Enrollment of older metastatic breast cancer patients in first-line clinical trials: 9-year experience of the large-scale real-life multicenter French ESME cohort.

PURPOSE: Older cancer patients are underrepresented in clinical trials. We aimed to evaluate the enrollment of older women aged 70 years old (yo) or over with metastatic breast cancer (MBC) in clinical trials. METHODS: We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real-life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment in older ones. RESULTS: 5552 women were aged ≥ 70 (median 74yo; IQR 72-77). 14,611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 [95%CI 0.33-0.76] for the 80-85yo class; OR 0.17 [95%CI 0.06-0.39] for the 85yo and more class), good ECOG Performance Status (PS 0-1) (OR 0.15 [95%CI 0.08-0.27] for the PS 2-4 class), HER2 + disease (OR 1.78 [95%CI 1.27-2.48]), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 [95%CI 3.13-8.18]), and period (OR 1.65 [95%CI 1.22-2.26] for 2012-2016, compared to 2008-2011). CONCLUSION: In this large database, few older MBC patients were enrolled in a trial compared with younger ones.

Weight of salivary gland ultrasonography compared to other items of the 2016 ACR/EULAR classification criteria for Primary Sjögren's syndrome.

OBJECTIVE: Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion. METHODS: A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS. RESULTS: A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%. CONCLUSION: SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria.

Impact of Sjögren's syndrome on oral health and quality of life: an observational cross-sectional study.

Sjögren's Syndrome is a complex disease, due to an autoimmune physiopathology, that strongly impacts both patients' primary needs (nutrition and speaking), and patients' relationship life related factors (psychological health and quality of life). In Literature, few studies had investigated oral health status in Sjögren's syndrome and its impact on patients' quality of life, so the aim of this study was to analyse that issue. 30 patients were enrolled, within the Department of Rheumatology (University of Pisa), both first diagnosis patients' and both patients who had been diagnosed with Sjögren's syndrome in the past. For each patient, a medical record was filled out together with the compilation of the Oral Health Impact Profile questionnaire. Then, during a specialistic rheumatologic visit, Sjögren's Syndrome Disease Damage Index Score (SSDDI) was determined. Results showed a direct proportion between years from diagnosis and severity of oral health issues. It was found that these issues were related to soft tissue damage and an overall worse, reported quality of life and psychological health.

The P2X7 receptor-NLRP3 inflammasome complex predicts the development of non-Hodgkin's lymphoma in Sjogren's syndrome: a prospective, observational, single-centre study.

BACKGROUND: P2X7 receptor (P2X7R), trigger of acute inflammatory responses via the NLRP3 inflammasome, is hyperfunctioning in patients with Sjögren's syndrome (SS), where it stimulates IL-18 production. Some patients with SS develop a mucosa-associated lymphoid tissue non-Hodgkin's lymphoma (MALT-NHL). OBJECTIVES: To prospectively evaluate the involvement and the putative prognostic role of this inflammatory pathway in the development of MALT-NHL. METHODS: A total of 147 women with SS have been prospectively followed for a mean of 52 months, relating the expression and function of the P2X7R-inflammasome axis in salivary glands and circulating lymphomonocytes to the prognosis and the degree of the disease. RESULTS: At baseline, gene expression of P2X7R and of the inflammasome components NLRP3, caspase-1 and IL-18 increased according to the presence of germinative centres and was higher in autoantibody-positive individuals and strongly higher in those developing a MALT-NHL over the follow-up. Glandular expression of IL-18 was threefold higher in MALT-NHL than in controls or in the other patients with SS. P2X7R did not colocalize with generic markers of inflammatory infiltrate, like CD20, being selectively expressed by epithelial cells. P2X4R, sharing functional characteristics with P2X7R, did not differ in SS and controls. The increased P2X7R gene and protein expression was tissue specific, no difference being observed in peripheral lymphomonocytes between SS with MALT-NHL and SS not developing MALT-NHL. CONCLUSION: We propose the P2X7R-inflammasome axis as a novel potential pathway involved in both SS exocrinopathy and lymphomagenesis, reinforcing the hypothesis of a key role of IL-18, via its increased P2X7R-mediated production, in the pathogenesis of lymphoproliferative malignancies, and opening novel opportunities for the early diagnosis of lymphoproliferative complications and the development of potential targeted therapies.

