Daratumumab plus bortezomib or daratumumab plus lenalidomide as salvage therapy for patients with myeloma: initial follow-up of an Italian multicentre retrospective clinical experience by 'Rete Ematologica Pugliese'.

We report herein a multicentre retrospective analysis of 192 consecutive patients with symptomatic refractory/relapsed multiple myeloma (RRMM) treated with daratumumab in combination with bortezomib or lenalidomide as salvage therapy at 9 haematological centres in Puglia. Choice of both regimens was based on previous treatment and/or physicians' preference. Considering the under-representation of older patients (very old patient ≥ 80 years) in clinical trials and the prognostic and predictive importance and value of frailty status, here, we further characterised the patient cohort by age. The overall response rate (ORR) was generally lower than what was previously reported in the CASTOR (ORR 72.6% vs 85%) and POLLUX (ORR 86.5% vs 93%) trials. The lower ORR in our analysis compared to the CASTOR and POLLUX trials could be related to a less selected population. Similarly, amongst very old patients, the ORR was encouraging: ORR to treatment with DVd (daratumumab + bortezomib + dexamethasone) was 66.7%, and ORR to treatment with DRd (daratumumab + lenalidomide + dexamethasone) was 92.3%. Median TTP (time to progression) was 10.8 months (1-year TTP: 44.7%; 2-year TTP: 25.3%) in the DVd group; median TTP was not reached in the DRd group (1-year TTP: 82.7%; 2-year TTP: 71.4%). Median OS (overall survival) was not reached either in the DRd group (1-year OS: 85.9%; 2-year OS: 73.7%) or the DVd group (1-year OS: 70.2%; 2-year OS: 58.9%).

Melanoma detection in Italian pigmented lesion clinics.

AIM: Accuracy in melanoma detection is important to recognize early curable melanomas and to minimize the unnecessary excision of benign lesions. The aim of this paper was to evaluate melanoma screening accuracy of Italian pigmented lesion clinics in terms of number needed to excise (NNE), melanoma thickness, and number of melanomas diagnosed during patient follow-up. METHODS: Information on all skin tumors excised in 2011 were extracted from the databases of the participating centers. Information whether the lesion was excised at the baseline examination or during patient follow-up was recorded, as well as the overall number of patients examined in each center in 2011. RESULTS: After e-mail solicitation, 22 of 40 centers agreed to participate. A total of 8229 excised lesions were collected. The overall number of examined patients was 86.564, thus 9.5% of screened patients had a lesion removed. Of the excised lesions, 866 were diagnosed as melanoma (1% of examined patients) and 5311 (88.9%) were melanocytic nevi. Three NNE were calculated giving values of 7.9 excised lesions to find 1 melanoma, 7.1 melanocytic lesions to find 1 melanoma, and 3.7 lesions to find 1 skin malignancy. The median melanoma thickness was 0.6 mm, with only 15.1% of melanomas ≥ 1 mm of thickness. Melanomas detected over time were 96 (11.1%; mean thickness, 0.3 mm), with 15.6% of lesions excised after short-term follow-up and 84.4% after long-term follow-up. CONCLUSION: The NNE values comparable to those achieved in specialized clinical settings and the high number of early melanomas diagnosed at the baseline examination or during patient follow-up indicate a high level of accuracy in melanoma screening achieved by Italian pigmented lesion clinics.

Early regression index (ERI) on MR images as response predictor in esophageal cancer treated with neoadjuvant chemo-radiotherapy: Interim analysis of the prospective ESCAPE trial.

