L'immunoterapia in associazione alla terapia standard per i pazienti con Mieloma Multiplo di nuova diagnosi candidabili alla chemioterapia ad alte dosi

Lo scenario terapeutico del Mieloma Multiplo (MM) si è ampiamente evoluto nelle ultime decadi con l’introduzione di un numero sempre maggiore di combinazioni di nuovi farmaci molto efficaci. In tal contesto, spicca Daratumumab (dara), grazie ai suoi dati di efficacia e di sicurezza dimostrati sia nel setting del paziente ricaduto/refrattario che di nuova diagnosi. Lo scopo del presente studio è quello di aggiungere dati circa la combinazione di dara con la terapia standard nel contesto di un programma trapiantologico per pazienti di nuova diagnosi candidabili alla chemioterapia ad alte dosi, con un particolare focus sull’impatto dell’anticorpo monoclonale sulla raccolta delle cellule staminali (PBSC). Sono stati analizzati 41 pazienti trattati presso il nostro centro nell’ambito di due studi clinici (EMN17 e EMN18). Con un follow-up mediano pari a 19 mesi, dara aggiunto alla terapia standard ha dimostrato un’ottima efficacia, in termini di risposte profonde e sopravvivenza libera da malattia, ed un buon profilo di sicurezza, senza tossicità aggiuntive o inaspettate. Inoltre, nello studio registrativo CASSIOPEIA dara non ha avuto un impatto negativo sulla raccolta delle PBSC; infatti, nei pazienti sottoposti a dara il numero il numero mediano di PBSC raccolte è risultato inferiore e questi hanno necessitato più frequentemente di Plerixafor, senza, tuttavia, modifiche nell’iter trapiantologico rispetto al gruppo di controllo. Analogamente, nella nostra analisi i pazienti del gruppo dara hanno utilizzato maggiormente Plerixafor ed è emerso come questi possano beneficiare da un dosaggio maggiore di Ciclofosfamide mobilizzante (3 g/mq rispetto 2 g/mq). Durante lo svolgimento del presente progetto dara è stato approvato in pratica clinica prima in Europa (2020) e poi in Italia (2021). Il presente studio ha confermato come dara aggiunto ad un regime di induzione Bortezomib-based rappresenti un nuovo standard of care per i pazienti con MM di nuova diagnosi eleggibili alla chemioterapia ad alte dosi.

Identificazione di nuove strategie per la valutazione della malattia minima residua nel Mieloma Multiplo: la Biopsia Liquida

Il Mieloma Multiplo (MM) è una patologia neoplastica delle cellule B caratterizzata dalla proliferazione di più cloni di plasmacellule portatrici di diverse anomalie genomiche. Il MM presenta tipicamente un’eterogeneità genomica spaziale e intraclonale, che rende l’aspirato midollare "a singolo sito", attualmente utilizzato per la valutazione della malattia residua (MRD) dopo trattamento, non realmente informativo sulla taglia di malattia e sul panorama genomico della malattia. In considerazione della crescente importanza che sta assumendo la valutazione della MRD, i test per monitorarla dovrebbero essere non invasivi, affidabili e in grado di rappresentare le eterogeneità che caratterizzano il MM. Il presente studio ha permesso di dimostrare la possibilità di utilizzare la biopsia liquida, una metodica innovativa e non invasiva, per caratterizzare i pazienti con MM attivo o con MM smoldering ad alto rischio di evoluzione (HR-SMM) e per determinale l’MRD nei pazienti sottoposti a terapia di prima linea, integrando le metodiche attualmente validate. Nei pazienti arruolati nel presente studio è stato possibile identificare la frazione tumorale di DNA libero circolante (cfDNA-TF) nel sangue periferico, ed è stato possibile caratterizzare la malattia da un punto di vista qualitativo, dimostrando un’elevata concordanza del profilo genomico tra DNA libero circolante e DNA midollare (100% nei pazienti con HR-SMM e 86% nei pazienti con MM attivo). L’esecuzione seriata di biopsie liquide in corso di terapia, con un follow-up mediano di 24 mesi, ha mostrato una rapida e netta riduzione della cfDNA-TF xdalle prime fasi di terapia, con una tendenza a mantenersi mediamente sotto la soglia di sensibilità della metodica anche nelle fasi successive, indipendentemente dall’eventuale persistenza di MRD individuabile a livello midollare o mediante PET-CT. Con un follow-up più lungo probabilmente sarà possibile valutare meglio la capacità di questa metodica di affiancare o eventualmente sostituire l’aspirato midollare.

