Publications by authors named "Maria De Santis"

224 Publications

A European, prospective, observational study of enzalutamide in patients with metastatic castration-resistant prostate cancer: PREMISE.

Int J Cancer 2021 Oct 14. Epub 2021 Oct 14.

Department of Urology, Charité University Hospital, Berlin, Germany, and Medical University of Vienna, Vienna, Austria.

In randomized clinical trials, the androgen receptor inhibitor enzalutamide has demonstrated efficacy and safety in metastatic castration-resistant prostate cancer (mCRPC). This study captured efficacy, safety, and patient-reported outcomes (PROs) of enzalutamide in mCRPC patients in a real-world European setting. PREMISE (NCT0249574) was a European, long-term, prospective, observational study in mCRPC patients prescribed enzalutamide as part of standard clinical practice. Patients were categorized based on prior docetaxel and/or abiraterone use. The primary endpoint was time to treatment failure (TTF), defined as time from enzalutamide initiation to permanent treatment discontinuation for any reason. Secondary endpoints included prostate-specific antigen (PSA) response, time to PSA progression, time to disease progression, and safety. PROs included EuroQol 5-Dimension, 5-Level questionnaire, Functional Assessment of Cancer Therapy-Prostate, and Brief Pain Inventory-Short Form. Overall, 1732 men were enrolled. Median TTF with enzalutamide was 12.9 months in the chemotherapy- and abiraterone-naïve cohort (cohort 1) and 8.4 months in the post-chemotherapy and abiraterone-naïve cohort (cohort 2). Clinical outcomes based on secondary endpoints also varied between cohorts. Cohorts 1 and 2 showed small improvements in health-related quality of life and pain status. The proportions of patients reporting treatment-emergent adverse events (TEAEs) were 51.0% and 62.2% in cohorts 1 and 2, respectively; enzalutamide-related TEAEs were similar in both cohorts. The most frequent TEAE across cohorts was fatigue. These data from unselected mCRPC patients in European, real-world, clinical-practice settings confirmed the benefits of enzalutamide previously shown in clinical trial outcomes, with safety results consistent with enzalutamide's known safety profile. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33845DOI Listing
October 2021

Serum ANCA and Overall Mortality: A 10-Year Retrospective Cohort Study on 1,024 Italian Subjects.

Front Immunol 2021 10;12:714174. Epub 2021 Sep 10.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy.

Background: Antineutrophil cytoplasmic antibodies (ANCA) are primarily involved in the pathogenesis of ANCA-associated vasculitides (AAV). However, ANCA may also be present in healthy subjects and in patients with autoimmune disorders different from AAV. We hypothesized that serum ANCA are associated with a worse prognosis in disorders other than AAV.

Objective: We investigated the association between the overall survival and the presence of serum ANCA in 1,024 Italian subjects with various testing indications in a 10-year interval.

Methods: In this retrospective cohort study, a population of 6,285 patients (many of whom were subsequently excluded due to our criteria) who tested for ANCA at a single center in 10 years was considered, and life status and comorbidities of subjects were collected. We compared the overall survival of ANCA-positive and ANCA-negative patients by means of Kaplan-Meier curves, while a multivariable adjusted Cox regression was used to evaluate the association between the ANCA status and the outcome (death) in terms of hazard ratios (HR) with 95% confidence intervals (CI).

Results: The positivity of perinuclear ANCA (pANCA) increased significantly mortality (HR, 1.60; 95% CI, 1.10-2.32), while cytoplasmic ANCA (cANCA) positivity failed to show a significant association (HR, 1.43; 95% CI, 0.77-2.68). The increased mortality rate was observed for both pANCA and cANCA in patients suffering from rheumatic disorders. No association was found between mortality and anti-MPO (HR, 0.63; 95% CI, 0.20-2.00) or anti-PR3 (HR, 0.98; 95% CI, 0.24-3.96) after adjusting for confounders.

Conclusions: Serum pANCA and cANCA are independent negative prognostic factors in patients with concurrent autoimmune diseases.
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http://dx.doi.org/10.3389/fimmu.2021.714174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461098PMC
September 2021

Environmental triggers for connective tissue disease: the case of COVID-19 associated with dermatomyositis-specific autoantibodies.

Curr Opin Rheumatol 2021 11;33(6):514-521

Department of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center - IRCCS.

Purpose Of Review: The aim of the present review is to analyze the link between autoimmune diseases and environmental factors, in particular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) as it shares numerous features with the interstitial lung disease associated with connective tissue diseases positive for rare autoantibodies directed at highly specific autoantigens (i.e., MDA5 and RIG1) among the intracellular sensors of SARS-CoV-2 in the innate response against viruses.

Recent Findings: As shown in recent publications and in our original data, specific autoantibodies may be functionally relevant to COVID-19 infection. We evaluated sera from 35 hospitalized patients with COVID-19 to identify antinuclear antibodies and autoantibodies directed against specific antigenic targets, and we identified anti-nuclear antibodies (ANA) in 20/35 of patients with COVID-19 (57%), in patients with need for supplemental oxygen (90% vs. 20% in ANA-negative cases; P < 0.0001). In 7/35 COVID-19 sera, we detected anti-MJ/NXP2 (n = 3), anti-RIG1 (n = 2), anti-Scl-70/TOPO1 (n = 1), and anti-MDA5 (n = 1), overall associated with a significantly worse pulmonary involvement at lung computerized tomography scans. Eleven (31%) patients were positive for antibodies against the E2/E3 subunits of mitochondrial pyruvate dehydrogenase complex.

Summary: Viral infections such as COVID-19 are associated with ANA and autoantibodies directed toward antiviral signaling antigens in particular in patients with worse pulmonary involvement.
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http://dx.doi.org/10.1097/BOR.0000000000000844DOI Listing
November 2021

5 reasons to encourage anti-SARS-CoV-2 vaccination in patients with rheumatic diseases.

Expert Rev Clin Immunol 2021 Sep 23:1-4. Epub 2021 Sep 23.

Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center- IRCCS, Milan, Italy.

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http://dx.doi.org/10.1080/1744666X.2021.1978289DOI Listing
September 2021

Covid-19 And Rheumatic Autoimmune Systemic Diseases: Role of Pre-Existing Lung Involvement and Ongoing Treatments.

Curr Pharm Des 2021 09 2. Epub 2021 Sep 2.

Humanitas Clinical and Research Center IRCCS, Milano, Italy

Background: The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations.

Objective: To investigate the prevalence of symptomatic Covid-19 and its correlations with both organ involvement and ongoing treatments in a large series of Italian ASD patients during the first wave of pandemic.

Method: Our multicenter telephone 6-week survey included 3,029 unselected ASD patients enrolled at 36 tertiary referral centers of northern, central, and southern Italian macro-areas with different diffusion of pandemic. Symptomatic SARS-CoV-2 infection was classified as definite Covid-19 (presence of symptoms plus positive oral/nasopharyngeal swabs) or highly suspected Covid-19 (highly suggestive symptoms, in absence of a swab testing).

Results: A significantly higher prevalence of definite plus highly suspected Covid-19 compared to Italian general population was detected in the whole ASD series (p=.000), as well as in patients from the three macro-areas (p=.000 in all). Statistically higher prevalence of Covid-19 was also found in connective tissue diseases compared to chronic arthritis subgroup (p=.000) and in ASD patients with pre-existing interstitial lung involvement (p=.000). Patients treated with either conventional disease modifying anti-rheumatic drugs (DMARDs) and/or biological DMARDs showed a significantly lower prevalence of Covid-19 (p=.000 in both). Finally, scleroderma patients undergoing low-dose aspirin showed significantly lower rate of Covid-19 compared to those without (p=0.003).

Conclusion: The higher prevalence of Covid-19 in ASD patients along with the significant correlations with important clinical features and therapeutic regimens suggests the need to develop targeted prevention/management strategies during the current pandemic wave.
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http://dx.doi.org/10.2174/1381612827666210903103935DOI Listing
September 2021

Hypofractionated whole-breast radiotherapy in large breast size patients: is it really a resolved issue?

Med Oncol 2021 Aug 3;38(9):107. Epub 2021 Aug 3.

Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Via Giacomo Venezian, 1, 23100, Milano, Italy.

The purpose of this study was to evaluate the impact of breast size on acute and late side effects in breast cancer (BC) patients treated with hypofractionated radiotherapy (Hypo-RT). In this study we analyzed patients over 50 years with a diagnosis of early BC, candidate for Hypo-RT after conservative surgery. Acute and late skin toxicities were evaluated in accordance with the RTOG scale. Multivariable logistic analysis was performed using dosimetric/anatomical factors resulted associated with toxicity outcome in univariable analysis. Among patients treated between 2009 and 2015, 425 had at least 5 years of follow-up. At RT end, acute skin toxicity ≥ G2 and edema ≥ G2 occurred in 88 (20.7%) and 4 (0.9%) patients, respectively. The multivariable analysis showed association of skin toxicity with boost administration (p < 0.01), treated skin area (TSA) receiving more than 20 Gy (p = 0.027) and breast volume receiving 105% of the prescription dose (V105%) (p = 0.016), but not breast size. At 5 years after RT, fibrosis ≥ G1 occurred in 89 (20.9%) patients and edema ≥ G1 in 36 (8.5%) patients. Fibrosis resulted associated with breast volume ≥ 1000 cm (p = 0.04) and hypertension (p = 0.04). As for edema, multivariable logistic analysis showed a correlation with hypertension and logarithm of age, but not with boost administration. Breast volume had an unclear impact (p = 0.055). A recurrent association was found between acute and late toxicities and breast V105%, which is correlated with breast size. This may suggest that a more homogenous RT technique may be preferred for patients with larger breast size.
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http://dx.doi.org/10.1007/s12032-021-01550-6DOI Listing
August 2021

Eine offene, randomisierte Phase-III-Studie mit MK-6482 versus Everolimus bei Teilnehmern mit fortgeschrittenem Nierenzellkarzinom, das nach vorherigen, auf PD-1/L1- und VEGF-gezielten Therapien eine Tumorprogression aufweist (HIF-005) – AUO-Nr. AN 51/19.

Aktuelle Urol 2021 08 27;52(4):318-319. Epub 2021 Jul 27.

Organgruppe Nierenzellkarzinom der Arbeitsgemeinschaft Urologische Onkologie in der Deutschen Krebsgesellschaft, Kuno-Fischer-Straße 8, 14057 Berlin.

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http://dx.doi.org/10.1055/a-1525-7885DOI Listing
August 2021

Breast cancer patient perspective on opportunities and challenges of a genetic test aimed to predict radio-induced side effects before treatment: Analysis of the Italian branch of the REQUITE project.

Radiol Med 2021 Oct 15;126(10):1366-1373. Epub 2021 Jul 15.

Radiation Oncology 1 Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.

Aim: To explore breast cancer patient's perspective on future genetic testing for prediction of toxicity after breast radiotherapy (RT).

Materials And Methods: The study involved patient enrolled in the Italian branch of the REQUITE project conducted at the National Cancer Institute in Milan. Semi-structured interviews were conducted within one month from the end of radiotherapy treatment by two radiation oncologists and a radiotherapy technician previously trained by a clinical psychologist with experience in the oncology field. Semi-structured interviews are characterized by a set of pre-defined questions and developed ad hoc by researchers in Leicester within the REQUITE project. The interview questions investigated interest in undergoing the genetic test and expectations on its usefulness and disadvantages.

Results: Eighteen interviews were conducted and analysed. Forty-five initial codes were combined into nine themes which were then clustered in two main macro-areas (i) Opportunities and (ii) Challenges. Overall, all patients understand the aim of the genetic test and considered its intrinsic opportunity to make the physician more confident with the treatment. Regarding side effects, most of patients felt prepared to RT but not without fear. Many women considered important to have the largest and reliable information, also about negative experiences. Prevailing emotions were anxiety and fear but not connected to genetic test's result.

