% CI 1.06-11.69)]. High miR-375 was not correlated with improved prognosis in either histology. However, Forest plots demonstrated that both miR-21 and miR-375 were of prognostic impact in ESCC. CONCLUSION: In this study, miR-21 was identified as an independent prognostic biomarker for DSS in patients with EAC whereas miR-21 failed to show independent prognostic significance in ESCC. High miR-375 was not associated with enhanced survival in either histology.

Hypoxia-regulated gene expression and prognosis in loco-regional gastroesophageal cancer.

UNLABELLED: Gastroesophageal cancers are heterogeneous diseases with a poor outcome. Prognostic and predictive factors are needed to improve patient survival. Hypoxia is an adverse prognostic factor and is associated with resistance to chemo- and radiotherapy in various cancers. However, knowledge on the impact of hypoxia in gastroesophageal cancer is limited. The aim of this study was to evaluate potential prognostic factors in terms of a subset of hypoxia-responsive genes and clinicopathological parameters in patients with gastroesophageal cancer. MATERIAL AND METHODS: Ninety-five patients with loco-regional gastroesophageal cancer treated with curative intent were retrospectively analyzed. Based on formalin-fixed paraffin-embedded diagnostic biopsies gene expressions of 15 hypoxia-induced and pH-independent genes from a previously described hypoxia gene expression classifier was quantified. The prognostic impact was evaluated for overall survival (OS) and disease-specific survival (DSS). Uni- and multivariate Cox proportional hazards model was used to identify hypoxia-responsive gene expression and clinicopathological parameters as prognostic markers. RESULTS: An unsupervised hierarchical clustering of hypoxia regulated genes showed two well-differentiated patient clusters: One cluster of tumors with high gene expression and another with low gene expression, indicating a more hypoxic genotype versus a less hypoxic genotype respectively. As the group of esophageal squamous cell carcinomas (ESCC) alone showed intra-group heterogeneity this group was ranked according to the gene expression of the 15 genes. The most hypoxic third showed a trend towards a poorer outcome in terms of OS [HR = 0.48 (CI 0.21-1.07), p = 0.07] and DSS [HR = 0.48 (CI 0.18-1.24), p = 0.13]. Treatment response was identified as an independent prognostic factor for DSS in the group of ESCC [HR = 0.21 (CI 0.05-0.95), p = 0.04]. CONCLUSION: Gene expression analysis of 15 hypoxia-responsive genes was identified as a promising prognostic marker in patients with ESCC. Further studies confirming these results in larger patient cohorts are needed.

Active packaging of cheese with allyl isothiocyanate, an alternative to modified atmosphere packaging.

The natural antimicrobial compound allyl isothiocyanate (AITC), found in mustard oil, is effective against cheese-related fungi both on laboratory media and cheese. Penicillium commune, Penicillium roqueforti, and Aspergillus flavus were more sensitive to AITC when it was added just after the spores had completed 100% germination and branching had started on Czapek yeast extract agar than were spores in the dormant phase. The use of 1 AITC label (Wasaouro interior labels, LD30D, 20 by 20 mm) in combination with atmospheric air in the packaging extended the shelf life of Danish Danbo cheese from 4 1/2 to 13 weeks. Two AITC labels extended the shelf life from 4 1/2 to 28 weeks. Both 1 and 2 labels in combination with modified atmosphere packaging extended the shelf life of the cheese from 18 to 28 weeks. This study showed that AITC was absorbed in the cheese, but it was not possible to detect any volatile breakdown products from AITC in the cheese. Cheese stored for up to 12 weeks with an AITC label had an unacceptable mustard flavor. The mustard flavor decreased to an acceptable level between weeks 12 and 28. Cheese stored in atmospheric air had a fresher taste without a CO2 off-flavor than did cheese stored in modified atmosphere packaging. AITC may be a good alternative to modified atmosphere packaging for cheese. The extended shelf life of cheese in the package is very desirable: the cheese can be transported longer distances, and the packaging can be used for the final maturing of the cheese. Furthermore, AITC can address problems such as pinholes and leaking seals in cheese packaging.