Tumor-infiltrating lymphocytes as a predictor of axillary and primary tumor pathological response after neoadjuvant chemotherapy in patients with breast cancer: a retrospective cohort study.

PURPOSE: Tumor-infiltrating lymphocytes (TILs) can predict complete pathological response (pCR) of tumor in the breast but not so well-defined in the axilla after neoadjuvant chemotherapy. Since axillary surgery is being increasingly de-escalated after NACT, we aimed to investigate the relationship between TILs and pCR in the axilla and breast, as well as survival amongst NACT patients. METHODS: Clinicopathological data on patients who underwent NACT between 2013 and 2020 were retrospectively examined. Specifically, pre-TILs (before NACT), post-TILs (after NACT) and ΔTIL (changes in TILs) were assessed. Primary endpoint was pCR and secondary endpoints were breast cancer-free interval (BCFI) and overall survival (OS). RESULTS: Two hundred and twenty patients with nodal metastases were included. Overall axillary and breast pCR rates were 42.7% (94/220) and 39.1% (86/220), respectively, whereas the combined pCR rate was 32.7% (72/220). High pre-TILs (OR 2.03, 95% CI 1.02-4.05; p = 0.04) predicted axillary pCR whereas, high post-TILs (OR 0.33, 95% CI 0.14-0.76; p = 0.009) and increased ΔTILs (OR 0.25, 95% CI 0.08-0.79; p = 0.02) predicted non-axillary pCR. TILs were not a significant predictor for BCFI and OS. CONCLUSIONS: This study supports the potential use of pre-TILs to select initially node-positive patients for axillary surgical de-escalation after NACT.

Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is associated with poor prognosis and limited treatment options due to the lack of important receptors (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]) used for targeted therapy. However, high-throughput in vitro drug screening of cell lines is a powerful tool for identifying effective drugs for a disease. Here, we determine the intrinsic chemosensitivity of TNBC cell lines to proteasome inhibitors (PIs), thereby identifying potentially potent 2-drug combinations for TNBC. Eight TNBC cell lines (BT-549, CAL-148, HCC1806, HCC38, HCC70, MDA-MB-436, MDA-MB-453, and MDA-MB-468) and two controls (MCF-10A and MCF-7) were first exposed to 18 drugs (11 PIs and 7 clinically relevant chemotherapeutic agents) as monotherapy, followed by prediction of potent 2-drug combinations using the IDACombo pipeline. The synergistic effects of the 2-drug combinations were evaluated with SynergyFinder in four TNBC cell lines (CAL-148, HCC1806, HCC38, and MDA-MB-468) and three controls (BT-474, MCF-7, and T47D) in vitro, followed by further evaluation of tumor regression in zebrafish tumor models established using HCC1806 and MCF-7 cells. Monotherapy identified nine effective drugs (bortezomib, carfilzomib, cisplatin, delanzomib, docetaxel, epoxomicin, MLN-2238, MLN-9708, and nedaplatin) across all cell lines. PIs (e.g., bortezomib, delanzomib, and epoxomicin) were highly potent drugs in TNBC cells, of which bortezomib and delanzomib inhibited the chymotrypsin-like activity of the 20 S proteasome by 100% at 10 µM. Moreover, several potent 2-drug combinations (e.g., bortezomib+nedaplatin and epoxomicin+epirubicin) that killed virtually 100% of cells were also identified. Although HCC1806- and MCF-7-derived xenografts treated with bortezomib+nedaplatin and carboplatin+paclitaxel were smaller, HCC1806 cells frequently metastasized to the trunk region. Taken together, we show that PIs used in combination with platinum agents or topoisomerase inhibitors exhibit increased efficiency with almost 100% inhibition in TNBC cell lines, indicating that PIs are therefore promising compounds to use as combination therapy for TNBC.

Patient-derived scaffolds representing breast cancer microenvironments influence chemotherapy responses in adapted cancer cells consistent with clinical features.

