Real-World Evidence Study of Patients with KRAS-Mutated NSCLC in Finland.

While KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), KRAS-mutant tumors have long been considered difficult to treat and thus, an unmet need still remains. Partly due to the lack of targeted treatments, comprehensive real-world description of NSCLC patients with KRAS mutation is still largely missing in Finland. In this study, all adult patients diagnosed with locally advanced and unresectable or metastatic NSCLC from 1 January 2018 to 31 August 2020 at the Hospital District of Helsinki and Uusimaa were first identified in this retrospective registry-based real-world study. The final cohort included only patients tested with next generation sequencing (NGS) and was stratified by the KRAS mutation status. A total of 383 patients with locally advanced and unresectable or metastatic NSCLC and with NGS testing performed were identified. Patients with KRAS mutation (KRAS G12C n = 35, other KRAS n = 74) were younger than patients without KRAS mutations, were all previous or current smokers, and had more often metastatic disease at diagnosis. Also, these patients had poorer survival, with higher age, Charlson comorbidity index (CCI) being 5 or above, and KRAS G12C being the most significant risk factors associated with poorer survival. This suggests that the patients with KRAS mutation have a more aggressive disease and/or tumors with KRAS mutation are more difficult to treat, at least without effective targeted therapies.

Tofacitinib real-world experience in ulcerative colitis in Finland (FinTofUC): a retrospective non-interventional multicenter patient chart data study.

OBJECTIVES: The aim was to define the effectiveness of tofacitinib and to characterize the patient population receiving tofacitinib in a real-world cohort clinical setting for ulcerative colitis (UC) in Finland. METHODS: This is a retrospective non-interventional multicenter patient chart data study conducted in 23 Finnish Inflammatory Bowel Disease (IBD) centers. Baseline demographic and clinical data, clinical remission, steroid-free remission rate and time to tofacitinib discontinuation, colectomy or UC-related hospitalization were studied. RESULTS: The study included 252 UC patients of which 69% were male. Most patients had extensive disease (71%) and were bio-experienced (81%). Tofacitinib demonstrated positive treatment outcomes with clinical response, clinical remission, and steroid-free clinical remission at one year in 33%, 34% and 31% of patients, respectively. Moreover, 64% of patients in pMayo remission at week 16 from the start of tofacitinib were still in remission at one year. Only no or mild disease activity compared to moderate activity at baseline was associated with a higher probability of achieving remission according to pMayo at six months, p = .008. Hospitalizations and/or colectomies during the study period (before treatment discontinuation/end of follow-up) were low (n = 24), with less than 5 colectomies. CONCLUSIONS: In this real-world cohort, including a majority of bio-experienced UC patients, tofacitinib was effective in achieving steroid-free clinical remission in a third of the population at one year. A majority of patients in remission at week 16 were also in remission at one year. Results are in line with earlier published real-world studies. Registration: ClinicalTrials.gov NCT05082428.

Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis.

Periodontal infections increase the risk of atherosclerotic vascular disease via partly unresolved mechanisms. Of the natural IgM Abs that recognize molecular mimicry on bacterial epitopes and modified lipid and protein structures, IgM directed against oxidized low-density lipoprotein (LDL) is associated with atheroprotective properties. Here, the effect of natural immune responses to malondialdehyde-modified LDL (MDA-LDL) in conferring protection against atherosclerosis, which was accelerated by the major periodontopathogen Porphyromonas gingivalis, was investigated. LDL receptor-deficient (LDLR(-/-)) mice were immunized with mouse MDA-LDL without adjuvant before topical application challenge with live P. gingivalis. Atherosclerosis was analyzed after a high-fat diet, and plasma IgG and IgM Ab levels were measured throughout the study, and the secretion of IL-5, IL-10 and IFN-γ in splenocytes stimulated with MDA-LDL was determined. LDLR(-/-) mice immunized with MDA-LDL had elevated IgM and IgG levels to MDA-LDL compared with saline-treated controls. MDA-LDL immunization diminished aortic lipid depositions after challenge with P. gingivalis compared with mice receiving only P. gingivalis challenge. Immunization of LDLR(-/-) mice with homologous MDA-LDL stimulated the production of IL-5, implicating general activation of B-1 cells. Immune responses to MDA-LDL protected from the P. gingivalis-accelerated atherosclerosis. Thus, the linkage between bacterial infectious burden and atherogenesis is suggested to be modulated via natural IgM directed against cross-reactive epitopes on bacteria and modified LDL.

