Association of histological features with laryngeal squamous cell carcinoma recurrences:a population-based study of 1502 patients in the Netherlands

BACKGROUND: Recurrences remain an important problem in laryngeal squamous cell carcinoma. Little has been described about histological characteristics of the primary laryngeal tumor that may be associated with recurrences. Identifying risk factors for recurrences might help in adapting treatment or follow-up. Using real-life population-based data, we aimed to identify histological features of the primary tumor associated with recurrences and overall survival. MATERIAL AND METHODS: Demographic, clinical and treatment information on all first primary invasive laryngeal tumors diagnosed in 2010–2014 (N = 3705) were extracted from the population-based nationwide Netherlands cancer registry (NCR) and linked to PALGA, the nationwide Dutch pathology registry, to obtain data on histological factors and recurrences. For a random 1502 patients histological information i.e., keratinization, perineural invasion (PNI+), vascular invasion (VI+), growth pattern, degree of differentiation, extracapsular spread (ECS+), cartilage- and bone invasion and extralaryngeal extension, was manually extracted from narrative pathology reports and analyzed for locoregional recurrence and overall survival using cox regression analysis. RESULTS: In total, 299 patients developed a locoregional recurrence and 555 patients died. Keratinization (HR = 0.96 (95%CI: 0.68–1.34) p = 0.79), two or three adverse characteristics (PNI+, VI+, non-cohesive growth) (HR = 1.38 (95% CI: 0.63–3.01) p = 0.42), and ECS+ (HR = 1.38 (95% CI: 0.48–4.02) p = 0.55) were not associated to recurrence. For death, also no significant association was found. CONCLUSION: In this population-based real-life dataset on laryngeal carcinoma in the Netherlands, histological factors were not associated with locoregional recurrences or overall survival, but future studies should investigate the role of these features in treatment decisions. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-022-09533-0

Reverse remodeling of the extracellular matrix in heart failure after left ventricular mechanical support