BACKGROUND: The tumor microenvironment clearly influences cancer progressing properties but less is known about how individual cancer microenvironments potentially moderate cancer treatment effects. By cultivating and treating cancer cell lines in patient-derived scaffolds (PDS), the impact of specific characteristics of individual cancer microenvironments can be incorporated in human-like growth modelling and cancer drug treatment testing. METHODS: PDSs from 78 biobanked primary breast cancer samples with known patient outcomes, were prepared and repopulated with donor breast cancer cell lines, followed by treatment with 5-fluorouracil or doxorubicin after cellular adaption to the various microenvironments. Cancer cell responses to the treatments were monitored by RNA-analyses, highlighting changes in gene sets representative for crucial tumor biological processes such as proliferation, cancer stem cell features, differentiation and epithelial-to-mesenchymal transition. RESULTS: The chemotherapy treatments induced distinct gene expression patterns in adapted cancer cells with clusters of similar treatment responses depending on the patient-derived cancer microenvironment used as growth substrate. The doxorubicin treatment displayed a favorable gene signature among surviving cancer cells with low proliferation (MKI67) and pluripotency features (NANOG, POU5F1), in comparison to 5-fluorouracil showing low proliferation but increased pluripotency. Specific gene changes monitored post-treatment were also significantly correlated with clinical data, including histological grade (NANOG), lymph node metastasis (SLUG) and disease-free patient survival (CD44). CONCLUSIONS: This laboratory-based treatment study using patient-derived scaffolds repopulated with cancer cell lines, clearly illustrates that the human cancer microenvironment influences chemotherapy responses. The differences in treatment responses defined by scaffold-cultures have potential prognostic and treatment predictive values.

Evaluation of tumor-infiltrating lymphocytes and mammographic density as predictors of response to neoadjuvant systemic therapy in breast cancer.

BACKGROUND: Response rates vary among breast cancer patients treated with neoadjuvant systemic therapy (NAST). Thus, there is a need for reliable treatment predictors. Evidence suggests tumor-infiltrating lymphocytes (TILs) predict NAST response. Still, TILs are seldom used clinically as a treatment determinant. Mammographic density (MD) is another potential marker for NAST benefit and its relationship with TILs is unknown. Our aims were to investigate TILs and MD as predictors of NAST response and to study the unexplored relationship between TILs and MD. MATERIAL AND METHODS: We studied 315 invasive breast carcinomas treated with NAST between 2013 and 2020. Clinicopathological data were retrieved from medical records. The endpoint was defined as pathological complete response (pCR) in the breast. TILs were evaluated in pre-treatment core biopsies and categorized as high (≥10%) or low (<10%). MD was scored (a-d) according to the breast imaging reporting and data system (BI-RADS) fifth edition. Binary logistic regression and Spearman's test of correlation were performed using SPSS. RESULTS: Out of 315 carcinomas, 136 achieved pCR. 94 carcinomas had high TILs and 215 had low TILs. Six carcinomas had no available TIL data. The number of carcinomas in each BI-RADS category were 37, 122, 112, and 44 for a, b, c, and d, respectively. High TILs were independently associated with pCR (OR: 2.95; 95% CI: 1.59-5.46) compared to low TILs. In the univariable analysis, MD (BI-RADS d vs. a) showed a tendency of higher likelihood for pCR (OR: 2.43; 95% CI: 0.99-5.98). However, the association was non-significant, which is consistent with the result of the multivariable analysis (OR: 2.51; 95% CI: 0.78-8.04). We found no correlation between TILs and MD (0.02; p = .80). CONCLUSION: TILs significantly predicted NAST response. We could not define MD as a significant predictor of NAST response. These findings should be further replicated.

The Possible Clinical Significance of a Decreased Serum Level of Soluble PD-L1 in Discoid Lupus Erythematosus, but Not in Subacute Cutaneous Lupus Erythematosus-A Pilot Study.