Immunomodulatory drugs: Oral and systemic adverse effects

OBJECTIVES: The main objectives are to present the different adverses effects of the immunomodulatory drugs that can impair the quality of life of the immunosupressed patients and study the impact of immunomodualtion on oral diseases. Immunomodulatory drugs have changed the treatment protocols of many diseases where immune functions play a central role, such as rheumatic diseases. Their effect on oral health has not been systematically investigated, however. Study DESIGN: We review current data on the new immunomodulatory drugs from the oral health perspective based on open literature search of the topic. RESULTS: These target specific drugs appear to have less drug interactions than earlier immunomodulating medicines but have nevertheless potential side effects such as activating latent infections. There are some data showing that the new immunomodulatory drugs may also have a role in the treatment of certain oral diseases such as lichen planus or ameliorating symptoms in Sjögren's syndrome, but the results have not been overly promising. CONCLUSIONS: In general, data are sparse of the effect of these new drugs vs. oral diseases and there are no properly powered randomized controlled trials published on this topic

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Immunomodulatory drugs: oral and systemic adverse effects.

OBJECTIVE: The main objectives are to present the different adverse effects of the immunomodulatory drugs that can impair the quality of life of the immunosuppressed patients and study the impact of immunomodulation on oral diseases. Immunomodulatory drugs have changed the treatment protocols of many diseases where immune functions play a central role, such as rheumatic diseases. Their effect on oral health has not been systematically investigated, however. STUDY DESIGN: We review current data on the new immunomodulatory drugs from the oral health perspective based on open literature search of the topic. RESULTS: These target specific drugs appear to have less drug interactions than earlier immunomodulating medicines but have nevertheless potential side effects such as activating latent infections. There are some data showing that the new immunomodulatory drugs may also have a role in the treatment of certain oral diseases such as lichen planus or ameliorating symptoms in Sjögren's syndrome, but the results have not been overly promising. CONCLUSION: In general, data are sparse of the effect of these new drugs vs. oral diseases and there are no properly powered randomized controlled trials published on this topic.

Human papillomavirus in oral atrophic lichen planus lesions.

OBJECTIVES: Oral lichen planus (OLP) is potentially premalignant disorder in which human papillomavirus (HPV) DNA is detected more often than in normal oral mucosa. We assessed HPV-genotype distribution in atrophic OLPs as related to DNA content and repair, proliferation activity, apoptosis, cell adhesion and lymphocyte infiltration. MATERIALS AND METHODS: Eighty-two OLP patients (74.4% women) with a mean follow-up-time of 62.4 months were included in the study. HPV was genotyped with Luminex-based assay detecting 24 HPV-genotypes. Data on a panel of biomarkers and static cytometry performed in these samples before were compared with HPV data. RESULTS: HPV DNA was found in 15.9% of OLPs with genotypes: HPV6/11/16/31/33 and one multiple-type infection. Two of the five patients who developed cancer had low-risk HPV6/11 infection while three were HPV-negative. There was a statistically significant correlation between HPV DNA in OLP and DNA content and ploidy markers determined with static cytometry: in HPV-positive samples, proliferation index was higher (p=0.016), less cells were in resting state G1/G0 (p=0.021) but more often in the S-phase (p=0.036) than in HPV-negative lesions. HPV positivity was also related to topoisomerase IIα (p=0.051), caspase-3 (p=0.049) and CD20 (p=0.010) protein expression. CONCLUSION: HPV-infection is associated with a subgroup of atrophic OLP. Static cytometry is a sensitive method to identify HPV-associated changes in DNA content and cell proliferation. Of 16 markers, only topoisomerase IIα (proliferation and DNA repair), caspase-3 (apoptosis) and CD20 (B-lymphocytes) were related to HPV. None of the HR-HPVs but only LR-HPVs were associated with the lesions developed to cancer.

CD27 and CD38 lymphocytes are detected in oral lichen planus lesions.