This thesis describes a study of the changes in the extracellular matrix (ECM) of the myocardium, in patients with end stage heart failure and during mechanical support (Left Ventricular Assist Device support, LVAD) of the left ventricle. The changes during LVAD support may lead to recovery of the heart. Chapter 1 is a general introduction about heart failure, heart transplantation, and the LVAD, The process of remodeling which leads to heart failure, and of reverse remodeling during LVAD support. A summary is given of the ECM components, and of the role of enzymes, hormones, and cytokines in the myocardial ECM changes in patients before and after LVAD support. Chapter 2 gives an overview of the role of different cytokine polymorphisms in transplant rejection. Cytokines influence each other's function and production. Single nucleotide polymorphism (SNP) in the genes of cytokines may influence the production level. These SNPs have been studied extensively in the context of acute rejection after organ transplantation. A variety of results have been obtained by many different groups. The main focus in most studies has been SNP genotype of the recipient. However, it is becoming increasingly clear that, in addition to the recipient's immune system, the microenvironment of the donor organ does also contribute to cytokine production, and may thereby influence rejection events. Chapter 3 concerns a study of TNF alpha promoter polymorphisms, and their possible contribution to the severity of heart failure and transplant rejection. TNF? plasma levels were measured before heart transplantation, in patients on medication, and in patients supported by a LVAD. TNF alpha plasma levels were high in patients with end stage heart failure on pharmaco-therapy, compared to healthy controls, but were increased in patients which required LVAD support before heart transplantation. This increase seems to correlate with the G allele at position -308. After LVAD support the TNF alpha levels were decreased. The A allele at position -308 (in which A is associated with relatively high levels of TNF alpha) does not correlate with the severity of heart failure and transplant rejection. However, patients having donor hearts with the A-308 polymorphism suffered more rejection episodes than patients receiving hearts with the G allele. Chapter 4 deals with the changes in the fibrillar collagen network in the ECM. The cardiomyocyte size appeared to decreases by 36% in the first 100 days after LVAD support. This was paralleled by an increase in ECM volume. However, the ECM volume decreased after prolonged LVAD support (>365 days). In patients with end-stage heart failure, the degradation of the fibrillar collagens was high before LVAD support, and their synthesis was low compared to the healthy controls. After LVAD support the opposite was observed: increased synthesis of the fibrillar collagens and decreased degradation. Furthermore, we showed that the quality of the fibrillar collagens increases, because more un-denatured (uncoiled) collagen was detected. These results suggest that after LVAD support the heart becomes smaller and the fibrillar collagen network in the ECM improves. Chapter 5 describes the changes in the basement membrane (BM) surrounding the cardiomyocytes. Using quantitative PCR (QPCR), no changes were observed in terms of collagen α-chain mRNA expression . However, immunohistochemistry did disclose a decreased staining pattern of type IV collagen after LVAD support. Using electron microscopy we showed that in healthy control hearts, and in patients with severe end-stage heart failure, the BM is thick and irregular, in contrast to patients after LVAD support. There were close connections between the ECM collagen fibers and the BM. Post-LVAD the BM became more regular and the lamina lucida and lamina densa were compacter and could be clearly discerned then in the healthy control. However, the connection between the BM and the collagen fibers in the ECM appeared to be disturbed. Furthermore, it was investigated whether matrix metalloproteinases (MMP) plays a role in degradation of the BM. MMP-2, which is able to degrade type IV collagen, was high in patients before LVAD support, but was increased even more in patients on LVAD support. Using gel zymography, active MMP expression was increased in these patients and was localized in the BM. This suggests that MMP-2 degrades type IV collagen in the BM during LVAD support. Chapter 6 focuses on the role of neuro-hormone brain natriuretic peptide (BNP) in the remodeling process. BNP is a member of the natriuretic peptide family and is mainly synthesized and secreted in the left cardiac ventricle. BNP is known to have natriuretic, diuretic and vasorelaxant properties,and have antagonistic effects on the renin-angiotensin-aldosteron system; it is increased in patients with end-stage heart failure. Measurement of BNP plasma levels is of prognostic value for the assessment of cardiac morbidity and mortality. We did observe an increase of BNP in patients with end-stage heart failure. After LVAD, the BNP plasma levels were decreased. Immuno-histochemical staining indicated that, apart from cardiomyocytes, infiltrating T-cells are also capable of producing BNP. Chapter 7 describes the role of cathepsin K in the remodelings process. Cathepsin K mRNA and protein expression were high in patients with end stage heart failure before LVAD support. However, after LVAD support the mRNA expression was increased, but the protein level decreased. Immunohistochemistry disclosed that the macrophages in the heart are the main producers of cathepsin K. After LVAD support, their number was decreased. These results indicate that cathepsin K plays an important role in the remodeling process in patients before LVAD support. Chapter 8 is a general discussion of the investigations included in this thesis. Currently, LVADs serve as bridge to heart transplantation and, in some patients, even as bridge to recovery. However, recovery of the heart during LAVD support is generally neither complete nor permanent. In this thesis it is demonstrated that the cardiomyocytes, the ECM volume, and the fibrillar collagen network improves in quality and even almost normalizes. Yet, degradation of the basement membrane and of the connections between the collagens in the BM and the cardiomyocytes did also occur. Such connections are very important for the transmission of force between the cardiomyocytes, and as long as they are not restored, LVAD as a temporary tool for recovery would not appear to be a realistic option

HPV type in plantar warts influences natural course and treatment response: Secondary analysis of a randomised controlled trial