PURPOSE: The early regression index (ERI) predicts treatment response in rectal cancer patients. Aim of current study was to prospectively assess tumor response to neoadjuvant chemo-radiotherapy (nCRT) of locally advanced esophageal cancer using ERI, based on MRI. MATERIAL AND METHODS: From January 2020 to May 2023, 30 patients with esophageal cancer were enrolled in a prospective study (ESCAPE). PET-MRI was performed: i) before nCRT (tpre); ii) at mid-radiotherapy, tmid; iii) after nCRT, 2-6 weeks before surgery (tpost); nCRT delivered 41.4 Gy/23fr with concurrent carboplatin and paclitaxel. For patients that skipped surgery, complete clinical response (cCR) was assessed if patients showed no local relapse after 18 months; patients with pathological complete response (pCR) or with cCR were considered as complete responders (pCR + cCR). GTV volumes were delineated by two observers (Vpre, Vmid, Vpost) on T2w MRI: ERI and other volume regression parameters at tmid and tpost were tested as predictors of pCR + cCR. RESULTS: Complete data of 25 patients were available at the time of the analysis: 3/25 with complete response at imaging refused surgery and 2/3 were cCR; in total, 10/25 patients showed pCR + cCR (pCR = 8/22). Both ERImid and ERIpost classified pCR + cCR patients, with ERImid showing better performance (AUC:0.78, p = 0.014): A two-variable logistic model combining ERImid and Vpre improved performances (AUC:0.93, p < 0.0001). Inter-observer variability in contouring GTV did not affect the results. CONCLUSIONS: Despite the limited numbers, interim analysis of ESCAPE study suggests ERI as a potential predictor of complete response after nCRT for esophageal cancer. Further validation on larger populations is warranted.

Possible role of apoptosis in the pathogenesis and clinical evolution of radicular cyst: an immunohistochemical study.

AIM: To investigate whether the apoptotic cascade is activated through the extrinsic pathway in epithelial lining and connective tissue of radicular cysts. METHODOLOGY: Fifteen radicular cysts were fixed in formalin, embedded in paraffin wax and processed for immunohistochemistry to evaluate the expression of polyclonal antibodies against Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), DR5 and caspase-3. Immunocomplexes were treated with the secondary antibodies and finally detected using the avidin-biotin-peroxidase complex. Immunoreactivity was visualized by development with 3,3'-diaminobenzidine. Data were analysed using the Mann-Whitney U-test; P < 0.05 was considered significant. RESULTS: The three antibodies were detected in connective tissue fibroblasts of all radicular cysts; TRAIL and DR5 immunoexpression was significantly greater (P < 0.05) compared with that of caspase-3. The three antibodies were also expressed in almost all epithelial layers and in endothelial cells of newly formed vessels. CONCLUSION: The involvement of apoptosis in the pathogenesis of radicular cysts, demonstrated by the immunoexpression patterns of TRAIL, DR5 and caspase-3 in lining epithelium and connective tissue, may explain their bland clinical aggressiveness and slow, benign evolution.

The Evolution of the Cephalometric Superimposition Techniques from the Beginning to the Digital Era: A Brief Descriptive Review.

Superimposition of craniofacial structures from radiographic examination has been always used for assessing changes in the maxilla-mandibular complexes, especially for the evaluation of potential changes occurring during growth as well as after orthodontic treatment and/or maxillofacial surgery. However, the availability of cone beam computed tomography (CBCT) and the recent advancement in 3D imaging have allowed the development of specific techniques for the registration and superimposition of virtual three-dimensional anatomical structures, improving the diagnosis and treatment plan strategies. In the present paper, it will be discussed the evolution of superimposition techniques from the beginning (2D) to the newest 3D approach, describing the most used methods and their main advantages and disadvantages, focusing primarily on accuracy and reproducibility of each technique.

Ordering fluctuations in a shear-banding wormlike micellar system.

We present a first investigation about the non-linear flow properties and transient orientational-order fluctuations observed in the shear-thinning lecithin-water-cyclohexane wormlike micellar system at a concentration near to the zero-shear isotropic-nematic phase transition. From rheological measurements the stress plateau was found shifted to very low values of the applied shear rate gamma, compared to most of the concentrated living polymer systems reported in the literature. Rheo-small angle neutron scattering (Rheo-SANS) experiments performed in the flow-vorticity plane revealed periodical fluctuations of both the order parameter P(2) and the angular deviation phi from the vorticity axis as determined from the scattering peaks. The periods of the oscillations were not found to depend on imposed gamma. A theoretical model was also developed to explain the oscillatory dynamics of the shear-induced nematic order parameter in terms of the presence of standing waves of the director orientation profile along the circumference of the Couette cell. The experimental results of the periodic order parameter fluctuations together with their theoretical modelling shed significant new insights on the shear banding phenomenon, particularly its microscopic mechanism.