OBJECTIVE: Oral lichen planus (OLP) is a chronic disease with bandlike lymphocyte infiltration. STUDY DESIGN: To elucidate the immunologic phenotype of OLP, we analyzed the presence of CD5(+), CD20(+), CD27(+) and/or CD38(+) lymphocytes in a series of 70 atrophic OLP biopsy samples. RESULTS: CD27(+) and CD38(+) cells were present in 84% and 54% of the lesions, respectively. The lesions were graded as T-cell dominant, B-cell dominant, or a mixed lesion based on CD5(+) and CD20(+) cells in the inflammatory infiltration with the following results: 26%, 7%, and 67%, respectively. CD27 expression was found in 67% of the T-cell dominant, in 80% of the B-cell dominant, and in 91% of mixed lesions. The corresponding figures for CD38 were 72%, 80%, and 62%. CONCLUSIONS: CD27(+) and CD38(+) lymphocytes represent abnormal mononuclear cell populations in atrophic OLP lesions indicating 2 forms of OLP might exist with different pathogenesis, despite similar histology and clinical behavior.

Caspase cascade pathways in apoptosis of oral lichen planus.

OBJECTIVE: Apoptosis is frequently found in oral lichen planus (OLP) lesions, but the pathways leading to apoptosis are unknown. STUDY DESIGN: This study focused on analysis of caspase expression which is essential for apoptosis. Expression of caspases 2, 3, 8, 9, and 12 was studied in 70 biopsy samples from atrophic OLP to identify which cascade pathway, extrinsic or intrinsic, is of importance in apoptosis in OLP. RESULTS: Caspase-2 expression was present in every sample, and >70% of the epithelial cells were positive in 33% of the lesions. More than 70% of the epithelial cells expressed caspase-12 in 84% of the specimens. Caspase-8 expression was shown totally in 87% of the specimens. No caspase-3 expression was found in 57% of the samples, and caspase-9 expression was absent in the entire OLP specimen. CONCLUSIONS: The high frequency of intrinsic apoptotic pathway markers caspases 2 and 12 indicates intracellular stress in atrophic OLP epithelial cells.

Herpes simplex virus type 1 Us3 gene deletion influences toll-like receptor responses in cultured monocytic cells.

BACKGROUND: Toll-like receptors have a key role in innate immune response to microbial infection. The toll-like receptor (TLR) family consists of ten identified human TLRs, of which TLR2 and TLR9 have been shown to initiate innate responses to herpes simplex virus type 1 (HSV-1) and TLR3 has been shown to be involved in defence against severe HSV-1 infections of the central nervous system. However, no significant activation of the TLR3 pathways has been observed in wild type HSV-1 infections. In this work, we have studied the TLR responses and effects on TLR gene expression by HSV-1 with Us3 and ICP4 gene deletions, which also subject infected cells to apoptosis in human monocytic (U937) cell cultures. RESULTS: U937 human monocytic cells were infected with the Us3 and ICP4 deletion herpes simplex virus (d120), its parental virus HSV-1 (KOS), the Us3 deletion virus (R7041), its rescue virus (R7306) or wild type HSV-1 (F). The mRNA expression of TLR2, TLR3, TLR4, TLR9 and type I interferons (IFN) were analyzed by quantitative real-time PCR. The intracellular expression of TLR3 and type I IFN inducible myxovirus resistance protein A (MxA) protein as well as the level of apoptosis were analyzed by flow cytometry. We observed that the mRNA expression of TLR3 and type I IFNs were significantly increased in d120, R7041 and HSV-1 (F)-infected U937 cells. Moreover, the intracellular expression of TLR3 and MxA were significantly increased in d120 and R7041-infected cells. We observed activation of IRF-3 in infections with d120 and R7041. The TLR4 mRNA expression level was significantly decreased in d120 and R7041-infected cells but increased in HSV-1 (KOS)-infected cells in comparison with uninfected cells. No significant difference in TLR2 or TLR9 mRNA expression levels was seen. Both the R7041 and d120 viruses were able to induce apoptosis in U937 cell cultures. CONCLUSION: The levels of TLR3 and type I IFN mRNA were increased in d120, R7041 and HSV-1 (F)-infected cells when compared with uninfected cells. Also IRF-3 was activated in cells infected with the Us3 gene deletion viruses d120 and R7041. This is consistent with activation of TLR3 signaling in the cells. The intracellular TLR3 and type I IFN inducible MxA protein levels were increased in d120 and R7041-infected cells but not in cells infected with the corresponding parental or rescue viruses, suggesting that the HSV-1 Us3 gene is involved in control of TLR3 responses in U937 cells.

