Based on the results obtained in clinical trials, the use of the combination of lenalidomide and dexamethasone (Len/Dex) has become a potential therapeutic choice for newly diagnosed multiple myeloma ...(NDMM) ineligible for autologous stem cell transplantation. This study evaluated 89 frail NDMM patients treated with first-line oral association. At the last follow-up, 34 out of 89 patients (38.2%) were alive, and 22 were still in treatment with Len/Dex. Among 73 evaluable patients who received at least two cycles, the overall response rate was 71% (N = 52). The disease control rate, defined as any level of clinical response to therapy, occurred in 71 patients (97%). We reported one or more adverse events of grade 3 or 4 (G3/4) in 65.2% (N = 58) of patients, with a prevalence of hematological toxicity (24 patients), leading to an overall discontinuation of treatment in two cases. In univariate analysis, high ISS, high serum β2-microglobulin, and creatinine clearance <30 mL/min negatively impact OS, while the depth of response positively impacts OS. Moreover, G3-4 anemia, ISS, frailty score, and ECOG negatively impacts PFS. In conclusion, elderly and more frail patients benefit from the Len/Dex combination also in the era of monoclonal antibodies, ensuring an increased PFS and OS in patients where the therapeutic choice is often limited and usually not very effective.
Non-melanoma skin cancer (NMSC) is the most common malignant tumor affecting fair-skinned people. Increasing incidence rates of NMSC have been reported worldwide, which is an important challenge in ...terms of public health management. Surgical excision with pre-operatively identified margins is one of the most common and effective treatment strategies. Incomplete tumor removal is associated with a very high risk of recurrence and re-excision. Biological tissues can absorb and re-emit specific light wave-lengths, detectable through spectrophotometric devices. Such a phenomenon is known as autofluorescence (AF). AF spectroscopy has been widely explored for non-invasive, early detection of NMSC as well as for evaluation of surgical margins before excision. Fluorescence-aided diagnosis is based on differences in spectral characteristics between healthy and neoplastic skin. Understanding the biological basis of such differences and correlating AF intensity to histological features could improve the diagnostic accuracy of skin fluorescence spectroscopy. The primary objective of the present pre-clinical ex vivo study is to investigate the correlation between the intensity of cutaneous AF and the histopathological features of NMSC. Ninety-eight lesions suggestive for NMSCs were radically excised from 75 patients (46 M; 29 F; mean age: 79 years). After removal, 115 specific reference points on lesions (“cases”; 59 on BBC, 53 on SCC and 3 on other lesions) and on peri-lesional healthy skin (controls; 115 healthy skin) were identified and marked through suture stitches. Such reference points were irradiated at 400–430 nm wavelength, and resulting emission AF spectra were acquired through spectrophotometry. For each case, AFIR (autofluorescence intensity ratio) was measured as the ratio between the number of photons emitted at a wavelength ranging between 450 and 700 nm (peak: 500 nm) in the healthy skin and that was captured in the pathological tissue. At the histological level, hyperkeratosis, neoangiogenesis, cellular atypia, epithelial thickening, fibrosis and elastosis were quantified by light microscopy and were assessed through a previously validated grading system. Statistical correlation between histologic variables and AFIR was calculated through linear regression. Spectrometric evaluation was performed on 230 (115 cases + 115 controls) reference points. The mean AFIR for BCC group was 4.5, while the mean AFIR for SCC group was 4.4 and the fluorescence peaks at 500 nm were approximately 4 times lower (hypo-fluorescent) in BCCs and in SCCs than in healthy skin. Histological variables significantly associated with alteration of AFIR were fibrosis and elastosis (p < 0.05), neoangiogenesis, hyperkeratosis and epithelial thickening. Cellular atypia was not significantly associated with alteration of AFIR. The intensity of fluorescence emission in neoplastic tissues was approximately 4 times lower than that in healthy tissues. Histopathological features such as hyperkeratosis, neoangiogenesis, fibrosis and elastosis are statistically associated with the decrease in AFIR. We hypothesize that such tissue alterations are among the possible biophysical and biochemical bases of difference in emission AF between neoplastic and healthy tissue. The results of the present evaluation highlighted the possible usefulness of autofluorescence as diagnostic, non-invasive and real-time tool for NMSCs.
Multiple myeloma is a chronic hematologic malignancy that obstinately tends to relapse. Basic research has made giant strides in better characterizing the molecular mechanisms of the disease. The ...results have led to the manufacturing of new, revolutionary drugs which have been widely tested in clinical trials. These drugs have been approved and are now part of the therapeutic armamentarium. As a consequence, it is essential to combine what we know from clinical trials with real-world data in order to improve therapeutic strategies. Starting with this premise, our review aims to describe the currently employed regimens in multiple myeloma and compare clinical trials with real-life experiences. We also intend to put a spotlight on promising therapies such as T-cell engagers and chimeric antigen receptor T-cells (CAR-T) which are proving to be effective in changing the course of advanced-stage disease.