Morphometric evaluation of the temporomandibular joint and the masticatory spaces: the role of high-definition MRI.

AIM: The aim of this work was to describe the anatomy of the temporomandibular joint (TMJ), the masticator spaces and their possible variance by means of magnetic resonance imaging MRI. METHODS: We evaluated one TMJ in each of 28 volunteers (14 males and 14 females) without temporomandibular disorders. The TMJ with mouth closed was evaluated on axial, coronal and sagittal planes obtained with a 1.5 Tesla magnetic resonance scanner. MRI scans of the anatomic patterns of the temporomandibular region were analyzed and compared with the classical anatomy notions reported in the literature. Morphometric evaluation of the temporomandibular region and the medial and lateral pterygoid muscles was carried out. RESULTS: MRI anatomy of the TMJ, the masticator spaces and their possible variance were accurately described. In addition, morphometric evaluation of the TMJ and the masticator spaces was performed. Statistical analysis of the measurements showed that the length of the structures related to the glenoid fossa were usually longer in the female than in the males, whereas the condyle and masticator muscles were usually greater in the males than in the females. T-tests showed no significant differences (P > 0.05) between the measurements of the right and left TMJ. CONCLUSIONS: In preoperative maxillofacial surgery assessment, MRI is a useful tool to reduce operating time, avert surgical complications and improve patient outcome.

[Can tobacco companies be good corporate citizens?]. / Les entreprises du tabac peuvent-elles être citoyennes?

Tobacco companies have jumped on the Corporate social responsibility (CSR) bandwagon as a tentative to be societally accepted as responsible actors and good corporate citizens. This is however not possible for two reasons. First, the product they sell is lethal and thus not compatible with the precondition of doing no harm to be a good corporate citizen. Second, the behavior of tobacco firms is not responsible, being illustrated by four examples: junk science versus sound science strategy, seducing young smokers, political lobbying and getting customers on new markets. To conclude, three implications for regulating the activities of the tobacco industry are given.

New method for low molecular weight heparin quantification in tablets by suppressed conductivity detection and cryptand column.

Unfractioned Heparins (UFH) and Low Molecular Weight Heparins (LMWHs) are non-chromophoric, high charged sulphated molecules which are difficult to elute and detect with conventional liquid chromatography methods. Moreover, the detection of LMWHs at low concentration level, like in samples coming from dissolution test of tablets formulated with Heparins is problematic due to the weak response by UV or refractive index detection. According to the European Pharmacopoeia requirements, the assay of LMWHs is based on the anti-Xa activity and anti-IIa activity factors, which are biological parameters related to the antithrombotic activity of this compound family. The same assay method could also be applied to determine the dissolution rate of LMWHs contained in tablets, but it is time consuming and expensive test. The challenge was to develop a simpler and faster alternative method based on Ion Chromatography coupled with Suppressed Conductivity detection, but the particular polycharge interaction of LMWHs with anions exchanger makes the analyte with standard eluents and columns difficult to elute . The analytical problem could be solved by using a particular chromatographic phase with 2,2,2 cryptand sites which gives variable capacity in anion exchange depending on the used eluent. Such phase was very effective for the elution of strongly retained polyanions using simple inorganic eluent phase suitable for suppressed conductivity detection as well. The developed method allows the elution of a unique peak, which represents the whole polymeric distribution, and therefore it makes easy to quantify quickly and selectively the active ingredient in case of multiple analysis like when a dissolution test is required to characterize and discriminate between different tablets formulations. The method was tested and developed in Cosmo Pharmaceuticals QC labs and the validation results are reported in the present paper. Besides, a comparison between biological and chromatographic methods was carried out as well.

Aluminium speciation in natural water by sorption on a complexing resin.

