Decision Making in Patients With Metastatic Spine. The Role of Minimally Invasive Treatment Modalities

Spine metastases affect more than 70% of terminal cancer patients that eventually suffer from severe pain and neurological symptoms. Nevertheless, in the overwhelming majority of the cases, a spinal metastasis represents just one location of a diffuse systemic disease. Therefore, the best practice for treatment of spinal metastases depends on many different aspects of an oncological disease, including the assessment of neurological status, pain, location, and dissemination of the disease as well as the ability to predict the risk of disease progression with neurological worsening, benefits and risks associated to treatment and, eventually, expected survival. To address this need for a framework and algorithm that takes all aspects of care into consideration, we reviewed available evidence on the multidisciplinary management of spinal metastases. According to the latest evidence, the use of stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) for spinal metastatic disease is rapidly increasing. Indeed, aggressive surgical resection may provide the best results in terms of local control, but carries a significant rate of post-surgical morbidity whose incidence and severity appears to be correlated to the extent of resection. The multidisciplinary management represents, according to current evidence, the best option for the treatment of spinal metastases. Noteworthy, according to the recent literature evidence, cases that once required radical surgical resection followed by low-dose conventional radiotherapy, can now be more effectively treated by minimally invasive spinal surgery (MISS) followed by spine SRS with decreased morbidity, improved local control, and more durable pain control. This combination allows also extending this standard of care to patients that would be too sick for an aggressive surgical treatment

La radioterapia nelle metastasi cutanee da carcinoma mammario: case report

Breast cancer is the most frequent tumour in women around the world and it accounts for 25% of all cases of cancer. It may spread through the body in various districts, and as a consequence pulmonary, bone, liver, cerebral, lymph node and skin metastases are commonly seen. Skin metastases can be both locoregional (near the tumor) and distant. The skin appearance should not be underestimated in multi-metastatic patients, as tumorous progression in the skin inevitably causes ulceration, extreme difficulty in cicatrization and consequent pain. In this study, we describe the case of a multiple treated patient for destructive cutaneous metastases (Oncology)

circPVT1 and PVT1/AKT3 show a role in cell proliferation, apoptosis, and tumor subtype-definition in small cell lung cancer

Small cell lung cancer (SCLC) is treated as a homogeneous disease, although the expression of NEUROD1, ASCL1, POU2F3, and YAP1 identifies distinct molecular subtypes. The MYC oncogene, amplified in SCLC, was recently shown to act as a lineage-specific factor to associate subtypes with histological classes. Indeed, MYC-driven SCLCs show a distinct metabolic profile and drug sensitivity. To disentangle their molecular features, we focused on the co-amplified PVT1, frequently overexpressed and originating circular (circRNA) and chimeric RNAs. We analyzed hsa_circ_0001821 (circPVT1) and PVT1/AKT3 (chimPVT1) as examples of such transcripts, respectively, to unveil their tumorigenic contribution to SCLC. In detail, circPVT1 activated a pro-proliferative and anti-apoptotic program when over-expressed in lung cells, and knockdown of chimPVT1 induced a decrease in cell growth and an increase of apoptosis in SCLC in vitro. Moreover, the investigated PVT1 transcripts underlined a functional connection between MYC and YAP1/POU2F3, suggesting that they contribute to the transcriptional landscape associated with MYC amplification. In conclusion, we have uncovered a functional role of circular and chimeric PVT1 transcripts in SCLC; these entities may prove useful as novel biomarkers in MYC-amplified tumors.</p

Novel and Rare Fusion Transcripts Involving Transcription Factors and Tumor Suppressor Genes in Acute Myeloid Leukemia.