Item does not contain fulltextBACKGROUND: Cryotherapy is effective for common warts, but for plantar warts available treatments often fail. OBJECTIVES: Within a pragmatic randomised controlled trial, we examined whether subgroups of common and plantar warts have a favourable natural course or response to treatment based on wart-associated HPV type. STUDY DESIGN: Consecutive patients with new common or plantar warts were recruited in 30 Dutch family practices. Patients (n=250) were randomly allocated to liquid-nitrogen cryotherapy, 40% salicylic acid self-application, or wait-and-see policy. Before treatment, swabs were taken from all separate warts and analysed by a broad spectrum HPV genotyping assay. At 13 weeks, cure rates with 95% confidence intervals of common and plantar warts on intention to treat basis were compared between treatment arms for the different wart-associated HPV types. RESULTS: In total, 7% of swabs tested negative for HPV DNA and 16% contained multiple types, leaving 278 of 371 common swabs (75%) and 299 of 373 plantar swabs (80%) with a single type for analysis. After wait-and-see policy, cure rates were 2/70 (3%, 95% confidence interval 1-10) for HPV 2/27/57-associated common warts, 4/58 (7%, 3-16) for HPV 2/27/57-associated plantar warts, and 21/36 (58%, 42-73) for HPV 1-associated plantar warts. After cryotherapy, cure rates were 30/44 (68%, 53-80), 6/56 (11%, 5-21), and 15/23 (65%, 45-81); after salicylic acid 16/87 (18%, 12-28), 15/60 (25%, 16-37), and 24/26 (92%, 76-98), respectively. CONCLUSIONS: HPV type influenced the natural course and response to treatment for plantar warts. HPV testing potentially optimises wart treatment in primary care

Overexpression of transforming growth factor-α and epidermal growth factor receptor, but not epidermal growth factor, in exocrine pancreatic tumours in hamsters

Using immunohistochemistry, Northern blotting and a semi-quantitative PCR technique, epidermal growth factor (EGF), transforming growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR) expression were studied in the pancreas of N-nitrosobis(2-oxopropyl)-amine (BOP)-treated hamsters. After initiation pancreatic carcinogenesis was modulated by a high fat diet or by injections with the cholecystokinin analogue caerulein. Autopsies were performed 6 and 12 months after the last injection with BOP. Immunohistochemistry revealed a weak expression of TGF-α in normal acinar cells and a stronger expression in ductular and centro-acinar cells. Overexpression of TGF-α was observed in advanced putative preneoplastic lesions (classified as borderline lesions) and in ductular adenocarcinomas. EGFR immunoreactivity was present only in ductular adenocarcinomas. EGF peptide expression was observed both in acinar and ductular normal and tumorous cells and the level of expression did not change significantly during carcinogenesis. Moreover, the post-initiation treatments did not cause differences in EGF, TGF-α or EGFR peptide or mRNA levels, except for a significantly lower expression of TGF-α mRNA in hamsters fed a high fat diet when compared with those fed a low fat diet. TGF-α mRNA levels increased, whereas EGF mRNA levels decreased significantly in total pancreatic homogenates of BOP-treated hamsters in comparison with untreated controls. Also, in ductular adenocarcinomas TGF-α and EGFR (but not EGF) mRNA levels were significantly higher than in normal pancreatic homogenates. In pancreatic homogenates obtained 6 months after the last BOP injection, these differences were less pronounced in comparison with those obtained after 12 months. The present results indicate that TGF-α (but not EGF) might act in a paracrine or autocrine manner in pancreatic tumours in BOP-treated hamsters via simultaneously expressed EGFR. However, TGF-α, EGF and EGFR do not seem to be involved in the modulating effects of a high fat diet or caerulein treatment on pancreatic carcinogenesis in BOP-treated hamsters