A human myeloma cell line suitable for the generation of human monoclonal antibodies

Ever since monoclonal antibodies were produced in 1975 with mouse myeloma cells there has been interest in developing human myeloma cultures for the production of monoclonal antibodies. However, despite multiple attempts, no human myeloma line suitable for hybridoma production has been described. Here we report the derivation of a hypoxanthine–aminopterin–thymidine-sensitive and ouabain-resistant human myeloma cell line (Karpas 707H) that contains unique genetic markers. We show that this line is useful for the generation of stable human hybridomas. It can easily be fused with ouabain-sensitive Epstein–Barr virus-transformed cells as well as with fresh tonsil and blood lymphocytes, giving rise to stable hybrids that continuously secrete very large quantities of human immunoglobulins. The derived hybrids do not lose immunoglobulin secretion over many months of continuous growth. The availability of this cell line should enable the in vitro immortalization of human antibody-producing B cells that are formed in vivo. The monoclonal antibodies produced may have advantages in immunotherapy.

The Clinical Impact Of Cerebellar Grey Matter Pathology In Multiple Sclerosis.

The cerebellum is an important site for cortical demyelination in multiple sclerosis, but the functional significance of this finding is not fully understood. To evaluate the clinical and cognitive impact of cerebellar grey-matter pathology in multiple sclerosis patients. Forty-two relapsing-remitting multiple sclerosis patients and 30 controls underwent clinical assessment including the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale (EDSS) and cerebellar functional system (FS) score, and cognitive evaluation, including the Paced Auditory Serial Addition Test (PASAT) and the Symbol-Digit Modalities Test (SDMT). Magnetic resonance imaging was performed with a 3T scanner and variables of interest were: brain white-matter and cortical lesion load, cerebellar intracortical and leukocortical lesion volumes, and brain cortical and cerebellar white-matter and grey-matter volumes. After multivariate analysis high burden of cerebellar intracortical lesions was the only predictor for the EDSS (p<0.001), cerebellar FS (p = 0.002), arm function (p = 0.049), and for leg function (p<0.001). Patients with high burden of cerebellar leukocortical lesions had lower PASAT scores (p = 0.013), while patients with greater volumes of cerebellar intracortical lesions had worse SDMT scores (p = 0.015). Cerebellar grey-matter pathology is widely present and contributes to clinical dysfunction in relapsing-remitting multiple sclerosis patients, independently of brain grey-matter damage.

Multiple Desmoid Tumors In A Patient With Gardner's Syndrome - Report Of A Case.

Desmoid tumor (DT) is a common manifestation of Gardner's Syndrome (GS), although it is a rare condition in the general population. DT in patients with GS is usually located in the abdominal wall and/or intra-abdominal cavity. We report a case of a 32 years-old female patient with familial adenomatous polyposis (FAP), who was already submitted to total colectomy and developed multiple DT, located in the abdominal wall and in the left breast. The patient underwent several surgical procedures, with a multidisciplinary team of surgeons. Wide surgical resections of the left breast and the abdominal wall tumors were performed in separate steps. Polypropylene mesh reconstruction and muscle flaps were needed to cover the defects of the thoracic and abdominal walls. After partial necrosis of the adipose-cutaneous flap in the abdomen that required a new skin graft, she had a satisfactory outcome with complete healing of the surgical incisions. DT is frequent in GS, however, breast localization is very rare, with few cases reported in the literature. Recurrence of DT is not negligible, even after a wide surgical resection. GS patients must be followed up closely, and clinical examination, associated with imaging studies, should be performed to detect any signs of tumor. DT represents one of the most significant causes of the morbidity and mortality that affects FAP patients following colectomy. In general, the surgical procedures to excise DT are highly complex, requiring a multidisciplinary team.

The Effect Of Pelvic Floor Muscle Training Alone Or In Combination With Electrostimulation In The Treatment Of Sexual Dysfunction In Women With Multiple Sclerosis.

Sexual dysfunction (SD) affects up to 80% of multiple sclerosis (MS) patients and pelvic floor muscles (PFMs) play an important role in the sexual function of these patients. The objective of this paper is to evaluate the impact of a rehabilitation program to treat lower urinary tract symptoms on SD of women with MS. Thirty MS women were randomly allocated to one of three groups: pelvic floor muscle training (PFMT) with electromyographic (EMG) biofeedback and sham neuromuscular electrostimulation (NMES) (Group I), PFMT with EMG biofeedback and intravaginal NMES (Group II), and PFMT with EMG biofeedback and transcutaneous tibial nerve stimulation (TTNS) (Group III). Assessments, before and after the treatment, included: PFM function, PFM tone, flexibility of the vaginal opening and ability to relax the PFMs, and the Female Sexual Function Index (FSFI) questionnaire. After treatment, all groups showed improvements in all domains of the PERFECT scheme. PFM tone and flexibility of the vaginal opening was lower after the intervention only for Group II. All groups improved in arousal, lubrication, satisfaction and total score domains of the FSFI questionnaire. This study indicates that PFMT alone or in combination with intravaginal NMES or TTNS contributes to the improvement of SD.