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease with various clinical forms, including the subtypes of discoid lupus erythematosus (DLE) and subacute cutaneous lupus erythematosus (SCLE). The altered function of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) axis in CLE pathogenesis has been suggested. Here, the soluble forms of PD-1 (sPD-1) and PD-L1 (sPD-L1) were explored in untreated DLE and SCLE. Levels of sPD-1 and sPD-L1 were determined by enzyme-linked immunosorbent assay in serums of 21 DLE, 18 SCLE, 13 systemic lupus erythematosus (SLE) patients and 20 healthy controls (HCs). Differences between patient groups and HCs, and the association between clinical activity of skin symptoms and sPD-1/sPD-L1 levels were analyzed with Mann-Whitney U-test and Spearmann's correlation. Regarding sPD-1 levels, no statistically significant differences were found between DLE and SCLE groups, nor compared to HCs. As for sPD-L1, a significantly lower level was found in the DLE group compared to the SCLE and HC groups (p = 0.027 and p = 0.009, respectively). In SLE, significantly higher sPD-1 was found compared to HCs (p = 0.002). No association between skin symptom activity and sPD-1/sPD-L1 levels was found in CLE. Alterations of the inhibitory effect of sPD-L1 on T-cell activity might elucidate the differences between DLE and SCLE.

Clinical relevance of biomarker discordance between primary breast cancers and synchronous axillary lymph node metastases.

Clinical decision-making for patients with breast cancer (BC) is still primarily based on biomarker characteristics of the primary tumor, together with the evaluation of synchronous axillary lymph node metastasis (LNM). In this study, we investigated the prevalence of discordance in the biomarkers and surrogate subtyping between the primary BC and the LNM, and whether subsequent changes would have altered clinical treatment recommendations. In this retrospective study, 94 patients treated for unifocal primary BC and synchronous LNM at Sahlgrenska UniversityHospital during 2018 were included. Estrogen (ER) and progesterone (PR) receptor, Ki67, and HER2 status were assessed in the primary tumor and LNM using immunohistochemistry. Discordances between the primary tumor and the LNM were analyzed for each individual biomarker and surrogate subtyping. The concordance between the primary tumor and the LNM for ER, PR, Ki67, and HER2 status was 98.9%, 89.4%, 72.3%, and 95.8%, respectively. Discordance in surrogate subtyping was found in 28.7% of the tumors and matched LNMs, the majority (81.5%) of which changed to a more favorable subtype in the LNM; most commonly from Luminal B to Luminal A (48.6%). No changes in surrogate subtyping were detected where ER or HER2 status changed from negativity in the BC to positivity in the LNM, thereby showing no additional value in performing immunohistochemistry on the LNM from a treatment decision-making perspective. However, large studies need to be performed that test both the primary BCs and synchronous LNMs for more accurate diagnostics.

Assessment of Frontal Hemispherical Lateralization in Plaque Psoriasis and Atopic Dermatitis.

BACKGROUND: Each brain hemisphere plays a specialized role in cognitive and behavioral processes, known as hemispheric lateralization. In chronic skin diseases, such as plaque psoriasis (Pso) and atopic dermatitis (AD), the degree of lateralization between the frontal hemispheres may provide insight into specific connections between skin diseases and the psyche. This study aims to analyze the hemispherical lateralization, neurovegetative responses, and psychometric characteristics of patients with Pso and AD. METHODS: The study included 46 patients with Pso, 56 patients with AD, and 29 healthy control (Ctrl) subjects. The participants underwent frontal electroencephalogram (EEG) measurement, heart rate variability (HRV) assessment, and psychological tests. Statistical analyses were performed using ANOVA, with Bonferroni correction applied for multiple comparisons. RESULTS: This study shows a significant right-lateralized prefrontal activity in both AD patients (p < 0.001) and Pso patients (p = 0.045) compared with Ctrl, with no significant difference between the AD and Pso groups (p = 0.633). AD patients with right-hemispheric dominant prefrontal activation exhibited increased inhibition and avoidance markers, while Pso patients showed elevated sympathetic nervous system activity. CONCLUSION: Psychophysiological and psychometric data suggest a shared prevalence of right-hemispheric dominance in both AD and Pso patient groups. However, the findings indicate distinct psychodermatological mechanisms in AD and Pso.

Combining histological grade, TILs, and the PD-1/PD-L1 pathway to identify immunogenic tumors and de-escalate radiotherapy in early breast cancer: a secondary analysis of a randomized clinical trial.