Desmocollin expression in oral atrophic lichen planus correlates with clinical behavior and DNA content.

BACKGROUND: Oral lichen planus (OLP) is a chronic mucocutaneous inflammatory disease, with some tendency toward malignant transformation. Markers are needed to identify the lesions at risk. METHODS: A series of 82 biopsies from 70 patients with atrophic OLP was analyzed for desmocollin-1, E-cadherin, cyclin-dependent kinase 1 (cdk-1) and Rad-51 expression using immunohistochemistry and static DNA cytometry, with particular reference to clinical outcome. RESULTS: Desmocollin-1 and E-cadherin expression were each detected in 24.4% (20/82) of the samples. Of the positive samples, only eight specimens expressed both desmocollin-1 and E-cadherin. Strong desmocollin-1 and E-cadherin expression was found in 8.5% and 3.7% of OLP biopsies, respectively. Desmocollin-1 expression increased the risk of dysplasia 31.8-fold (95% confidence intervals (CI) 3.6-280.9; p = 0.0001), while E-cadherin was significantly related to cancer (odds ratio (OR) = 5.13; 95% CI 3.3-8.1; p = 0.001). In univariate survival analysis, desmocollin-1 was a significant predictor of both cancer (log-rank test; p = 0.033) and dysplasia (p = 0.0001), while E-cadherin predicted the development of cancer (p = 0.0001). Neither cdk-1 nor Rad-51 had any predictive value. Importantly, desmocollin-1 retained its value as the only independent predictor of dysplasia in the multivariate (Cox) model (adjusted Hazard Ratio (HR) = 44.13; 95% CI 3.7-525.6). CONCLUSIONS: In atrophic OLP, desmocollin-1 is a powerful predictor of an important intermediate endpoint marker (dysplasia) in the causal pathway toward oral cancer.

The effects of lifestyle intervention for hypertension on low back pain: a randomized controlled trial.

STUDY DESIGN: Randomized controlled trial. OBJECTIVE: To assess the effects of a lifestyle intervention for hypertension on low back pain. SUMMARY OF BACKGROUND DATA: According to prospective etiologic studies, a causal association exists between certain lifestyle factors and low back pain. These factors are similar to those that elevate the risk for hypertension. Nevertheless, no randomized controlled trial has assessed effectiveness of lifestyle intervention for the treatment of hypertension on the prevalence of low back pain. METHODS: A total of 731 hypertensive employees from 45 worksites were assigned to multidisciplinary lifestyle interventions for hypertension in a rehabilitation center or to routine care in occupational or primary healthcare services during 12 months. Questionnaire data on low back pain were used to assess the effects of the intervention on the extent of low back pain and disability. RESULTS: The changes in prevalence and duration of low back pain, and related disability did not differ between the 2 groups, although there were favorable changes in some risk factors, such as body weight and physical inactivity. Subgroup analyses among patients with moderately heavy or heavy work showed that the prevalence of low back pain during the previous 12 months decreased more in the intervention than in the control group. CONCLUSION: Multidisciplinary lifestyle intervention aimed to reduce hypertension is not effective at reducing prevalence of low back pain or disability. However, in the subgroup of persons doing moderate or heavy work, the intervention seemed to reduce prevalence of low back pain during the 1-year follow-up.

Immunohistochemical study on topoisomerase IIalpha, Ki-67 and cytokeratin-19 in oral lichen planus lesions.