Conclusions: A genetic test could be an opportunity because generate knowledge and give patients a dynamic role in the decision-making approach. Prediction of single patient radiosensitivity before RT could prompt suggestion to entail a more and more tailored radiation treatment in the era of personalized approach.
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http://dx.doi.org/10.1007/s11547-021-01395-zDOI Listing
October 2021

A data science approach for early-stage prediction of Patient's susceptibility to acute side effects of advanced radiotherapy.

Comput Biol Med 2021 08 5;135:104624. Epub 2021 Jul 5.

The Health Innovation Ecosystem, University of Westminster, London, UK.

The prediction by classification of side effects incidence in a given medical treatment is a common challenge in medical research. Machine Learning (ML) methods are widely used in the areas of risk prediction and classification. The primary objective of such algorithms is to use several features to predict dichotomous responses (e.g., disease positive/negative). Similar to statistical inference modelling, ML modelling is subject to the class imbalance problem and is affected by the majority class, increasing the false-negative rate. In this study, seventy-nine ML models were built and evaluated to classify approximately 2000 participants from 26 hospitals in eight different countries into two groups of radiotherapy (RT) side effects incidence based on recorded observations from the international study of RT related toxicity "REQUITE". We also examined the effect of sampling techniques and cost-sensitive learning methods on the models when dealing with class imbalance. The combinations of such techniques used had a significant impact on the classification. They resulted in an improvement in incidence status prediction by shifting classifiers' attention to the minority group. The best classification model for RT acute toxicity prediction was identified based on domain experts' success criteria. The Area Under Receiver Operator Characteristic curve of the models tested with an isolated dataset ranged from 0.50 to 0.77. The scale of improved results is promising and will guide further development of models to predict RT acute toxicities. One model was optimised and found to be beneficial to identify patients who are at risk of developing acute RT early-stage toxicities as a result of undergoing breast RT ensuring relevant treatment interventions can be appropriately targeted. The design of the approach presented in this paper resulted in producing a preclinical-valid prediction model. The study was developed by a multi-disciplinary collaboration of data scientists, medical physicists, oncologists and surgeons in the UK Radiotherapy Machine Learning Network.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104624DOI Listing
August 2021

MicroRNAs in Axial Spondylarthritis: an Overview of the Recent Progresses in the Field with a Focus on Ankylosing Spondylitis and Psoriatic Arthritis.

Curr Rheumatol Rep 2021 Jul 3;23(8):59. Epub 2021 Jul 3.

Division of Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.

Purpose Of Review: To highlight the recent discoveries and lines of evidence on the role of microRNAs in ankylosing spondylitis (AS) and psoriatic arthritis (PsA), focusing on their expression profiling and mechanisms of action.

Recent Findings: AS and PsA are chronic inflammatory musculoskeletal diseases with axial manifestations and represent an excellent model for studying microRNAs contribution to the disease pathogenesis, particularly through immunomodulation, inflammation, and bone remodelling, or their value as candidate diagnostic and prognostic biomarkers. MicroRNAs are single-stranded nucleotides able to regulate gene expression. They are a key component of the epigenetic machinery, involved in physiological and pathological processes. The contribution of microRNAs in AS and PsA (such as miR-29a in regulating bone metabolism) is highlighted by several works in the field but their utility as possible markers must be still confirmed, particularly in larger patients' cohorts.
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http://dx.doi.org/10.1007/s11926-021-01027-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254706PMC
July 2021

Evaluation of Oncological Outcomes and Data Quality in Studies Assessing Nerve-sparing Versus Non-Nerve-sparing Radical Prostatectomy in Nonmetastatic Prostate Cancer: A Systematic Review.

Eur Urol Focus 2021 Jun 16. Epub 2021 Jun 16.

Department of Urology, University Hospital, St. Etienne, France.

Context: Surgical techniques aimed at preserving the neurovascular bundles during radical prostatectomy (RP) have been proposed to improve functional outcomes. However, it remains unclear if nerve-sparing (NS) surgery adversely affects oncological metrics.

Objective: To explore the oncological safety of NS versus non-NS (NNS) surgery and to identify factors affecting the oncological outcomes of NS surgery.

Evidence Acquisition: Relevant databases were searched for English language articles published between January 1, 1990 and May 8, 2020. Comparative studies for patients with nonmetastatic prostate cancer (PCa) treated with primary RP were included. NS and NNS techniques were compared. The main outcomes were side-specific positive surgical margins (ssPSM) and biochemical recurrence (BCR). Risk of bias (RoB) and confounding assessments were performed.

Evidence Synthesis: Out of 1573 articles identified, 18 studies recruiting a total of 21 654 patients were included. The overall RoB and confounding were high across all domains. The most common selection criteria for NS RP identified were characteristic of low-risk disease, including low core-biopsy involvement. Seven studies evaluated the link with ssPSM and showed an increase in ssPSM after adjustment for side-specific confounders, with the relative risk for NS RP ranging from 1.50 to 1.53. Thirteen papers assessing BCR showed no difference in outcomes with at least 12 mo of follow-up. Lack of data prevented any subgroup analysis for potentially important variables. The definitions of NS were heterogeneous and poorly described in most studies.

Conclusions: Current data revealed an association between NS surgery and an increase in the risk of ssPSM. This did not translate into a negative impact on BCR, although follow-up was short and many men harbored low-risk PCa. There are significant knowledge gaps in terms of how various patient, disease, and surgical factors affect outcomes. Adequately powered and well-designed prospective trials and cohort studies accounting for these issues with long-term follow-up are recommended.