Safety and efficacy of FOLFIRINOX in elderly patients with metastatic or locally advanced pancreatic adenocarcinoma: A retrospective analysis.

BACKGROUND: FOLFIRINOX is a polychemotherapy regimen currently used to treat inoperable pancreatic cancer in patients with a good performance status (PS). FOLFIRINOX lengthens overall survival time (OS), but no specific data are available in elderly patients. METHODS: All cases of inoperable pancreatic adenocarcinoma in patients over 70 years old treated with FOLFIRINOX were retrospectively reviewed between 2008 and 2015 in five institutions in France. The primary objective was to evaluate the safety and efficacy of FOLFIRINOX in the elderly. RESULTS: Forty-two patients with a median age of 73 years (range: 70-79) and a median PS of 1 (range: 0-2) were included. 88% of patients treated with FOLFIRINOX were enrolled between 2012 and 2015. 24 patients (57%) needed a primary dose reduction but this did not impact OS (median OS 11.7 months (6.9-16.4) compared to 16.6 months (0.37-32.8) without dose reduction, p = 0.69). Twelve patients (29%) experienced grade 3 toxicity. Sensory neuropathy occurred most often (56%). Primary prophylaxis with granulocyte colony stimulating factor (GCSF) was administered to 14 patients (33%). One treatment-related death occurred (septic shock), although this patient had not had primary prophylaxis with GCSF. Median follow-up was 86 months. Median OS was 11.6 months (95%CI: 8.9-14.3). CONCLUSION: Median OS observed in the elderly was similar to OS previously reported in younger patients in the ACCORD 11 trial. FOLFIRINOX is effective in selected, fit elderly patients but with greater grade 3 neurotoxicity. Primary dose reduction and primary GCSF prophylaxis may control tolerance.

Cardiovascular disease risk burden in primary Sjögren's syndrome: results of a population-based multicentre cohort study.

OBJECTIVE: Systemic autoimmune diseases, in particular systemic lupus erythematosus and rheumatoid arthritis, are characterized by a high risk of premature cardiovascular (CV) events. Disease-related characteristics and traditional CV disease risk factors may contribute to atherosclerotic damage. However, there are limited data on the risk of overt CV events in primary Sjögren's syndrome (pSS). METHODS: We retrospectively analysed a cohort of patients with 1343 pSS. Disease-related clinical and laboratory data, traditional CV disease risk factors and overt CV events were recorded. Prevalence of traditional CV disease risk factors and of major CV events was compared between a subgroup of 788 female patients with pSS aged from 35 to 74 years and 4774 age-matched healthy women. RESULTS: Hypertension and hypercholesterolaemia were more prevalent, whereas smoking, obesity and diabetes mellitus were less prevalent, in women with pSS than in control subjects. Cerebrovascular events (2.5% vs. 1.4%, P = 0.005) and myocardial infarction (MI) (1.0% vs. 0.4%, P = 0.002) were more common in patients with pSS. In the whole population, central nervous system involvement (odds ratio (OR) 5.6, 95% confidence interval (CI) 1.35-23.7, P = 0.02) and use of immunosuppressive therapy (OR 1.9, 95% CI 1.04-3.70, P = 0.04) were associated with a higher risk of CV events. Patients with leucopenia had a higher risk of angina (P = 0.01). CONCLUSIONS: pSS is associated with an increased risk of cerebrovascular events and MI. Disease-related clinical and immunological markers may have a role in promoting CV events.

A retrospective, multicenter study evaluating the prognostic value of minor salivary gland histology in a large cohort of patients with primary Sjögren's syndrome.

OBJECTIVE: The objective of this report is to investigate the prognostic value of minor salivary glands (MSG) assessment, routinely performed with hematoxilin-eosin (H&E) staining, for the diagnosis of primary Sjögren's syndrome (pSS). METHODS: We retrospectively evaluated clinical, serological and histological features of 794 pSS patients. H&E-stained sections were assessed using the Chisholm and Mason grading system and/or the focus score (FS). RESULTS: FS allowed the identification of a number of differences in the disease spectrum, and its prognostic role was further confirmed by quantifying the association between FS value and clinical/serological variables with binary logistic regression. Moreover, hypocomplementemia and FS resulted the only variables associated with lymphoma at univariate analysis, and FS appeared to be associated with lymphoma independently on complement fraction concentrations. Conversely, when patients were divided according to the Chisholm and Mason grading system, we failed to observe any significant difference between subgroups. CONCLUSION: In addition to its diagnostic role, our data seem to support that the routine assessment of MSG-FS with H&E staining is useful to predict at the time of diagnosis the adverse outcomes, such as lymphoma and extraglandular manifestations, that complicate the pSS course. On this basis, it should be recommended that an MSG biopsy be performed even in those patients displaying clinical and serological criteria, allowing the diagnosis of pSS independent of histological status.

Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome: results of a large multicentre study.

OBJECTIVES: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome (pSS), in a large Italian multicentre cohort. METHOD: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. RESULTS: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. CONCLUSIONS: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS.

Pain in Sjögren's syndrome.

Sjögren's syndrome (SjS) is an autoimmune disease that affects the salivary and lacrimal glands, but it can also have extra-glandular manifestations. Although pain has not yet been fully studied and characterized, it is a symptom that can be often found in patients with SjS, who mainly complain of neuropathic pain, followed by nociceptive pain. The latter when combined with widespread dysfunctional symptoms is defined fibromyalgia. The aim of this work is to analyze the scientific literature on the presence of pain in patients with primary Sjögren's syndrome.

Patients' selection and trial matching in early-phase oncology clinical trials.

BACKGROUND: Early-phase clinical trials (EPCT) represent an important part of innovations in medical oncology and a valuable therapeutic option for patients with metastatic cancers, particularly in the era of precision medicine. Nevertheless, adult patients' participation in oncology clinical trials is low, ranging from 2% to 8% worldwide, with unequal access, and up to 40% risk of early discontinuation in EPCT, mostly due to cancer-related complications. DESIGN: We review the tools and initiatives to increase patients' orientation and access to early phase cancer clinical trials, and to limit early discontinuation. RESULTS: New approaches to optimize the early-phase clinical trial referring process in oncology include automatic trial matching, tools to facilitate the estimation of patients' prognostic and/or to better predict patients' eligibility to clinical trials. Classical and innovative approaches should be associated to double patient recruitment, improve clinical trial enrollment experience and reduce early discontinuation rates. CONCLUSIONS: Whereas EPCT are essential for patients to access the latest medical innovations in oncology, offering the appropriate trial when it is relevant for patients should increase by organizational and technological innovations. The oncologic community will need to closely monitor their performance, portability and simplicity for implementation in daily clinical practice.

Adequate assessment yields appropriate care-the role of geriatric assessment and management in older adults with cancer: a position paper from the ESMO/SIOG Cancer in the Elderly Working Group.

With the aging population, older adults constitute a growing proportion of the new cancer cases. Given the heterogeneous health status among older adults and their susceptibility to aging-related vulnerabilities, understanding their diversity and its implications becomes increasingly crucial for prognostication and guiding diagnostics, treatment decisions, and follow-up, as well as informing supportive care interventions. Geriatric assessment and management (GAM) refers to the comprehensive evaluation of an older individual's health status with subsequent management plans focusing on both oncologic and non-oncologic interventions. In 2019, the European Society for Medical Oncology (ESMO) and the International Society of Geriatric Oncology (SIOG) established the ESMO/SIOG Cancer in the Elderly Working Group. This position paper reflects the recommendations of the working group. Our paper summarizes the existing evidence with a focus on recent key trials and based on this, we propose several recommendations and future directions.

The P2X7 receptor-inflammasome complex has a role in modulating the inflammatory response in primary Sjögren's syndrome.