BACKGROUND: The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT. METHODS: The SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated immune response was defined as stromal TILs ≥10% and PD-1 and/or PD-L1 expression in ≥1% of lymphocytes. Tumors were categorized as high-risk or low-risk using assessments of histological grade and proliferation as measured by gene expression. The risk of ipsilateral breast tumor recurrence (IBTR) and benefit of RT were then analyzed with 10 years follow-up based on the integration of immune activation and tumor-intrinsic risk group. RESULTS: Among high-risk tumors, an activated immune infiltrate was associated with a reduced risk of IBTR (HR 0.34, 95% CI 0.16 to 0.73, p=0.006). The incidence of IBTR in this group was 12.1% (5.6-25.0) without RT and 4.4% (1.1-16.3) with RT. In contrast, the incidence of IBTR in the high-risk group without an activated immune infiltrate was 29.6% (21.4-40.2) without RT and 12.8% (6.6-23.9) with RT. Among low-risk tumors, no evidence of a favorable prognostic effect of an activated immune infiltrate was seen (HR 2.0, 95% CI 0.87 to 4.6, p=0.100). CONCLUSIONS: Integrating histological grade and immunological biomarkers can identify tumors with aggressive characteristics but a low risk of IBTR despite a lack of RT boost and systemic therapy. Among high-risk tumors, the risk reduction of IBTR conferred by an activated immune infiltrate is comparable to treatment with RT. These findings may apply to cohorts dominated by estrogen receptor-positive tumors.

Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial.

PURPOSE: The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation. EXPERIMENTAL DESIGN: The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR). RESULTS: The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09-0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2-30.3). CONCLUSIONS: Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.

Co-administration with A1M does not influence apoptotic response of 177Lu-octreotate in GOT1 neuroendocrine tumors.

Recombinant α1-microglobulin (A1M) is a proposed radioprotector during 177Lu-octreotate therapy of neuroendocrine tumors (NETs). To ensure a maintained therapeutic effect, we previously demonstrated that A1M does not affect the 177Lu-octreotate induced decrease in GOT1 tumor volume. However, the underlying biological events of these findings are still unknown. The aim of this work was to examine the regulation of apoptosis-related genes in GOT1 tumors short-time after i.v. administration of 177Lu-octreotate with and without A1M or A1M alone. Human GOT1 tumor-bearing mice received 30 MBq 177Lu-octreotate or 5 mg/kg A1M or co-treatment with both. Animals were sacrificed after 1 or 7 days. Gene expression analysis of apoptosis-related genes in GOT1 tissue was performed with RT-PCR. In general, similar expression patterns of pro- and anti-apoptotic genes were found after 177Lu-octreotate exposure with or without co-administration of A1M. The highest regulated genes in both irradiated groups compared to untreated controls were FAS and TNFSFRS10B. Administration of A1M alone only resulted in significantly regulated genes after 7 days. Co-administration of A1M did not negatively affect the transcriptional apoptotic response of 177Lu-octreotate in GOT1 tumors.

Clinical evaluation of molecular surrogate subtypes in patients with ipsilateral multifocal primary breast cancer.

BACKGROUND: When ipsilateral multifocal primary breast cancer (IMBC) is detected, standard routine is to evaluate the largest tumor with immunohistochemistry (IHC). As all foci are not routinely characterized, many patients may not receive optimal adjuvant treatment. Here, we assess the clinical relevance of examining at least two foci present in patients with IMBC. METHODS: Patients diagnosed and treated for IMBC at Sahlgrenska University Hospital (Gothenburg, Sweden) between 2012 and 2017 were screened. In total, 180 patients with ≥ 2 invasive foci (183 specimens) were assessed with IHC and included in this study. Expression of the estrogen (ER) and progesterone (PR) receptors, Ki67, HER2, and tumor grade were used to determine the molecular surrogate subtypes and discordance among the foci was recorded. An additional multidisciplinary team board was then held to re-assess whether treatment recommendations changed due to discordances in molecular surrogate subtype between the different foci. RESULTS: Discordance in ER, PR, HER2, and Ki67 was found in 2.7%, 19.1%, 7.7%, and 16.9% of invasive foci, respectively. Discordance in the molecular surrogate subtypes was found in 48 of 180 (26.7%) patients, which resulted in therapy changes for 11 patients (6.1%). These patients received additional endocrine therapy (n = 2), chemotherapy (n = 3), and combined chemotherapy and trastuzumab (n = 6). CONCLUSION: Taken together, when assessing at least two tumor foci with IHC, regardless of shared morphology or tumor grade between the different foci, 6.1% of patients with IMBC were recommended additional adjuvant treatment. A pathologic assessment using IHC of all foci is therefore recommended to assist in individualized treatment decision making.