Patient Summary: Neurovascular bundles (NVBs) are structures containing nerves and blood vessels. The NVBs close to the prostate are responsible for erections. We reviewed the literature to determine if a technique to preserve the NVBs during removal of the prostate causes worse cancer outcomes. We found that NVB preservation was poorly defined but, if applied, was associated with a higher risk of cancer at the margins of the tissue removed, even in patients with low-risk prostate cancer. The long-term importance of this finding for patients is unclear. More data are needed to provide recommendations.
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http://dx.doi.org/10.1016/j.euf.2021.05.009DOI Listing
June 2021

Breast reconstruction and radiation therapy: An Italian expert Delphi consensus statements and critical review.

Cancer Treat Rev 2021 Sep 27;99:102236. Epub 2021 May 27.

Group for Reconstructive and Therapeutic Advancements (G.RE.T.A.), Milan, Naples, Catania, Italy.

Breast conserving surgery (BCS) plus radiation therapy (RT) or mastectomy have shown comparable oncological outcomes in early-stage breast cancer and are considered standard of care treatments. Postmastectomy radiation therapy (PMRT) targeted to both the chest wall and regional lymph nodes is recommended in high-risk patients. Oncoplastic breast conserving surgery (OBCS) represents a significant recent improvement in breast surgery. Nevertheless, it represents a challenge for radiation oncologists as it triggers different decision-making strategies related to treatment volume definition and target delineation. Hence, the choice of the best combination and timing when offering RT to breast cancer patients who underwent or are planned to undergo reconstruction procedures should be carefully evaluated and based on individual considerations. We present an Italian expert Delphi Consensus statements and critical review, led by a core group of all the professional profiles involved in the management of breast cancer patients undergoing reconstructive procedures and RT. The report was structured as to consider the main recommendations on breast reconstruction and RT and analyse the current open issues deserving investigation and consensus. We used a three key-phases and a Delphi process. The final expert panel of 40 colleagues selected key topics as identified by the core group of the project. A final consensus on 26 key statements on RT and breast reconstruction after three rounds of the Delphi voting process and harmonisation was reached. An accompanying critical review of available literature was summarized. A clear communication and cooperation between surgeon and radiation oncologist is of paramount relevance both in the setting of breast reconstruction following mastectomy when PMRT is planned and when extensive glandular rearrangements as OBCS is performed. A shared-decision making, relying on outcome-based and patient-centred considerations, is essential, while waiting for higher level-of-evidence data.
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http://dx.doi.org/10.1016/j.ctrv.2021.102236DOI Listing
September 2021

Clinical relevance of clonal hematopoiesis in the oldest-old population.

Blood 2021 Jun 14. Epub 2021 Jun 14.

IRCCS Humanitas Clinical Institute, Rozzano, Italy.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
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http://dx.doi.org/10.1182/blood.2021011320DOI Listing
June 2021

Patient- and Tumour-related Prognostic Factors for Urinary Incontinence After Radical Prostatectomy for Nonmetastatic Prostate Cancer: A Systematic Review and Meta-analysis.

Eur Urol Focus 2021 May 6. Epub 2021 May 6.

Department of Urology, Antonius Hospital, Utrecht, The Netherlands.

Context: While urinary incontinence (UI) commonly occurs after radical prostatectomy (RP), it is unclear what factors increase the risk of UI development.

Objective: To perform a systematic review of patient- and tumour-related prognostic factors for post-RP UI. The primary outcome was UI within 3 mo after RP. Secondary outcomes included UI at 3-12 mo and ≥12 mo after RP.

Evidence Acquisition: Databases including Medline, EMBASE, and CENTRAL were searched between January 1990 and May 2020. All studies reporting patient- and tumour-related prognostic factors in univariable or multivariable analyses were included. Surgical factors were excluded. Risk of bias (RoB) and confounding assessments were performed using the Quality In Prognosis Studies (QUIPS) tool. Random-effects meta-analyses were performed for all prognostic factor, where possible.

Evidence Synthesis: A total of 119 studies (5 randomised controlled trials, 24 prospective, 88 retrospective, and 2 case-control studies) with 131 379 patients were included. RoB was high for study participation and confounding; moderate to high for statistical analysis, study attrition, and prognostic factor measurement; and low for outcome measurements. Significant prognostic factors for postoperative UI within 3 mo after RP were age (odds ratio [OR] per yearly increase 1.04, 95% confidence interval [CI] 1.03-1.05), membranous urethral length (MUL; OR per 1-mm increase 0.81, 95% CI 0.74-0.88), prostate volume (PV; OR per 1-ml increase 1.005, 95% CI 1.000-1.011), and Charlson comorbidity index (CCI; OR 1.28, 95% CI 1.09-1.50).

Conclusions: Increasing age, shorter MUL, greater PV, and higher CCI are independent prognostic factors for UI within 3 mo after RP, with all except CCI remaining prognostic at 3-12 mo.

Patient Summary: We reviewed the literature to identify patient and disease factors associated with urinary incontinence after surgery for prostate cancer. We found increasing age, larger prostate volume, shorter length of a section of the urethra (membranous urethra), and lower fitness were associated with worse urinary incontinence for the first 3 mo after surgery, with all except lower fitness remaining predictive at 3-12 mo.
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http://dx.doi.org/10.1016/j.euf.2021.04.020DOI Listing
May 2021

A Systematic Review of the Impact of Surgeon and Hospital Caseload Volume on Oncological and Nononcological Outcomes After Radical Prostatectomy for Nonmetastatic Prostate Cancer.

Eur Urol 2021 May 4. Epub 2021 May 4.

Department of Urology, University Hospital, St. Etienne, France.

Context: The impact of surgeon and hospital volume on outcomes after radical prostatectomy (RP) for localised prostate cancer (PCa) remains unknown.

Objective: To perform a systematic review on the association between surgeon or hospital volume and oncological and nononcological outcomes following RP for PCa.