OBJECTIVE: Innate and adaptive immunity may contribute to gland dysfunction in patients with primary Sjögren's syndrome (pSS). The P2X7 receptor (P2X7 R)-NLRP3 inflammasome complex modulates the release of the inflammatory cytokines IL-1ß and IL-18. The presence of P2X7 R in salivary glands suggests an interesting scenario for the initiation and amplification of the innate immune response in pSS. Therefore, the aim of this study was to assess the role of the P2X7 R-NLRP3 inflammasome in pSS. SUBJECTS AND METHODS: Twenty-one consecutive patients with pSS according to the American-European Consensus Group criteria and 15 patients with sicca syndrome (i.e. without Sjögren's syndrome, non-SS) were enrolled in this study, together with six control (CTL) subjects. Expression of the P2X7R-NLRP3 platform and IL-18 was determined by real-time PCR and western blotting in gland specimens and peripheral lymphomonocytes; data were related to patients\x92 clinical, serological and histopathological characteristics. The presence of IL-18 was determined in gland and saliva samples. RESULTS: P2X7 R expression was significantly higher in salivary glands from individuals with pSS than in those from non-SS and CTL subjects. Accordingly, the gene expression levels of the inflammasome components NLRP3, ASC and caspase-1 were significantly higher in pSS gland specimens, and this was paralleled by an increased expression of mature IL-18 in pSS saliva samples. The expression of both the P2X7 R and the inflammasome components was a marker of disease-related glandular involvement, being increased in patients with anti-Ro/SSA positivity and correlated with focus score. CONCLUSION: The results of this study suggest an involvement of the P2X7 R-inflammasome-caspase-1-IL-18 axis in the development of pSS exocrinopathy. This finding provides the basis for studying the complex mechanisms underlying pSS, as well as for developing novel potential therapeutic strategies.

Systemic vasculitis: a critical digest of the recent literature.

Herewith we provide a critical digest of the recent literature on systemic vasculitis. In this manuscript, we reviewed all the articles published during the last 12 months on large-, medium- and small-vessel vasculitis and selected the most relevant studies regarding the epidemiology, pathogenesis and management of systemic vasculitis. In particular we focused the attention on giant cell arteritis, ANCA-associated vasculitis and cryoglobulinemia.

Infections occurring following IL6 blockade for the management of cytokine release syndrome in onco-hematology patients.

BACKGROUND: Cytokine release syndrome (CRS) is a common adverse event of CAR T cell or bispecific antibody (bsAb) therapy. Anti-IL6/IL6R drugs are used in the management of auto-immune diseases. Some reports showed increased risk of bacterial infection in this context. In onco-hematology, there are few data about the occurrence of infection after administration of an anti-IL6/IL6R for CRS. METHODS: We retrospectively reviewed all consecutive patients treated in Gustave Roussy Cancer Campus between 2018 and 2021, who received anti-IL6/IL6R for CRS due to bsAb in phase I clinical trials or adoptive cellular therapy (ACT). We constituted a control group including all the patients treated in the same clinical trials or standard of care ACT, naïve of anti-IL6/IL6R. RESULTS: Fifty-two patients have been included. In the anti-IL6/IL6R group (n = 26), five patients developed a grade 2 to 5 infection within a month after anti-IL6/IL6R treatment, including two grade 5 infections. In the control group (n = 26), only one patient had a grade 3 infection. The two patients who had grade 5 infections were treated for diffuse large B cell lymphoma (DLBCL), one with bsAb and the other with CAR T cell. Fifty percent (3/6) of DLBCL patients who received an anti-IL6/IL6R presented an infection, one of which was a grade 5. In solid tumor patients treated with bsAb and anti-IL6/IL6R, only one patient (/9, 11%) developed a grade 2 viral infection. CONCLUSION: It seems that the use of anti-IL6/IL6R in CRS secondary to bsAb administration in solid tumors patients does not significantly increase the risk of infection, as opposed to DLBCL patients where secondary infection might be a concern.

Inequality factors in access to early-phase clinical trials in oncology in France: results of the EGALICAN-2 study.

BACKGROUND: Investigation of the disparities in the access to experimental treatment in early-phase clinical trials is lacking. The objective of the EGALICAN-2 study was to identify the factors underpinning such inequalities. METHODS: A national prospective survey was conducted in 11 early-phase clinical trial centers (CLIP2) certified by the French National Cancer Institute. Sociodemographic, socioeconomic and medical data were collected. Univariate logistic regression models were carried out to estimate odds ratios and 90% confidence intervals associated with the effect of each study variable. A multivariate logistic regression model was built to explore the independent factors associated with the administration of the experimental treatment (C1D1). A post hoc analysis was carried out excluding female cancer patients. RESULTS: Between 2015 and 2016, 1355 patients referred from 11 CLIP2 centers in France were included in the study. Eight hundred and forty-eight patients received C1D1 (73%) and 320 patients (27%) were screening failure. Median age was 58 years (range 17-97 years) and 667 patients (54%) were female. Most patients had a metastatic disease (n = 751, 87%). In the multivariate logistic regression analysis, the significant independent factors associated with C1D1 were male sex, initial care received in a hospital with an early-phase unit and living in wealthy metropolitan areas (P values <0.05). In the post hoc analysis, the sex factor was no longer significant [odds ratio = 1.21 (95% confidence interval 0.86-1.70), P value = 0.271]. CONCLUSIONS: This study investigated the factors producing social inequalities in the context of early-phase clinical trials in oncology. Our research highlights factors of sex, care pathway and geographic location. Gynecological cancer was found to impact C1D1 significantly, unlike breast cancer. The results of this study should contribute to improve patient access to early-phase clinical trials.