Unfavorable Outcomes During Treatment Of Multiple Sclerosis With High Doses Of Vitamin D.

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The Real-life Experience With Cardiovascular Complications In The First Dose Of Fingolimod For Multiple Sclerosis.

Fingolimod is a new and efficient treatment for multiple sclerosis (MS). The drug administration requires special attention to the first dose, since cardiovascular adverse events can be observed during the initial six hours of fingolimod ingestion. The present study consisted of a review of cardiovascular data on 180 patients with MS receiving the first dose of fingolimod. The rate of bradycardia in these patients was higher than that observed in clinical trials with very strict inclusion criteria for patients. There were less than 10% of cases requiring special attention, but no fatal cases. All but one patient continued the treatment after this initial dose. This is the first report on real-life administration of fingolimod to Brazilian patients with MS, and one of the few studies with these characteristics in the world.

Systemic Granulomatous Diseases Associated With Multiple Palpable Masses That May Involve The Breast: Case Presentation And An Approach To The Differential Diagnosis.

Palpable mass is a common complaint presented to the breast surgeon. It is very uncommon for patients to report breast mass associated with palpable masses in other superficial structures. When these masses are related to systemic granulomatous diseases, the diagnosis and initiation of specific therapy can be challenging. The purpose of this paper is to report a case initially assessed by the breast surgeon and ultimately diagnosed as granulomatous variant of T-cell lymphoma, and discuss the main systemic granulomatous diseases associated with palpable masses involving the breast.

Ten Years Of Proteomics In Multiple Sclerosis.

Multiple sclerosis, which is the most common cause of chronic neurological disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid analysis, which requires an invasive collection. Additionally, the molecular mechanisms of the disease are not completely elucidated, especially those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and molecular mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biological samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its experimental model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets.

Long-term follow-up of an 8-year-old boy with insulinoma as the first manifestation of a familial form of multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.

Creatina quinase e dor muscular tardia na musculação : estudo experimental em adultos e jovens com o "circuit weight training" e o "multiple set system"

Universidade Estadual de Campinas . Faculdade de Educação Física

Categorization skills and recall in brain damaged children: a multiple case study

During development, children become capable of categorically associating stimuli and of using these relationships for memory recall. Brain damage in childhood can interfere with this development. This study investigated categorical association of stimuli and recall in four children with brain damages. The etiology, topography and timing of the lesions were diverse. Tasks included naming and immediate recall of 30 perceptually and semantically related figures, free sorting, delayed recall, and cued recall of the same material. Traditional neuropsychological tests were also employed. Two children with brain damage sustained in middle childhood relied on perceptual rather than on categorical associations in making associations between figures and showed deficits in delayed or cued recall, in contrast to those with perinatal lesions. One child exhibited normal performance in recall despite categorical association deficits. The present results suggest that brain damaged children show deficits in categorization and recall that are not usually identified in traditional neuropsychological tests.

A closer look at multiple-clone Plasmodium vivax infections: detection methods, prevalence and consequences

The naturally occurring clonal diversity among field isolates of the major human malaria parasite Plasmodium vivax remained unexplored until the early 1990s, when improved molecular methods allowed the use of blood samples obtained directly from patients, without prior in vitro culture, for genotyping purposes. Here we briefly review the molecular strategies currently used to detect genetically distinct clones in patient-derived P. vivax samples, present evidence that multiple-clone P. vivax infections are commonly detected in areas with different levels of malaria transmission and discuss possible evolutionary and epidemiological consequences of the competition between genetically distinct clones in natural human infections. We suggest that, when two or more genetically distinct clones are present in the same host, intra-host competition for limited resources may select for P. vivax traits that represent major public health challenges, such as increased virulence, increased transmissibility and antimalarial drug resistance.

Working memory impairment in multiple sclerosis relapsing-remitting patients with episodic memory deficits

Episodic memory is impaired in multiple sclerosis (MS) patients, possibly because of deficits in working memory (WM) functioning. If so, WM alterations should necessarily be found in patients with episodic memory deficits, but this has not yet been demonstrated. In this study we aimed at determining whether episodic memory deficits in relapsing-remitting MS are found in conjunction with impaired WM. We evaluated 32 MS patients and 32 matched healthy controls. Nineteen of the 32 patients had episodic memory impairment, and as a group only these individuals showed deficits in WM capacity, which may lead to difficulty in encoding, and/or retrieving information from episodic memory.