Evidence Acquisition: Medline, Medline In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched. All comparative studies for nonmetastatic PCa patients treated with RP published between January 1990 and May 2020 were included. For inclusion, studies had to compare hospital or surgeon volume, defined as caseload per unit time. Main outcomes included oncological (including prostate-specific antigen persistence, positive surgical margin [PSM], biochemical recurrence, local and distant recurrence, and cancer-specific and overall survival) and nononcological (perioperative complications including need for blood transfusion, conversion to open procedure and within 90-d death, and continence and erectile function) outcomes. Risk of bias (RoB) and confounding assessments were undertaken. Both a narrative and a quantitative synthesis were planned if the data allowed.

Evidence Synthesis: Sixty retrospective comparative studies were included. Generally, increasing surgeon and hospital volumes were associated with lower rates of mortality, PSM, adjuvant or salvage therapies, and perioperative complications. Combining group size cut-offs as used in the included studies, the median threshold for hospital volume at which outcomes start to diverge is 86 (interquartile range [IQR] 35-100) cases per year. In addition, above this threshold, the higher the caseload, the better the outcomes, especially for PSM. RoB and confounding were high for most domains.

Conclusions: Higher surgeon and hospital volumes for RP are associated with lower rates of PSMs, adjuvant or salvage therapies, and perioperative complications. This association becomes apparent from a caseload of >86 (IQR 35-100) per year and may further improve hereafter. Both high- and low-volume centres should measure their outcomes, make them publicly available, and improve their quality of care if needed.

Patient Summary: We reviewed the literature to determine whether the number of prostate cancer operations (radical prostatectomy) performed in a hospital affects the outcomes of surgery. We found that, overall, hospitals with a higher number of operations per year have better outcomes in terms of cancer recurrence and complications during or after hospitalisation. However, it must be noted that surgeons working in hospitals with lower annual operations can still achieve similar or even better outcomes. Therefore, making hospital's outcome data publicly available should be promoted internationally, so that patients can make an informed decision where they want to be treated.
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http://dx.doi.org/10.1016/j.eururo.2021.04.028DOI Listing
May 2021

Lymphocyte modulation by tofacitinib in patients with rheumatoid arthritis.

Clin Exp Immunol 2021 Aug 28;205(2):142-149. Epub 2021 May 28.

Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital IRCCS, Rozzano, Milan, Italy.

Tofacitinib is an oral small molecule targeting the intracellular Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways approved for the treatment of active rheumatoid arthritis (RA). We investigated the effects of tofacitinib on the response of RA lymphocytes to B and T cell collagen epitopes in their native and post-translationally modified forms. In particular, peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy subjects were cultured with type II collagen peptides (T261-273, B359-369, carT261-273, citB359-369) or with phorbol myristate acetate (PMA)/ionomycin/CD40L in the presence or absence of 100 nM tofacitinib for 20 h and analyzed by fluorescence activated cell sorter (FACS). Cultures without brefeldin A were used for cytokine supernatant enzyme-linked immunosorbent assay (ELISA) analysis. Tofacitinib down-regulated inflammatory cytokines by stimulated B [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] and T [interferon (IFN)-γ, IL-17 or TNF-α] cells in the short term, while a significant reduction of IL-17 and IL-6 levels in peripheral blood mononuclear cell (PBMC) supernatant was also observed. IL-10 was significantly reduced in collagen-stimulated B cells from patients with RA and increased in controls, thus mirroring an altered response to collagen self-epitopes in RA. Tofacitinib partially prevented the IL-10 down-modulation in RA B cells stimulated with collagen epitopes. In conclusion, the use of tofacitinib exerts a rapid regulatory effect on B cells from patients with RA following stimulation with collagen epitopes while not reducing inflammatory cytokine production by lymphocytes.
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http://dx.doi.org/10.1111/cei.13609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274203PMC
August 2021

Geometric contour variation in clinical target volume of axillary lymph nodes in breast cancer radiotherapy: an AIRO multi-institutional study.

Br J Radiol 2021 Jul 21;94(1123):20201177. Epub 2021 Apr 21.

Radiation Oncology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy.

Objectives: To determine interobserver variability in axillary nodal contouring in breast cancer (BC) radiotherapy (RT) by comparing the clinical target volume of participating single centres (SC-CTV) with a gold-standard CTV (GS-CTV).

Methods: The GS-CTV of three patients (P1, P2, P3) with increasing complexity was created in DICOM format from the median contour of axillary CTVs drawn by BC experts, validated using the simultaneous truth and performance-level estimation and peer-reviewed. GS-CTVs were compared with the correspondent SC-CTVs drawn by radiation oncologists, using validated metrics and a total score (TS) integrating all of them.

Results: Eighteen RT centres participated in the study. Comparative analyses revealed that, on average, the SC-CTVs were smaller than GS-CTV for P1 and P2 (by -29.25% and -27.83%, respectively) and larger for P3 (by +12.53%). The mean Jaccard index was greater for P1 and P2 compared to P3, but the overlap extent value was around 0.50 or less. Regarding nodal levels, L4 showed the highest concordance with the GS. In the intra-patient comparison, L2 and L3 achieved lower TS than L4. Nodal levels showed discrepancy with GS, which was not statistically significant for P1, and negligible for P2, while P3 had the worst agreement. DICE similarity coefficient did not exceed the minimum threshold for agreement of 0.70 in all the measurements.

Conclusions: Substantial differences were observed between SC- and GS-CTV, especially for P3 with altered arm setup. L2 and L3 were the most critical levels. The study highlighted these key points to address.

Advances In Knowledge: The present study compares, by means of validated geometric indexes, manual segmentations of axillary lymph nodes in breast cancer from different observers and different institutions made on radiotherapy planning CT images. Assessing such variability is of paramount importance, as geometric uncertainties might lead to incorrect dosimetry and compromise oncological outcome.
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http://dx.doi.org/10.1259/bjr.20201177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248216PMC
July 2021

Lymph nodal radiotherapy in breast cancer: what are the unresolved issues?

Expert Rev Anticancer Ther 2021 Aug 25;21(8):827-840. Epub 2021 Apr 25.

UOC Di Radioterapia, Presidio Ospedaliero San Filippo Neri, Roma, Italy.