Impact of Surgical Care Bundle on Surgical Site Infection after Non-Reconstructive Breast Cancer Surgery: A Single-Centre Retrospective Comparative Cohort Study.

BACKGROUND: Surgical-site infections (SSIs) are the commonest cause of healthcare-related infections. Although a surgical care bundle (SCB), defined as a group of preventative measures, is effective in reducing SSIs, it has not been well documented in breast cancer surgery. We aimed to investigate the impact of SCB on SSI. METHODS: A single-centre retrospective comparative cohort study between 2016 and 2020 was carried out. An SCB including eight different measures was implemented in October 2018 at Sahlgrenska University Hospital, Sweden. Patients who underwent non-reconstructive breast cancer surgery were included for analysis. The primary endpoint was SSI within 30 days after surgery. RESULTS: Overall, 10.4% of patients (100/958) developed SSI. After SCB implementation, the overall SSI rate reduced from 11.8% to 8.9% (p = 0.15). The largest SSI rate reduction was seen in the subgroup that underwent breast conservation and sentinel lymph node biopsy (SLNB), from 18.8% to 9.8% (p = 0.01). In this multivariable analysis adjusting for patient and treatment factors, the implementation of SCB resulted in a statistically significant reduction in SSI risk (OR 0.63, 95% CI 0.40-0.99, p = 0.04). CONCLUSIONS: The implementation of a SCB could reduce the incidence of SSI in breast cancer surgery.

ONEST (Observers Needed to Evaluate Subjective Tests) Analysis of Stromal Tumour-Infiltrating Lymphocytes (sTILs) in Breast Cancer and Its Limitations.

Tumour-infiltrating lymphocytes (TILs) reflect antitumour immunity. Their evaluation of histopathology specimens is influenced by several factors and is subject to issues of reproducibility. ONEST (Observers Needed to Evaluate Subjective Tests) helps in determining the number of observers that would be sufficient for the reliable estimation of inter-observer agreement of TIL categorisation. This has not been explored previously in relation to TILs. ONEST analyses, using an open-source software developed by the first author, were performed on TIL quantification in breast cancers taken from two previous studies. These were one reproducibility study involving 49 breast cancers, 23 in the first circulation and 14 pathologists in the second circulation, and one study involving 100 cases and 9 pathologists. In addition to the estimates of the number of observers required, other factors influencing the results of ONEST were examined. The analyses reveal that between six and nine observers (range 2-11) are most commonly needed to give a robust estimate of reproducibility. In addition, the number and experience of observers, the distribution of values around or away from the extremes, and outliers in the classification also influence the results. Due to the simplicity and the potentially relevant information it may give, we propose ONEST to be a part of new reproducibility analyses.

[Characteristics of the course of lupus erythematosus panniculitis in a retrospective analysis of 17 patients]. / A lupus erythematosus panniculitis lefolyásának jellegzetességei 17 betegünk retrospektív vizsgálata alapján.