Very stable aluminium complexes may be present in natural waters, which can be detected only using appropriate methods. One of them is the resin titration based on the sorption of aluminium on a strongly sorbing resin, Chelex 100. It was here used to detect strong aluminium complexes, and to characterize them by determining their concentration, and the corresponding stability constant. High and low salinity waters were sampled in different sites in the North of Italy. In all the samples aluminium complexes with high stability constant, up to 10(17.4) M(-1) in the less acidic solution, were detected. The stability constant depends mainly on the solution acidity, increasing with increasing pH up to 7. The concentration of the ligands responsible for the strong complexation is similar to that of aluminium (from 0.5 to 1.5 microM), or somewhat lower in the case of estuarine and sea waters. A small fraction of aluminium (from 0% to 2%) in freshwaters, higher in estuarine and sea waters (14% and 10%, respectively), is present in weakly bound forms which could also be the hydrolysis products. The conditional constants of the strong complexes were determined for the different samples examined. They were found to be slightly lower in the case of the high salinity waters, in which a value of 10(16.1) M(-1) at pH 7.5 was obtained. This is probably due to the higher ionic strength in marine water, which strongly influences the complexation of trivalent metal ions, as seen for example also in the hydrolysis. It could be deduced that similar substances, but at different concentration, would be responsible for the aluminium complexation in the sea and freshwaters here examined. They could be natural organics like fulvic substances, or better some particular complexing sites in this substances with very high affinity for aluminium.

"Real world" outcome of lenalidomide plus dexamethasone in the setting of recurrent and refractory multiple myeloma: extended follow-up of a retrospective multicenter study by the "rete ematologica pugliese".

This current retrospective multicenter analysis represents, to our knowledge, the first Italian study evaluating the efficacy and toxicity profile of "lenalidomide plus dexamethasone" as salvage therapy in patients with recurrent-refractory MM in the real life contest. Our study included patients who are usually excluded from clinical trials because of unfavorable baseline characteristics. Median OS was significantly longer in patients receiving "lenalidomide plus dexamethasone" for more than 12 months compared with those who had received "lenalidomide plus dexamethasone" for a shorter interval (P<0.0001). Median OS was not affected by best response achieved (P 0.4) and age (P 0.3). Quality of response did not correlate with number of previous lines of therapy (P 0.77) and age. Higher ORRs were recorded in the patients group with relapsed MM compared to those with refractory disease, but this difference was not statistically significant (P 0.38).

1-Halobenzyl-1H-indazole-3-carboxylic acids. A new class of antispermatogenic agents.

The synthesis of a series of halogenated 1-benzylindazole-3-carboxylic acids and related derivatives is described. These compounds were studied for their effect on testicular weight and on the inhibition of spermatogenesis. Many of the derivatives, but in particular 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid (11), 1-(2,4-dibromobenzyl)-1H-indazole-3-carboxylic acid (13), 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylic acid (27), and their glycerol esters, showed potent antispermatogenic activity.

PIP: The synthesis of 1-halobenzyl-1H-indazole-3-carboxylic acids is described and the effects of these compounds on testicular weight and inhibition of spermatogenesis are reported. Histologically, the antispermatogenic activity of all the active derivatives was similar. Rat testis showed disorganization of the seminiferous tubules consisting mainly of lesion and loss of spermatocytes and spermatids while the spermatogonia and interstitial tissue appeared normal. 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid, 1-(4-chloro-2-methylbenzyl)-1H-indazole-3-carboxylic acid and their glycerol esters showed the most potent antispermatogenic activity.

Comparison of rest-redistribution thallium-201 imaging and reinjection after stress-redistribution for the assessment of myocardial viability in patients with left ventricular dysfunction secondary to coronary artery disease.

Thallium (Tl)-201 reinjection after stress-redistribution (RI) imaging has been proven to accurately identify ischemic and viable myocardium. Quantitative Tl-201 analysis after stress has also shown viable myocardium in most mild to moderate (51% to 85% of normal uptake) irreversible Tl-201 defects. However, if the main clinical question is whether a region is viable, and not whether there is inducible ischemia, a resting protocol may be more appropriate. The aim of this study was to determine whether rest-redistribution (RD) quantitative Tl-201 single-photon emission tomographic imaging provides the same information on viable myocardium as Tl-201 RI. Thus, 15 patients (mean age 58 +/- 9 years) with chronic coronary artery disease and left ventricular dysfunction (ejection fraction 35 +/- 8%) were studied by both RI and RD Tl-201 single-photon emission tomography. Regional Tl-201 uptake was assessed quantitatively using a 16-segment model. When Tl-201 images were classified as normal/reversible (viable) or irreversible (nonviable), RI showed viable myocardium in 145 of 240 myocardial regions (60%), whereas RD showed it in 103 of 240 myocardial regions (43%). The 2 imaging protocols provided concordant information in 176 of 240 myocardial regions (73%). Among the 64 (27%) discordant regions, 53 (22%) were viable by RI and nonviable by RD, whereas 11 (5%) were viable by RD and nonviable by RI (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Myeloablative therapy and bone marrow transplantation in Jehovah's Witnesses with malignancies: single center experience.