: Sentinel lymph node biopsy (SLNB) is the gold standard in invasive breast cancer. Axillary dissection (ALND) is controversial in some presentations.: Key questions were formulated and explored focused on four different scenarios in adjuvant axillary radiation management in early and locally advanced breast cancer. Answers to these questions were searched in MEDLINE, PubMed from June 1946 to August 2020. Clinical trials, retrospective studies, international guidelines, meta-analysis, and reviews were explored.: Analysis according to biological disease characteristics is necessary to establish the impact of ALND avoidance in unexpectedly positive SLNB (pN1) in cN0 patients. A low-risk probability of axillary recurrence was observed if axillary radiotherapy (ART) or ALND were offered without impact on outcomes. Adjuvant RNI in pT1-3 pN1 treated with mastectomy or BCS should be proposed in unfavorable disease and risk factors. In ycN0 after NACT, SLNB can be offered in selected cases or ALND should be performed. After SLNB post-NACT (ypN1), ALND and adjuvant radiotherapy are mandatory.
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http://dx.doi.org/10.1080/14737140.2021.1917390DOI Listing
August 2021

The Archaeal Elongation Factor EF-2 Induces the Release of aIF6 From 50S Ribosomal Subunit.

Front Microbiol 2021 24;12:631297. Epub 2021 Mar 24.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

The translation factor IF6 is a protein of about 25 kDa shared by the Archaea and the Eukarya but absent in Bacteria. It acts as a ribosome anti-association factor that binds to the large subunit preventing the joining to the small subunit. It must be released from the large ribosomal subunit to permit its entry to the translation cycle. In Eukarya, this process occurs by the coordinated action of the GTPase Efl1 and the docking protein SBDS. Archaea do not possess a homolog of the former factor while they have a homolog of SBDS. In the past, we have determined the function and ribosomal localization of the archaeal () IF6 homolog (aIF6) highlighting its similarity to the eukaryotic counterpart. Here, we analyzed the mechanism of aIF6 release from the large ribosomal subunit. We found that, similarly to the Eukarya, the detachment of aIF6 from the 50S subunit requires a GTPase activity which involves the archaeal elongation factor 2 (aEF-2). However, the release of aIF6 from the 50S subunits does not require the archaeal homolog of SBDS, being on the contrary inhibited by its presence. Molecular modeling, using published structural data of closely related homologous proteins, elucidated the mechanistic interplay between the aIF6, aSBDS, and aEF2 on the ribosome surface. The results suggest that a conformational rearrangement of aEF2, upon GTP hydrolysis, promotes aIF6 ejection. On the other hand, aSBDS and aEF2 share the same binding site, whose occupation by SBDS prevents aEF2 binding, thereby inhibiting aIF6 release.
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http://dx.doi.org/10.3389/fmicb.2021.631297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024482PMC
March 2021

Viral Respiratory Pathogens and Lung Injury.

Clin Microbiol Rev 2021 06 31;34(3). Epub 2021 Mar 31.

Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy

Several viruses target the human respiratory tract, causing different clinical manifestations spanning from mild upper airway involvement to life-threatening acute respiratory distress syndrome (ARDS). As dramatically evident in the ongoing SARS-CoV-2 pandemic, the clinical picture is not always easily predictable due to the combined effect of direct viral and indirect patient-specific immune-mediated damage. In this review, we discuss the main RNA (orthomyxoviruses, paramyxoviruses, and coronaviruses) and DNA (adenoviruses, herpesviruses, and bocaviruses) viruses with respiratory tropism and their mechanisms of direct and indirect cell damage. We analyze the thin line existing between a protective immune response, capable of limiting viral replication, and an unbalanced, dysregulated immune activation often leading to the most severe complication. Our comprehension of the molecular mechanisms involved is increasing and this should pave the way for the development and clinical use of new tailored immune-based antiviral strategies.
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http://dx.doi.org/10.1128/CMR.00103-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142519PMC
June 2021

Estimated glomerular filtration rate is a marker of mortality in the European Scleroderma Trials and Research Group (EUSTAR) database.

Rheumatology (Oxford) 2021 Mar 26. Epub 2021 Mar 26.

Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.

Objectives: Study aim was to evaluate estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with mortality in systemic sclerosis (SSc) patients from the European Scleroderma Trials and Research Group (EUSTAR) database.

Methods: SSc patients from the EUSTAR database with available items for calculation of eGFR at baseline visit and with a second follow-up visit were included. A cut-off of 60 ml/min was chosen for all SSc patients and 30 ml/min for scleroderma renal crisis (SRC). Cox regression and competing risk analysis were performed to evaluate the role of eGFR as predictive factor of mortality.

Results: 3650 SSc patients were included. Mean serum level of creatinine and eGFR were 0.8 mg/dl (IQR 0.6-0.9) and 86.6 ± 23.7 ml/min. The eGFR was significantly lower in patients with pulmonary hypertension. Overall survival (OS) was significantly reduced in SSc patients with eGFR <60 ml/min respect to patients with eGFR ≥ 60 ml/min [OS at five years 0.763 (CI 95%: 0.700-0.814) vs 0.903 (CI 95%: 0.883-0.919 p< 0.001)]. In multivariable analysis, OS was associate with male gender (p< 0.01), systolic pulmonary arterial pressure (sPAP) (p< 0.001) and eGFR (p< 0.001). Cumulative incidence of deaths due to SSc was associate with increased sPAP (p< 0.001) and reduced eGFR (p< 0.05). OS at five years of 53 SRC patients was not significantly different in SSc patients with eGFR > 30 ml/min or eGFR < 30 ml/min.

Conclusion: eGFR represents a predictive risk factor of overall survival in SSc. The eGFR is not a risk factor for death in SRC.
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http://dx.doi.org/10.1093/rheumatology/keab302DOI Listing
March 2021

The biology, pathogenetic role, clinical implications, and open issues of serum anti-neutrophil cytoplasmic antibodies.