Background Waldenström macroglobulinemia (WM) is a rare and indolent B-cell lymphoproliferative disorder with greater incidence in elderly patients where a precise algorithm of initial therapy is ...still not clear. Immunochemotherapy regimen consisting of dexamethasone, rituximab, and oral cyclophosphamide (DRC) is considered a suitable first-line treatment because of its safety, efficacy, and manageability. Patients and methods We retrospectively describe the results of 36 consecutive treatment-naïve patients with WM who were treated from June 2013 until June 2021 with the DRC regimen every 4 weeks instead of 3 weeks, for six cycles. The median age was 69 years (range, 42–85 years), with one-third being older than 75 years. Most patients had features of advanced disease, with nearly 60% being high risk. Median IgM level prior to treatment initiation was 2.9 g/dL. Results Overall response rate was 80% after a median time of two cycles, with 67% of patients achieving at least partial response. After a median follow-up of 59 months, the median overall survival (OS) was not reached and the median time to next treatment (TTNT) was 48 months (95% CI 25–87 months). Approximately 70% of the evaluable study population had a 3-year survival without additional treatment, while 75% had a 3-year OS rate. The treatment was well-tolerated with only two patients (6%) recorded to have grade 3 pneumonia and no grade 3 hematological toxicity maybe due to the regular use of growth factors for red and white blood cells. Baseline albumin level and achievement of at least minimal or partial response had a significant impact on TTNT, while baseline hemoglobin and IgA level affected outcome in terms of OS ( p < 0.05). Conclusion This is the first real-life experience describing the use of the DRC regimen in treatment-naive patients with WM with administration of therapy every 4 weeks instead of 3 weeks showing apparent comparable efficacy, along with good tolerability and safety, especially in terms of hematological toxicity, independently from comorbidity burden.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named Autoimmune regulator gene (AIRE) which ...results in a failure of T-cell tolerance. Central tolerance takes place within the thymus and represents the mechanism by which potentially auto-reactive T-cells are eliminated through the negative selection process. The expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) in the thymus is a key process in the central tolerance and is driven by the protein encoded by AIRE gene, the transcription factor autoimmune regulator (AIRE). A failure in this process caused by AIRE mutations is thought to be responsible of the systemic autoimmune reactions of APECED. APECED is characterized by several autoimmune endocrine and non-endocrine manifestations and the phenotype is often complex. Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression even between siblings with the same genotype, thus implying that additional mechanisms, other than the failure of Aire function, are involved in the pathogenesis of the disease. Unraveling open issues of the molecular basis of APECED, will help improve diagnosis, management, and therapeutical strategies of this complex disease.
OBJECTIVEThe objective of the study was to assess the variability in the management of paediatric MHT in European emergency departments (EDs).
METHODSThis was a multicentre retrospective study of ...children ≤18 years old with minor head trauma (MHT) (Glasgow Coma Scale ≥14) who presented to 15 European EDs between 1 January 2013 and 31 December 31. Data on clinical characteristics, imaging tests, and disposition of included patients were collected at each hospital over a 3-year period.
RESULTSWe included 11 212 patients. Skull radiography was performed in 3416 (30.5%) patients, range 0.4–92.3%. A computed tomography (CT) was obtained in 696 (6.2%) patients, range 1.6–42.8%. The rate of admission varied from 0 to 48.2%.
CONCLUSIONWe found great variability in terms of the type of imaging and rate of CT scan obtained. Our study suggests opportunity for improvement in the area of paediatric head injury and the need for targeted individualised ED interventions to improve management of MHT.
Introduction
Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by ...FIRST trial (Facon et al, Blood 2018).
Methods and results
This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was <30 ml/min in 7.1% of pts. 16, 30 and 54% resulted respectively fit, unfit and frail by IMWG Frailty score. ISS was respectively I, II and III in 27.5, 40.5 and 32% while R-ISS was I, II and III in 31.8, 42.4 and 25.8% of pts. t(4;14), t(14;16), del(17p) or amp(1q) by FISH were respectively found in 9.2%, 5.5%, 5.8% and 36.6% of pts. Extramedullary disease (EMD) was documented in 11% of pts.
After a median follow-up of 11 months, most pts are still on treatment (60,4%), the median number of administered cycles was 7 (range 2-33).
Overall response rate (ORR, ≥PR) was 74.5% with 34.1% of pts obtaining at least a VGPR. Clinical Benefit Rate (CBR, including minimal responses) was 83.3%. Responses were rapid with median time to first and to best response respectively of 1.8 (range 1-8) and 5 (1-26) months. Median OS and PFS were not reached with a 1-y and 2-y OS of 84.8 and 73.8% and a 1-y and 2-y PFS of 78.6 and 65%. Median EFS was 19.8 months.