Approximately 18% of acute myeloid leukemia (AML) cases express a fusion transcript. However, few fusions are recurrent across AML and the identification of these rare chimeras is of interest to characterize AML patients. Here, we studied the transcriptome of 8 adult AML patients with poorly described chromosomal translocation(s), with the aim of identifying novel and rare fusion transcripts. We integrated RNA-sequencing data with multiple approaches including computational analysis, Sanger sequencing, fluorescence in situ hybridization and in vitro studies to assess the oncogenic potential of the ZEB2-BCL11B chimera. We detected 7 different fusions with partner genes involving transcription factors (OAZ-MAFK, ZEB2-BCL11B), tumor suppressors (SAV1-GYPB, PUF60-TYW1, CNOT2-WT1) and rearrangements associated with the loss of NF1 (CPD-PXT1, UTP6-CRLF3). Notably, ZEB2-BCL11B rearrangements co-occurred with FLT3 mutations and were associated with a poorly differentiated or mixed phenotype leukemia. Although the fusion alone did not transform murine c-Kit+ bone marrow cells, 45.4% of 14q32 non-rearranged AML cases were also BCL11B-positive, suggesting a more general and complex mechanism of leukemogenesis associated with BCL11B expression. Overall, by combining different approaches, we described rare fusion events contributing to the complexity of AML and we linked the expression of some chimeras to genomic alterations hitting known genes in AML

Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease:diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A beta 42 levels

The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82\u201396%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-\u3b2 (A\u3b2) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median A\u3b242 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of A\u3b2 brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and A\u3b242 as markers of brain tauopathy and \u3b2-amyloidosis

Skin flap complications after decompressive craniectomy and cranioplasty: Proposal of classification and treatment options

BACKGROUND: The list of complications reported after decompressive craniectomy (DC) and cranioplasty is progressively increasing. Nonetheless, the exact incidence of these events is still ill-defined. Problems affecting skin flaps after DC and cranioplasty have never been accurately analyzed in papers and their impact on patients’ prognosis is largely underestimated. METHODS: In a 10-year time, we treated by DC 450 patients, 344 of whom underwent cranioplasty, either with autologous bone or artificial implants (hydroxyapatite, polyetheretherketone, titanium, polymethylmethacrylate). Complications involving skin flaps and requiring re-surgery were observed and treated in 38 cases. We classified three main types of lesions: (1) dehiscence, (2) ulcer, and (3) necrosis. In all cases surgical decision making was performed in cooperation with plastic surgeons, to select the best treatment option. RESULTS: Dehiscence was reported in 28 cases, ulcer in 6, and necrosis in 4. Surgeries included flap re-opening and re-suturing, Z-plasty, rotational, advancement, or free flaps. Treatment complications required further surgical procedures in six patients. CONCLUSIONS: In our experience, complications involving skin flaps after DC and post-DC cranioplasty cannot be considered a minor event because of their potential to further compromise the yet fragile conditions of these patients. Their management is complex and requires a multidisciplinary approach to get the better results

Benefits of image-guided stereotactic hypofractionated radiation therapy as adjuvant treatment of craniopharyngiomas. A review

Purpose: Craniopharyngiomas account for 5.6–13% of intracranial tumors in children. Despite being histologically benign, these tumors remain a major neurosurgical challenge because of the typical tight adherence to adjacent critical structures. The optimal therapeutic approach for this disease is controversial. Large cystic size and adherence to neurovascular, neuroendocrine, and optic structures without a clear line of cleavage make complete resection problematic and often hazardous. For these reasons, partial resection and adjuvant treatment play an important role. Post-operative radiation therapy (RT) following either complete or incomplete tumor removal is associated with significantly decreased recurrence rates. The aim of this review is to analyze the potential advantage of the most modern technical advancements for RT of craniopharyngiomas. Methods: This narrative review on the topic of craniopharyngiomas was based on published data available on PUBMED/Medline. All data concerning adjuvant or upfront radiation therapy treatment of craniopharyngioma were reviewed and summarized. A more detailed analysis of fractionated frameless steretactic radiosurgery of these tumors is provided as well. Results: We reviewed the possible improvement provided by intensity modulated beams, arc therapy, image guidance, proton radiation, and fractionated stereotactic radiosurgery. Many published findings on outcome and toxicity after RT involve the use of relatively outdated RT techniques. Technologic improvements in imaging, radiation planning, and delivery have improved the distribution of radiation doses to desired target volumes and reduced the dose to nearby critical normal tissues. Currently available techniques, providing image guidance and improved radiation doses distribution profile, have shown to maintain the efficacy of conventional techniques while significantly reducing the toxicity. Conclusions: Image-guided radiosurgery holds the dose distributions and precision of frame-based techniques with the remarkable advantage of multiple-session treatments that are better tolerated by sensitive peritumoral structures, such as the optic pathway and hypothalamus. This, together with the comfort of a frameless technique, candidates frameless image-guided radiosurgery to be the first option for the adjuvant post-operative treatment of craniopharyngiomas in children and young adults when total resection cannot be achieved, in particular those with hypothalamic involvement, and when the residual tumor is mostly soli