Hematological malignancies in Jehovah's Witnesses are often difficult to cure since these patients deny transfusions. By a retrospective analysis, we report the possibility of treating some tumors, mostly hematological, with either autologous or allogeneic bone marrow transplantation (BMT) without blood support. Eight patients were evaluated, including lymphoma (two patients), acute lymphoblastic (one patient) and myeloblastic (one patient) leukemia, chronic lymphocytic leukemia (one patient), refractory anemia with blasts in transformation (one patient), chronic myeloid leukemia (one patient) and metastatic breast cancer (one patient). All patients experienced a severe cytopenia with no major side effects or life-threatening complications. We had four deaths: three from relapse and progression of the disease (at 5, 8 and 15 months after the stem cell infusion), and one from acute intestinal GVHD (at 2 months after the stem cell infusion). Four patients are in complete clinical remission (at 8, 10, 16 and 26 months after the stem cell infusion), and this was related to the disease outcome. We conclude that autologous and allogeneic BMT are feasible without the support of transfusions. We believe that this should be performed as soon as possible in the course of the disease.

Successful one antigen mismatched bone marrow transplant for chronic myeloid leukemia (CML) after two failed syngeneic transplants.

In May 1989, a 43-year-old woman with chronic myelocytic leukemia diagnosed in 1988 underwent a syngeneic bone marrow transplant (BMT), conditioned with cyclophosphamide-TBI while in chronic phase. Three years later, because of both cytogenetic and hematological relapse, she was treated with interferon-alpha (IFN-alpha) and hydroxyurea (HU) for 3 years. In 1994 while still in chronic phase, she was conditioned with busulfan-cyclophosphamide (BU-CY) and underwent a second syngeneic BMT. In 1996, following a further cytogenetic and hematological relapse, she was again placed on IFN-alpha and HU therapy for 13 months, when she was referred to our hospital in accelerated phase. In October 1997 following thiotepa, CY and anti-thymocyte globulin conditioning, she underwent an allogeneic BMT from her 1-Ag mismatched brother. She became Ph1 negative with full chimerism and normal hematological parameters; acute graft-versus-host disease (GVHD) grade 3 of the skin and chronic GVHD of the liver occurred. At 11 months follow-up she is in good clinical condition and with a Karnofsky score of 90%. The role of a graft-versus-leukemia (GVL) effect in securing and maintaining the complete remission is discussed.

Analysis of feasibility of myeloablative therapy and autologous peripheral stem cell (PBSC) transplantation in the elderly: an interim report.

An interim report evaluating the feasibility of myeloablative therapy followed by peripheral blood stem cell (PBSC) autotransplant in patients aged >60 years is presented. In the last 2 years 19 patients >60 years old with several oncological conditions, mostly hematological, underwent PBSC autotransplant either as salvage therapy following relapse or resistance to conventional treatment, or as consolidating therapy as a part of a well defined protocol. There were 13 males and six females; the mean age was 66.9 years (range 61-76 years); nine patients had resistant or relapsed lymphoma, six myeloma, two acute leukemia, one Waldenstrom's disease and one lung cancer. Myeloablative schemes included BEAM exclusively for lymphomas, busulfan and melphalan (Bu-MPH) mainly for myeloma, busulfan and cyclophosphamide (Bu-CTX) for lymphomas and leukemia and VP-16 and CTX for lung cancer. Mobilization of CD34+ cells was achieved in all patients with the combination of high-dose CTX and G-CSF with collections between 2.83 to 19.04 x 10(6)/kg (mean 7.1). All patients engrafted with a median time for recovery of PMN (>0.5 x 10(3)/microl) of 10 days (range 8-12 days) and for PLT (>20 x 10(3)/microl) of 12 days (range 10-17 days). Major responses were obtained in 15 of 16 patients evaluable for response and eight patients entered CR; overall eight patients are in CR, five are alive with disease, five are dead from disease progression and one is dead because of congestive heart failure 7 months following PBSC autotransplant. No early deaths following the procedure occurred; major side-effects were grade I-II mucositis (58%), fever with documented sepsis (10%), pneumonia (5%), cardiac, renal and liver toxicity (5%). Cardiac function was evaluated before and after myeloablative therapy by VEF in all patients; no significant modifications were necessary. In conclusion, our experience demonstrates that myeloablative therapies in older selected patients can be feasible; the feasibility of introducing PBSC autotransplantation following myeloablative therapy as a front-line treatment in patients aged >60 years, needs accurate guide lines for selection of appropriate patients.