INTRODUCTION: Lupus erythematous panniculitis (LEP) is a rare type of chronic cutaneous lupus erythematous. Clinical characteristics are tender, subcutaneous nodules, erythematous plaques. Disfigurement of face and body might develop which affects the patient's quality of life. LEP can be the first sign of systemic lupus erythematous (SLE). OBJECTIVE: Our aim was to review the clinicopathological characteristics and the course of LEP through our own patients. METHODS: We retrospectively analyzed the clinical records of 17 LEP patients at Semmelweis University's Department of Dermatology, Venerology and Dermatooncology between 2000 and 2022. RESULTS: The male : female ratio was 1 : 16, average age was 37.8 years. Lesion localisations were proximal lower (8/17) and upper extremities (7/17), face (4/17), breast (3/17), chest (2/17), buttocks (2/17), back (1/17) and distal lower extremity (1/17). Lesion morphologies were nodules (11/17), plaques (7/17), lipoatrophy (4/17), ulceration (3/17), calcification (1/17). Discoid changes covered in 6 cases. In 10 cases, systemic symptoms were observed (arthritis (4/17), haematological (5/17), renal (2/17), anti-phospholipid syndrome (2/17). 7 patients fulfilled the EULAR/ACR criteria for SLE. Histology showed mixed type panniculitis in 8, lobular in 3 cases. Average time until diagnosis was 24.3 months. Among all our SLE patients, skin symptoms regressed following systemic immunosuppressive treatment. LEP patients with only skin manifestation were often resistant for the therapy of cutaneous lupus erythematous. CONCLUSION: The diagnosis of LEP often takes months or years. Wider knowledge of LEP would shorten the time to diagnosis, preventing disfigurement and possible damage of internal organs. Based on our observations, LEP without SLE might be treated with early immunosuppression. Orv Hetil. 2023; 164(5): 172-178.

Low dose oral glucocorticoid therapy in lichen planus: A retrospective cohort study.

Background There are various topical and systemic treatment options for the management of lichen planus. However, it is often difficult to achieve long-term disease control and many of the common therapies may be associated with unwanted side effects. Aims To evaluate the effectiveness of 8 mg oral methylprednisolone administered daily in lichen planus by the analysis of medical records. Methods In this retrospective cohort study, we compared the rates of improvement between two groups of patients. The first group received 8 mg oral methylprednisolone daily for at least one month. In the second group, patients with similar parameters to the first group (age, sex, disease manifestation) but without systemic glucocorticoid therapy were included. Fisher's exact test was used to compare the rates of remission in the two groups. Results In the daily oral methylprednisolone (n = 24) and no systemic corticosteroids (n = 16) groups, 23 (95.8%) and 6 (37.5%) patients achieved partial or complete remission, respectively. The frequency of improvement was significantly higher in patients who received oral methylprednisolone (P < 0.0001). Limitations Limitations of this study include its retrospective design and the relatively small sample size. Conclusion Low dose oral glucocorticoid therapy may be an effective option for the systemic treatment of lichen planus. Based on our results and previous studies, instead of higher doses, longer therapy duration with low doses should be considered.

Comparing the psychometric properties of the EQ-5D-3L and EQ-5D-5L descriptive systems and utilities in atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disorder affecting up to 10% of adults. The EQ-5D is the most commonly used generic preference-accompanied measure to generate quality-adjusted life years (QALYs) for economic evaluations. OBJECTIVES: We aimed to compare psychometric properties of the three-level and five-level EQ-5D (EQ-5D-3L and EQ-5D-5L) in adult patients with AD. METHODS: In a multicentre cross-sectional study, 218 AD patients with a broad range of severity completed the EQ-5D-3L, EQ-5D-5L, Dermatology Life Quality Index (DLQI) and Skindex-16. Disease severity outcomes included the Investigator Global Assessment, Eczema Area and Severity Index and the objective SCORing Atopic Dermatitis. RESULTS: A good agreement was established between the two EQ-5D versions with an intraclass correlation coefficient of 0.815 (95% CI 0.758-0.859, p < 0.001). Overall, 33 different health state profiles occurred in the EQ-5D-3L and 84 in the EQ-5D-5L. Compared to the EQ-5D-3L, ceiling effect was reduced for the mobility, self-care, usual activities and pain/discomfort dimensions by 4.6-11.5%. EQ-5D-5L showed higher average relative informativity (Shannon's evenness index: 0.64 vs. 0.59). EQ-5D-5L demonstrated better convergent validity with EQ VAS, DLQI and Skindex-16. The two measures were similar in distinguishing between groups of patients based on disease severity and skin-specific quality of life with a moderate or large effect size (η2 = 0.083-0.489). CONCLUSION: Both instruments exhibited good psychometric properties in AD; however, the EQ-5D-5L was superior in terms of ceiling effects, informativity and convergent validity. We recommend the use of the EQ-5D-5L to measure health outcomes in clinical settings and for QALY calculations in AD.