Oral lichen planus (OLP) is a chronic muco-cutaneous inflammatory disease defined as a precancerous condition. We determined the expression patterns of proliferation markers topoisomerase IIalpha (topo IIalpha) and Ki-67 and an intermediated filament protein cytokeratin-19 (CK-19) in atrophic OLP. These markers were selected because our recent microarray analysis indicated they might aid in identification of potentially malignant lesions. The expression patterns were correlated with the DNA content of these lesions shown to be useful in detection lesions at risk for malignant transformation of OLP. A series of 81 formalin-fixed, paraffin-embedded biopsies from 70 patients suffering from atrophic OLP were immunostained with monoclonal antibodies against topo IIalpha, Ki-67 and CK-19 using standard methods. Of the 70 patients, there were eight patients who had dysplastic changes in OLP lesions. During the follow-up, altogether five patients got cancer in the OLP area even though no dysplastic changes were present in the preceding lesion. On light microscopy, 500 cells were examined in the basal and parabasal epithelial layers of biopsy samples at 400x magnification. All biopsy samples were topo IIalpha positive and approximately 70% of the counted cells were positive. Strong staining of topo IIalpha was significantly correlated with dysplasia (P = 0.019), basal cell hyperplasia (P = 0.005) and ulceration (P = 0.008) in the samples. Ki-67 was expressed in all samples but only 36% of the cells were positive. CK-19 positivity was found in 29% of the specimens. Histological parameters were not related to either Ki-67 or CK-19. The comparison of the staining patterns with the DNA content of lesions showed that strongly stained cells with topo IIalpha were significantly more frequent in the samples with 2.5cER higher than 15% than in those below 15% (P = 0.013; Mann-Whitney). The percentage of the measured cells is 2.5cER exceeding the 2.5c value on the DNA scale. We earlier showed that this cut-off value of 2.5cER discriminated DNA aneuploidy. To conclude, topo IIalpha is a proliferation and also an apoptotic marker in atrophic OLP lesions and it might have a predictive value in oral lichen planus lesions prone to develop malignancy.

DNA content as a prognostic marker of oral lichen planus with a risk of cancer development.

OBJECTIVE: To assess the presence of aneuploidy in oral lichen planus (OLP) and its usefulness as a prognostic marker. STUDY DESIGN: Eighty-one formalin-fixed, paraffin-embedded biopsy samples taken from atrophic-erosive OLP from 70 patients were studied. Approximately 150 random nuclei in basal and/or parabasal epithelia were analyzed with static cytometry. RESULTS: Aneuploidy was detected in 41% of samples. OLPs with ulcerations or location in the tongue had significantly higher values, respectively, for the 2.5c exceeding rate (ER) (p<0.001 and 0.001) and proliferation index (PI) (p = 0.012 and 0.013) than did lesions without ulcerations or at other locations. 2.5c ER was significantly higher in dysplastic OLP lesions (p < 0.001), and the significant value (p = 0.001)for 2.5c ER discriminating DNA aneuploidy was 15.3%. In multivariate analysis only the G2/M ER (G2/MER) was a significant independent predictor of developing cancer in OLP (OR 2.349, 95% CI 1.39-3.97, p = 0.001). CONCLUSION: Ulcerated atrophic-erosive OLPs of the tongue and with dysplasia are at increased risk of cancer development. 2.5c ER, PI and G2/MER might be useful in prognosticating the increased risk of malignancy in OLP.

Effects of lifestyle intervention on neck, shoulder, elbow and wrist symptoms.

OBJECTIVES: The objective of this study was to determine whether lifestyle intervention to control hypertension can affect neck, shoulder, elbow, and wrist symptoms. METHODS: In a randomized controlled trial, 731 employees from 45 worksites were assigned for 12 months to lifestyle intervention in a rehabilitation center or to usual care provided by occupational or primary health care services. The participants had a systolic blood pressure of 140-179 mm Hg or a diastolic blood pressure of 90-109 mm Hg, or antihypertensive drug treatment. In addition to the cardiovascular risk factors, the occurrences of neck, shoulder, elbow, and wrist symptoms and disability during the previous 12 months were recorded before the intervention and 1 year later. RESULTS: The reported disability due to neck pain during the previous 12 months fell significantly more (-7%) in the intervention group than in the group in usual care (-2%). The perceived shoulder pain during the previous 7 days also decreased significantly more in the intervention group than in the control group among the women (net change 16%) and among the participants who were more highly physically active (net change 10%). Weight, body mass index, and waist and hip circumferences decreased, and physical activity increased, substantially more in the intervention group. The changes in elbow or wrist pain and related disability did not differ significantly between the intervention and control groups. CONCLUSIONS: Lifestyle intervention to control hypertension has a favorable impact on perceived disability due to neck pain.