Behçet's disease: features of neurological involvement in a dedicated centre in Italy.

OBJECTIVES: The aim of the present study was to retrospectively assess the prevalence of neurological involvement and the clinical patterns of presentation in a monocentric cohort of patients with BD, who have been followed in the last twenty years at our centre. METHODS: One hundred and seventeen patients were retrospectively studied. The male/female ratio was 1.6:1, with a mean disease duration of 11±5 years. Their mean age was 42±9 years (min:18, max:77), while the mean age at disease onset was 25±4 years (min:10, max:58). The mean ± SD duration of follow-up at our centre was 7±2 (min:1, max:11) years. RESULTS: Neurological involvement was observed in 38% (44 patients, 36 males and 8 females; mean age at onset 25±4 years). Organic brain involvement, demonstrated by MRI was due to ischaemic pons-mesencephalon lesions in 19 patients and to meningoencephalitis with brainstem involvement in 16. Peripheral nervous system involvement was confirmed by electroneuromyographic study in 4 patients, and consisted of peripheral neuropathy prominent in the lower extremities in all cases; we have also observed only 2 cases of endocranial hypertension and 3 BD patients suffering from pulsatile, severe headache, without abnormal neurological examination, responding only to medium-high doses of steroids. Excluding peripheral neuropathy and isolated headache, the onset of CNS involvement (total prevalence: 32% of the cohort) was observed in 2 patients within the first year from the onset of BD, in 4 cases between the first and the third year, in 24 between the third and the fifth year, 7 between the fifth and the tenth year; none presented a CNS involvement after the first 10 years of disease. CONCLUSIONS: Neuro-BD is more frequent in young males and it never represents a presenting feature of the disease. The most frequent time of onset of neurological involvement seems to be within the first 10 years of disease. Since neurological involvement may result in severe functional disability or be a life-threatening disease, a careful follow-up during the first years after onset is recommended.

Access to early-phase clinical trials in older patients with cancer in France: the EGALICAN-2 study.

BACKGROUND: Access to clinical trials and especially early-phase trials (ECT) is an important issue in geriatric oncology. As cancer can be considered an age-related disease because the incidence of most cancers increases with age, new drugs should also be evaluated in older patients to assess their safety and efficacy. The EGALICAN-2 study was primarily designed to identify social and/or regional inequalities regarding access to ECT. We focused on the factors of inequalities in access to ECT in older patients. PATIENTS AND METHODS: During a 1-year period (2015-2016), a survey was conducted in 11 early-phase units certified by the French National Cancer Institute. RESULTS: A total of 1319 patients were included in the analyses: 1086 patients (82.3%) were <70 years and 233 patients (17.7%) were >70 years. The most common tumor types at referral in older patients were gastrointestinal (19.3%), hematological (19.3%), and thoracic tumors (18.0%). Most patients referred to the phase I unit had signed informed consent and the rate was similar across age (92.7% in younger patients versus 90.6% in older patients; P = 0.266). The rate of screening failure was also similar across age (28.5% in younger patients versus 24.3% in older patients; P = 0.219). Finally, in older patients, univariate analyses showed that initial care received in the hospital having a phase I unit was statistically associated with first study drug administration (odds ratio 0.49, 90% confidence interval 0.27-0.88; P = 0.045). CONCLUSIONS: Older patients are underrepresented in early clinical trials with 17.7% of patients aged ≥70 years compared with the number of new cases of cancer in France (50%). However, when invited to participate, older patients were prone to sign informed consent.