SARS-CoV-2 Infection in Pemphigus Vulgaris Two Weeks after Rituximab Therapy with Total Recovery: A Case Report.

The mortality risk factors for Corona Virus Disease-19 (COVID-19) infection (caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)) include advanced age, male sex, certain comorbidities, and immunosuppression (1). Pemphigus vulgaris is a rare mucocutaneous autoimmune disease with autoantibodies against desmosomal desmoglein-1 and desmoglein-3, resulting in acantholysis and blister formation. This epithelial barrier defect increases susceptibility to infections, which may lead to relapses (2). Additionally, therapy-associated immunosuppression can lead to severe infections. Corticosteroids are the mainstay therapy. For moderate and severe pemphigus, rituximab is recommended in first-line treatment along with other immunosuppressants, and it may also be added in refractory cases. It is a monoclonal antibody against CD20 with long-lasting B-cell depletion potency. Recovery of B-cell function may last from one to seven years. Consequently, patients receiving rituximab cannot produce enough COVID-19 specific plasma cells, leading to a severe course of COVID-19 (2). Shashidi-Dadras et al. reported five mild COVID-19 cases among 167 patients with pemphigus who had received rituximab one to five years earlier. The authors presumed rituximab use within five years increases COVID-19 susceptibility regardless the number of courses received (3). Among 48 patients with pemphigus treated with rituximab within five years, Uzuncakmak et al. reported one mild case of COVID-19 (in a patient who had received a single course seven months earlier) (4). In another study, high titers of SARS-CoV-2 antibodies and high counts of antibody-secreting cells were associated with severe COVID-19 (5), which may be the consequence of antibody-dependent enhancement (6). Mahmoudi et al. concluded that B-cells may not be necessary for recovery in COVID-19, but they may protect from reinfection (7). Considering these data, rituximab should be postponed during the pandemic (8). In exceptional cases, it may be applied with careful consideration of the risk-benefit ratio (2,4). Patients should be monitored for signs of COVID-19 before and during treatment. A 63-year-old woman with pemphigus vulgaris presented at our department with widespread skin lesions. Comorbidities included hypertension, hypothyroidism, and glaucoma. Diagnosis was established based on histology and direct and indirect immunofluorescent microscopy results. Both desmoglein-1 and desmoglein-3 autoantibodies were detectable by ELISA. The patient was initially treated with low-dose systemic methylprednisolone (8 mg/day), because glaucoma contraindicated a higher dose. Azathioprine was subsequently started (gradually increased from 0.6 to 2.5 mg/kg/day). Continuous mucocutaneous progression 4 weeks later led to the decision to add rituximab therapy. The patient was confirmed as SARS-CoV-2 negative and received 1000 mg 12 weeks after starting glucocorticoid treatment. Two weeks later, she developed fever and became SARS-CoV-2 positive, and therefore the second rituximab treatment had to be cancelled. The patient had fever for six weeks without any other complaints, hospitalization was not required, and immunosuppression was continued with 8 mg methylprednisolone and 2.5 mg/kg azathioprine. Two weeks after recovery, she was diagnosed with pulmonary embolism, but recovered completely. Pulmonary embolism is a relatively common complication of COVID-19 which may be triggered by inactivity, loss of body fluids due to fever, a hypercoagulable state, and direct toxic venous endothelial damage caused by the virus (9). At a follow-up 4 months later, minimal skin lesions and significantly decreased desmoglein-1 and desmoglein-3 titers were observed. Azathioprine and methylprednisolone therapy were continued, and a second dosage of rituximab was given 7 months from the first one without any side-effects. We conclude that rituximab is a highly effective therapy in pemphigus, but the risk-benefit ratio should be carefully considered during the COVID-19 pandemic. We have not observed irreversible or permanent consequences of its administration, but our patient had a potentially lethal complication, pulmonary embolism, which may be associated with a more severe COVID-19 course due to immunosuppression. Total recovery was observed despite COVID-19 shortly after the initiation of rituximab.

The Effect of Melatonin Intake on Survival of Patients with Breast Cancer-A Population-Based Registry Study.