Stem cell-derived cardiomyocytes after bone marrow and heart transplantation

Cardiomyocytes are a stable cell population with only limited potential for renewal after injury. Tissue regeneration may be due to infiltration of stem cells, which differentiate into cardiomyocytes. We have analysed the influx of stem cells in the heart of patients who received either a gender-mismatched BMT (male donor to female recipient) or a gender-mismatched cardiac transplant (HTX; female donor to male recipient). The proportion of infiltrating cells was determined by Y-chromosome in situ hybridization combined with immunohistochemical cell characterization. In BM transplanted patients and in cardiac allotransplant recipients, cardiomyocytes of apparent BM origin were detected. The proportions were similar in both groups and amounted up to 1% of all cardiomyocytes. The number of stem cell-derived cardiomyocytes did not alter significantly in time, but were relatively high in cases where large numbers of BMderived Y-chromosome-positive infiltrating inflammatory cells were present. The number of Y-chromosome-positive endothelial cells was small and present only in small blood vessels. The number of BM-derived cardiomyocytes in both BMT and HTX is not significantly different between the two types of transplantation and is at most 1

Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial

Background: Cryotherapy is widely used for the treatment of cutaneous warts in primary care. However, evidence favours salicylic acid application. We compared the effectiveness of these treatments as well as a wait-and-see approach. Methods: Consecutive patients with new cutaneous warts were recruited in 30 primary care practices in the Netherlands between May 1, 2006, and Jan. 26, 2007. We randomly allocated eligible patients to one of three groups: cryotherapy with liquid nitrogen every two weeks, self-application of salicylic acid daily or a wait-and-see approach. The primary outcome was the proportion of participants whose warts were all cured at 13 weeks. Analysis was on an intention-to-treat basis. Secondary outcomes included treatment adherence, side effects and treatment satisfaction. Research nurses assessed outcomes during home visits at 4, 13 and 26 weeks. Results: Of the 250 participants (age 4 to 79 years), 240 were included in the analysis at 13 weeks (loss to follow-up 4%). Cure rates were 39% (95% confidence interval [CI] 29%-51%) in the cryotherapy group, 24% (95% CI 16%-35%) in the salicylic acid group and 16% (95% CI 9.5%-25%) in the wait-and-see group. Differences in effectiveness were most pronounced among participants with common warts (n = 116): cure rates were 49% (95% CI 34%-64%) in the cryotherapy group, 15% (95% CI 7%-30%) in the salicylic acid group and 8% (95% CI 3%-21%) in the wait-and-see group. Cure rates among the participants with plantar warts (n = 124) did not differ significantly between treatment groups. Interpretation: For common warts, cryotherapy was the most effective therapy in primary care. For plantar warts, we found no clinically relevant difference in effectiveness between cryotherapy, topical application of salicylic acid or a wait-and-see approach after 13 weeks. (ClinicalTrial.gov registration no. ISRCTN42730629)

Cutaneous wart-associated HPV types: prevalence and relation with patient characteristics

Item does not contain fulltextBACKGROUND: Epidemiological data on cutaneous wart-associated HPV types are rare. OBJECTIVES: To examine the prevalence of cutaneous wart-associated HPV types and their relation with patient characteristics. STUDY DESIGN: Swabs were taken from all 744 warts of 246 consecutive immunocompetent participants and analysed by a broad spectrum HSL-PCR/MPG assay. Patient details including location, duration, and number of warts were recorded. RESULTS: No HPV DNA was detected in 49 (7%) swabs, a single HPV type in 577 (78%) swabs, and multiple HPV types in 118 (16%) swabs. HPV 2, 27 and 57 (alpha genus), HPV 4 (gamma genus) and HPV 1 (mu genus) were the most frequently detected HPV types, and HPV 63 (mu genus) was only frequently detected together with other HPV types. Less frequently detected HPV types were HPV 3, 7, 10 and 28 (alpha genus), 65, 88 and 95 (gamma genus) and 41 (nu genus). Warts containing HPV 1 showed the most distinct clinical profile, being related to children aged <12 years, plantar location, duration <6 months, and to patients with <4 warts. CONCLUSIONS: HPV 27, 57, 2 and 1 are the most prevalent HPV types in cutaneous warts in general population. Warts infected with HPV 1 have a distinct clinical profile