Autoimmun Rev 2021 Mar 18;20(3):102759. Epub 2021 Jan 18.

Humanitas Clinical and Research Center - IRCCS, 20089, Rozzano, Milan, Italy.

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.
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http://dx.doi.org/10.1016/j.autrev.2021.102759DOI Listing
March 2021

A Systematic Review of Focal Ablative Therapy for Clinically Localised Prostate Cancer in Comparison with Standard Management Options: Limitations of the Available Evidence and Recommendations for Clinical Practice and Further Research.

Eur Urol Oncol 2021 Jun 8;4(3):405-423. Epub 2021 Jan 8.

Division of Cancer & Genetics, Cardiff University School of Medicine, Velindre Cancer Centre, Cardiff, UK.

Context: The clinical effectiveness of focal therapy (FT) for localised prostate cancer (PCa) remains controversial.

Objective: To analyse the evidence base for primary FT for localised PCa via a systematic review (SR) to formulate clinical practice recommendations.

Evidence Acquisition: A protocol-driven, PRISMA-adhering SR comparing primary FT (sub-total, focal, hemi-gland, or partial ablation) versus standard options (active surveillance [AS], radical prostatectomy [RP], or external beam radiotherapy [EBRT]) was undertaken. Only comparative studies with ≥50 patients per arm were included. Primary outcomes included oncological, functional, and quality-of-life outcomes. Risk of bias (RoB) and confounding assessments were undertaken. Eligible SRs were reviewed and appraised (AMSTAR) and ongoing prospective comparative studies were summarised.

Evidence Synthesis: Out of 1119 articles identified, four primary studies (1 randomised controlled trial [RCT] and 3 retrospective studies) recruiting 3961 patients and ten eligible SRs were identified. Only qualitative synthesis was possible owing to clinical heterogeneity. Overall, RoB and confounding were moderate to high. An RCT comparing vascular-targeted focal photodynamic therapy (PDT) with AS found a significantly lower rate of treatment failure at 2 yr with PDT. There were no differences in functional outcomes, although PDT was associated with worse transient adverse events. However, the external validity of the study was contentious. A retrospective study comparing focal HIFU with robotic RP found no significant differences in treatment failure at 3 yr, with focal HIFU having better continence and erectile function recovery. Two retrospective cohort studies using Surveillance, Epidemiology and End Results data compared focal laser ablation (FLA) against RP and EBRT, reporting significantly worse oncological outcomes for FLA. The overall data quality and applicability of the primary studies were limited because of clinical heterogeneity, RoB and confounding, lack of long-term data, inappropriate outcome measures, and poor external validity. Virtually all the SRs identified concluded that there was insufficient high-certainty evidence to make definitive conclusions regarding the clinical effectiveness of FT, with the majority of SRs judged to have a low or critically low confidence rating. Eight ongoing prospective comparative studies were identified. Ways of improving the evidence base are discussed.

Conclusions: The certainty of the evidence regarding the comparative effectiveness of FT as a primary treatment for localised PCa was low, with significant uncertainties. Until higher-certainty evidence emerges from robust prospective comparative studies measuring clinically meaningful outcomes at long-term time points, FT should ideally be performed within clinical trials or well-designed prospective cohort studies.

Patient Summary: We examined the literature to determine the effectiveness of prostate-targeted treatment compared with standard treatments for untreated localised prostate cancer. There was no strong evidence showing that focal treatment compares favourably with standard treatments; consequently, focal treatment is not recommended for routine standard practice.
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http://dx.doi.org/10.1016/j.euo.2020.12.008DOI Listing
June 2021

The JANUS of chronic inflammatory and autoimmune diseases onset during COVID-19 - A systematic review of the literature.

J Autoimmun 2021 02 14;117:102592. Epub 2020 Dec 14.

Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center- IRCCS, Rozzano, MI, Italy; Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, MI, Italy. Electronic address:

The diverse clinical manifestations of COVID-19 is emerging as a hallmark of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. While the initial target of SARS-CoV-2 is the respiratory tract, it is becoming increasingly clear that there is a complex interaction between the virus and the immune system ranging from mild to controlling responses to exuberant and dysfunctional multi-tissue directed autoimmune responses. The immune system plays a dual role in COVID-19, being implicated in both the anti-viral response and in the acute progression of the disease, with a dysregulated response represented by the marked cytokine release syndrome, macrophage activation, and systemic hyperinflammation. It has been speculated that these immunological changes may induce the loss of tolerance and/or trigger chronic inflammation. In particular, molecular mimicry, bystander activation and epitope spreading are well-established proposed mechanisms to explain this correlation with the likely contribution of HLA alleles. We performed a systematic literature review to evaluate the COVID-19-related autoimmune/rheumatic disorders reported between January and September 2020. In particular, we investigated the cases of incident hematological autoimmune manifestations, connective tissue diseases, antiphospholipid syndrome/antibodies, vasculitis, Kawasaki-like syndromes, acute arthritis, autoimmune-like skin lesions, and neurologic autoimmune conditions such as Guillain-Barré syndrome. We screened 6263 articles and report herein the findings of 382 select reports which allow us to conclude that there are 2 faces of the immune response against SARS-CoV-2, that include a benign virus controlling immune response and a many faceted range of dysregulated multi-tissue and organ directed autoimmune responses that provides a major challenge in the management of this viral disease. The number of cases for each disease varied significantly while there were no reported cases of adult onset Still disease, systemic sclerosis, or inflammatory myositis.
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http://dx.doi.org/10.1016/j.jaut.2020.102592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833462PMC
February 2021

Comparing hypofractionated and conventionally fractionated whole breast irradiation for patients with ductal carcinoma in situ after breast conservation: a propensity score-matched analysis from a national multicenter cohort (COBCG-02 study).

J Cancer Res Clin Oncol 2021 Jul 2;147(7):2069-2077. Epub 2021 Jan 2.

Radiotherapy and Radiosurgery Department, Humanitas Clinical and Research Center-IRCCS, Rozzano, Milano, Italy.