Previous research has demonstrated the antitumoral effects of melatonin on breast cancer in both in vitro and in vivo studies. The aim of the present study was to investigate whether melatonin has a favorable effect on the survival of patients diagnosed with early breast cancer. This retrospective registry-based study included all patients diagnosed with breast cancer in Sweden between 2005 and 2015. Data were linked to the Swedish Prescribed Drug Registry and the Swedish Cause of Death Registry. A multivariate Cox regression model, including patient age, tumor size, tumor grade, ER status, HER2 status, nodal status and defined daily doses (DDDs) of melatonin, was used to analyze breast-cancer-specific survival as well as overall survival. Of the 37,075 included patients, 926 (2.5%) were prescribed melatonin, with a median DDD of 30. Melatonin was found to have a protective effect on breast-cancer-specific survival (BCSS) in the univariate analysis (HR: 0.736, 95% CI: 0.548-0.989, p = 0.042), but when adjusting for known prognostic factors in the multivariate analysis, this beneficial effect disappeared (HR: 1.037, 95% CI: 0.648-1.659, p = 0.879). Melatonin was not proven to have a favorable effect on the survival of patients diagnosed with early breast cancer in this retrospective registry study.

Pan-cancer analysis of genomic and transcriptomic data reveals the prognostic relevance of human proteasome genes in different cancer types.

BACKGROUND: The human proteasome gene family (PSM) consists of 49 genes that play a crucial role in cancer proteostasis. However, little is known about the effect of PSM gene expression and genetic alterations on clinical outcome in different cancer forms. METHODS: Here, we performed a comprehensive pan-cancer analysis of genetic alterations in PSM genes and the subsequent prognostic value of PSM expression using data from The Cancer Genome Atlas (TCGA) containing over 10,000 samples representing up to 33 different cancer types. External validation was performed using a breast cancer cohort and KM plotter with four cancer types. RESULTS: The PSM genetic alteration frequency was high in certain cancer types (e.g. 67%; esophageal adenocarcinoma), with DNA amplification being most common. Compared with normal tissue, most PSM genes were predominantly overexpressed in cancer. Survival analysis also established a relationship with PSM gene expression and adverse clinical outcome, where PSMA1 and PSMD11 expression were linked to more unfavorable prognosis in ≥ 30% of cancer types for both overall survival (OS) and relapse-free interval (PFI). Interestingly, PSMB5 gene expression was associated with OS (36%) and PFI (27%), and OS for PSMD2 (42%), especially when overexpressed. CONCLUSION: These findings indicate that several PSM genes may potentially be prognostic biomarkers and novel therapeutic targets for different cancer forms.

Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer.

Invasive lobular carcinoma (ILC) represents the second most common subtype of breast cancer (BC), accounting for up to 15% of all invasive BC. Loss of cell adhesion due to functional inactivation of E-cadherin is the hallmark of ILC. Although the current world health organization (WHO) classification for diagnosing ILC requires the recognition of the dispersed or linear non-cohesive growth pattern, it is not mandatory to demonstrate E-cadherin loss by immunohistochemistry (IHC). Recent results of central pathology review of two large randomized clinical trials have demonstrated relative overdiagnosis of ILC, as only ~60% of the locally diagnosed ILCs were confirmed by central pathology. To understand the possible underlying reasons of this discrepancy, we undertook a worldwide survey on the current practice of diagnosing BC as ILC. A survey was drafted by a panel of pathologists and researchers from the European lobular breast cancer consortium (ELBCC) using the online tool SurveyMonkey®. Various parameters such as indications for IHC staining, IHC clones, and IHC staining procedures were questioned. Finally, systematic reporting of non-classical ILC variants were also interrogated. This survey was sent out to pathologists worldwide and circulated from December 14, 2020 until July, 1 2021. The results demonstrate that approximately half of the institutions use E-cadherin expression loss by IHC as an ancillary test to diagnose ILC and that there is a great variability in immunostaining protocols. This might cause different staining results and discordant interpretations. As ILC-specific therapeutic and diagnostic avenues are currently explored in the context of clinical trials, it is of importance to improve standardization of histopathologic diagnosis of ILC diagnosis.