[Extramucosal single-layer suture with multifilament stainless steel wires in surgery of the colon. Experimental research]. / La sutura monostrato extramucosa con fili di acciaio inossidabile multifilamentoso nella chirurgia del colon. Ricerche sperimentali

With a view to evaluating whether and how far a fuller case documentation may contribute to a better knowledge of the real possibilities of multifilament stainless steel wires in surgery of the colon, the Authors present and discuss the results they obtained during the course of experimental research on extramucosa single-layer sutures. In the light of their personal histological documents, they emphasize the absolute biological inertia of this suture material, a property which, together with the capacity of not suffering the colliquative action of germs, means that multifilament stainless steel wires can be given full rights of domicile in colon surgery.

[Morphofunctional aspects of the stomatognathic apparatus in the totally edentulous patient. Prosthetic rehabilitation]. / Aspetti morfo-funzionali dell'apparato stomatognatico nell'edentulo totale. Riabilitazione protesica.

The authors examined the morphofunctional aspects of the various structures of the stomatognathic apparatus in the totally edentulous patient with the aim of carrying out and incorporating full prosthetic restoration. The following aspects are evaluated: 1) the reactive behaviour or resilience of the fibromucous support in the various areas under the functional load and its functional conditioning; 2) the vertical and horizontal intermaxillary ratios. Its modifications in an edentulous subject; 3) the evaluation and optimisation of the verticentre, namely the correct stable functional centre reference; 4) the regulation of muscle strength in relation to the length of contraction of muscle fibre; 5) type 3 lever mechanism in mandibular function and the creation of a balance distribution of occlusal forces in the centre. A suitable functional occlusive scheme in the total prosthesis achieves a correct adjustment of muscle contraddiction and a balanced distribution of load forces on the supporting tissues and on the temporomandibular joints. It constitutes a functional centre reference which centralises and stabilises the jaw and the prosthesis. In addition to correct technical installation, this also depends on a detailed preliminary diagnostic evaluation of the anatomofunctional conditions of all the structures in the stomatognathic apparatus of the subject to be treated.

[Method of functional impression in prosthetic treatment with distal extension with dental-mucosal support]. / Metodica d'impronta funzionale nella protesi dentaria ad estensione distale con appoggio dento-mucoso.

Having examined the biomechanical problems regarding free-end tooth-tissue borne dentures caused by the different resilience of denture support structures and changes in the resilience of fibre-mucosa, and having reviewed the impression methods now in use, the authors describe a functional impression method used to obtain a clinical and instrumental record of the individual conditioning of fibre-mucosa support by functional occlusal stress. The aim was to reduce the resilience of fibre-mucosa to levels comparable to periodontal and articular levels. The purpose was to achieve an optimal functional morphology of the prosthetic occlusal surface in order to guarantee the static and dynamic equilibrium of the denture. The authors describe a protocol based on weekly relining sessions and clinical and instrumental controls performed at every other session until optimal results have been obtained. Instrumental tests were carried out using the computerised occlusal analyser: T-SCAN version II. The authors used this device to measure the redistribution of occlusal forces acting on the occlusal surface in an antero-posterior and latero-lateral direction in subsequent sessions and the corresponding position of the centre of forces in the central area. In line with the results of earlier studies carried out by other researchers, the authors confirm that when maximum conditioning of the fibre-mucosa support is achieved, it only retains a slight residual elasticity.