In univariate analysis, factors significatively impairing ORR were frailty (fit/unfit/frail 91.2/77/55.9%, p<0.001), ECOG (0-1/>2 81.7/61.6%, p<0.001), presence of t(4;14) (52.9 vs 76.7%, p=0.033) and amp(1q) (53.4 vs 83.5, p<0.001), R-ISS (3 vs 2-1 55.3 vs 72.6%, p=0.027), LDH > upper level of normal (ULN) (65.8 vs 77%, p=0.034). 1-y PFS is significantly shorter in pts with lower ECOG (0-1 vs 2, 66.5 vs 84.8%, p<0.001), higher frailty score (fit/unfit/frail 100/86.4/66.6%, p=0.01), higher ISS (I-II-III 88.4-79.1-68.5%, p=0.002) and R-ISS (I-II-III 75.5-88-50.5% p=0.02), LDH >ULN (66.4 vs 83.2%, p=0.02), lower ClCr (<30/30-50/>50 57.2/81.3/80.1%, P=0.01), presence of t(14;16) (42.9 vs 80.4% p=0.01) and amp(1q) (63.5 vs 85.6%, p=0.01); factor impairing OS are ECOG (0-1/>2 93.4 vs 69.4%, p<0.001), frailty (fit/unfit/frail 100/90.5/75.3% p=0.001), higher ISS (I-II-III 93.6/87.8/74.6%, p=0.006) and R-ISS (I-II-III 87/93/72%, p<0.001)), LDH >ULN (75.1 vs 97.1, p=0004), impaired ClCr (<30/30-50/>50 64/83.7/88.2%, p<0.001); EFS was affected by ECOG (0-1/>2 74.2 vs 47.3%, p<0.001), frailty (fit/unfit/frail 83.4/74.5/52% p=0.09), R-ISS (I-II-III 61.4/74.9/37.5% p=0.006), presence of t(14;16) (35.5 vs 67.8% p=0.08) or amp(1q) (50.1 vs 69% p=0.02).
In multivariate analysis ORR is significantly correlated with ECOG>2 (p=0.05), LDH >ULN (p=0.005) and presence of amp1q (p=0.006); PFS was significantly affected by R-ISS III (p=0.04), LDH >ULN (P=0.01) and ClCr<30 (p=0.006) and EFS by R-ISS III (p=0.002); only ECOG>2 still impact on OS (p<0.0001)
Dose reduction of Len or dex was required respectively in 20.7% and 22.1% and 39.2% needed cycle delay for adverse events (AEs). Grade 3-4 (G3-4) AEs occurred in 52% of pts with 30.9 and 36.6% having at least a hematological or extra-hematological G3-4 AE. In particular, 17.9 and 16.6% of pts had severe neutropenia and anemia while the most common non-hematological AEs were infections (25.8%, G3-4 12.2%), mainly involving respiratory tract (71.2%). Gastroenteric and cutaneous AEs were quite common (22.1 and 19.2%), mainly diarrhea and itching, but in the vast majority were mild. G3-4 asthenia was present in 22.8% of pts. Although 99% of pts was given antithrombotic prophylaxis, 8.5% had a thromboembolic event, a third of severe entity. G-CSF and EPO analogs were required in 27.4 and 26% of pts.
Conclusion
Real-life data confirm efficacy and tolerability of Rd in elderly NDMM pts. Performance status by ECOG and IMWG frailty score and severe renal impairment but not age itself act as limiting factors affecting outcome. These data must be confirmed by longer follow-up.
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Conticello:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Mangiacavalli:Janssen cilag: Consultancy; celgene: Consultancy; Amgen: Consultancy. Zambello:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Belotti:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Aquino:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Del Fabro:Janssen: Consultancy. Galli:Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria.
Small supernumerary marker chromosomes (sSMC) occur with a frequency of approximately 0.4 per 1000 newborns and are more frequent in the population with mental retardation and/or with dysmorphic ...signs. Small supernumerary chromosome rings (sSCR) usually occur as apart of a mosaic karyotype (Liehr et al., 2004). Chromosome 19 supernumerary rings are very rare. Almost all cases of sSMC19 have been reported on Thomas Liehr's website (http://www.med.uni-jena.de/fish/sSMC/19.htm#Start19). Of these cases, 14 were with phenotypic abnormalities and a clear characterization of the sSMC; two cases were suitable for comparison with our case with regard to their genetic content, but not with regard to the structure ofthe sSMC (Manvelyan et al., 2008). The phenotype, associated with partial trisomy 19q, includes facial dysmorphism, growth and mental retardation, macrocephaly, heart malformation and anomalies of the genitourinary and gastrointestinal tracts. The phenotype associated with partial trisomy 19p is characterized by dysmorphic features, severe mental retardation, abnormalities of brain morphology and anomalies of the fingers (Tercanli et al., 2000; Qorri et al., 2002; Novelli et al., 2005; Vraneković et al., 2008). Herein, we report the phenotype and molecular cytogenetic analysis in a patient with the smallest de-novo constitutional ring extended from the p12 to q12 region of chromosome 19.
Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant ...functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF.
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