Background And Purpose: Randomized trials confirmed the efficacy and the safety of hypofractionated whole breast irradiation (HF-WBI) in patients with early-stage breast cancer. However, the role of HF-WBI in patients with DCIS after breast conserving surgery has not yet been clearly established in prospective randomized trials. The aim of this study was to evaluate if HF-WBI can be considered comparable to conventionally fractionated (CF)-WBI in DCIS patients.

Materials And Methods: The analysis included DCIS patients from four Italian centers treated with CF-WBI 50 Gy/25 fractions or HFRT 40.5 Gy/15 fractions, without tumor bed boost. A propensity score matching (PSM) analysis was performed using a logistic regression that considered age, grading, presence of necrosis, resection margin status and adjuvant endocrine therapy.

Results: Five hundred twenty-seven patients was included (367 in the CF-WBI-group and 160 in the HR-WBI group). After 1:1 matching, 101 patients were allocated to the CF-WBI-group and 104 to the HF-WBI group. No correlation was observed between the type of RT schedule and LRFS (HR 1.68, 95% CI 0.82-3.45; p = 0.152). After PSM, no statistical difference was observed between the two RT group (HR 1.11, 95% CI 0.40-3.04; p = 0.833), with 3- and 5-years LRFS rates of 100% and 97.9% for CF-WBI and 95.6% and 94% for HF-WBI.

Conclusion: A short course of radiation therapy seems to be comparable to CF-WBI in terms of clinical outcomes. These data support the use of hypofractionated schedules in DCIS patients, but considering the remaining uncertainties.
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http://dx.doi.org/10.1007/s00432-020-03483-5DOI Listing
July 2021

Explorative analysis of a score predicting the therapy response of patients with metastatic, castration resistant prostate cancer undergoing radioligand therapy with Lu-labeled prostate-specific membrane antigen.

Ann Nucl Med 2021 Mar 22;35(3):314-320. Epub 2020 Dec 22.

Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin and Berlin Institute of Health, Augustenburger Platz 1, 13353, Berlin, Germany.

Objective: Up to 60% of patients with metastatic, castration-resistant prostate cancer (mCRPC) treated with Lu prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) achieves a partial biochemical response with a decrease of > 50% in prostate-specific antigen (PSA) levels. The remaining fractions, however, do not respond to RLT. The aim of this explorative analysis was to identify pre-therapeutic factors for the prediction of response.

Methods: 46 patients [age = 68 years (50-87)] with mCRPC who consecutively underwent RLT with Lu PSMA [median applied activity = 6 GBq (2.9-6.2)] were included and analysed retrospectively. The association of different clinical and laboratory factors and parameters from pre-therapeutic Ga PSMA positron emission tomography (PET) with the outcome of RLT was tested (Fisher's test). Outcome was defined as PSA changes 8 weeks after second RLT [partial response (PR), PSA decrease > 50%; progressive disease (PD), PSA increase ≥ 25%; stable disease (SD), others]. Significant predictive factors were combined in a predictive score.

Results: 30% showed a post-treatment PR (median 73% PSA decrease), 35% SD (median 17% PSA decrease) and 35% PD (median 42% PSA increase). Significant predictors for PD were alkaline phosphatase (ALP) > 135 U/l (p = 0.002), PSA > 200 ng/ml (p = 0.036), and maximum standardized uptake value (SUVmax) of the "hottest lesion" in pre-therapeutic PET < 45 (p = 0.005). The predictive score including PSA, ALP and SUVmax could separate 2 distinct groups of patients: ≤ 2 predictive factors (19% PD) and 3 predictive factors (90% PD).

Conclusion: The presented predictive score allowed a pre-therapeutic estimate of the expected response to 2 cycles of RLT. As our study was retrospective, prospective trials are needed for validation.
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http://dx.doi.org/10.1007/s12149-020-01567-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902572PMC
March 2021

Efficacy and safety of baricitinib in 446 patients with rheumatoid arthritis: a real-life multicentre study.

Clin Exp Rheumatol 2021 Jul-Aug;39(4):868-873. Epub 2020 Dec 18.

Division of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, and Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy.

Objectives: Baricitinib, an oral Janus kinase (JAK) 1-2 inhibitor, is currently used along biologic DMARDs (bDMARDs) after the failure of methotrexate (MTX) in rheumatoid arthritis (RA). We investigated the efficacy and safety of baricitinib in real life.

Methods: We prospectively enrolled 446 RA patients treated with baricitinib from 11 Italian centres. Patients were evaluated at baseline and after 3, 6, and 12 months. They were arrayed based on previous treatments as bDMARD-naïve and bDMARD-insufficient responders (IR) after the failure or intolerance to bDMARDs. A sub-analysis differentiated the effects of methotrexate (MTX) and the use of oral glucocorticoids (OGC).

Results: Our cohort included 150 (34%) bDMARD-naïve and 296 (66%) bDMARD-IR patients, with 217 (49%) using baricitinib as monotherapy. Considering DAS-28-CRP as the primary outcome, at 3 and 6 months, 114/314 (36%) and 149/289 (51.6%) patients achieved remission, while those in low disease activity (LDA) were 62/314 (20%) and 46/289 (15.9%), respectively; finally at 12 months 81/126 (64%) were in remission and 21/126 (17%) in LDA. At all-timepoints up to 12 months, bDMARDs-naïve patients demonstrated a better clinical response, independently of MTX. A significant reduction in the OGC dose was observed at 3 and 12 months in all groups. The serum positivity for both rheumatoid factors (RF) and anti-citrullinated protein antibodies (ACPA) conferred a lower risk of stopping baricitinib due to inefficacy. Fifty-eight (13%) patients discontinued baricitinib due to adverse events, including thrombotic events and herpes zoster reactivation.

Conclusions: Real-life data confirm the efficacy and safety profiles of baricitinib in patients with RA and provide evidence that drug survival is higher in bDMARDs-naïve and seropositive patients.
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July 2021
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