Pharmacological Inhibition of WIP1 Sensitizes Acute Myeloid Leukemia Cells to the MDM2 Inhibitor Nutlin-3a

In acute myeloid leukemia (AML), the restoration of p53 activity through MDM2 inhibition proved efficacy in combinatorial therapies. WIP1, encoded from PPM1D, is a negative regulator of p53. We evaluated PPM1D expression and explored the therapeutic efficacy of WIP1 inhibitor (WIP1i) GSK2830371, in association with the MDM2 inhibitor Nutlin-3a (Nut-3a) in AML cell lines and primary samples. PPM1D transcript levels were higher in young patients compared with older ones and in core-binding-factor AML compared with other cytogenetic subgroups. In contrast, its expression was reduced in NPM1-mutated (mut, irrespective of FLT3-ITD status) or TP53-mut cases compared with wild-type (wt) ones. Either Nut-3a, and moderately WIP1i, as single agent decreased cell viability of TP53-wt cells (MV-4-11, MOLM-13, OCI-AML3) in a time/dosage-dependent manner, but not of TP53-mut cells (HEL, KASUMI-1, NOMO-1). The drug combination synergistically reduced viability and induced apoptosis in TP53-wt AML cell line and primary cells, but not in TP53-mut cells. Gene expression and immunoblotting analyses showed increased p53, MDM2 and p21 levels in treated TP53-wt cells and highlighted the enrichment of MYC, PI3K-AKT-mTOR and inflammation-related signatures upon WIP1i, Nut-3a and their combination, respectively, in the MV-4-11 TP53-wt model. This study demonstrated that WIP1 is a promising therapeutic target to enhance Nut-3a efficacy in TP53-wt AML

Effectiveness of Streptococcus Pneumoniae Urinary Antigen Testing in Decreasing Mortality of COVID-19 Co-Infected Patients: A Clinical Investigation

Background and objectives: Streptococcus pneumoniae urinary antigen (u-Ag) testing has recently gained attention in the early diagnosis of severe and critical acute respiratory syndrome coronavirus-2/pneumococcal co-infection. The aim of this study is to assess the effectiveness of Streptococcus pneumoniae u-Ag testing in coronavirus disease 2019 (COVID-19) patients, in order to assess whether pneumococcal co-infection is associated with different mortality rate and hospital stay in these patients. Materials and Methods: Charts, protocols, mortality, and hospitalization data of a consecutive series of COVID-19 patients admitted to a tertiary hospital in northern Italy during COVID-19 outbreak were retrospectively reviewed. All patients underwent Streptococcus pneumoniae u-Ag testing to detect an underlying pneumococcal co-infection. Covid19+/u-Ag+ and Covid19+/u-Ag- patients were compared in terms of overall survival and length of hospital stay using chi-square test and survival analysis. Results: Out of 575 patients with documented pneumonia, 13% screened positive for the u-Ag test. All u-Ag+ patients underwent treatment with Ceftriaxone and Azithromycin or Levofloxacin. Lopinavir/Ritonavir or Darunavir/Cobicistat were added in 44 patients, and hydroxychloroquine and low-molecular-weight heparin (LMWH) in 47 and 33 patients, respectively. All u-Ag+ patients were hospitalized. Mortality was 15.4% and 25.9% in u-Ag+ and u-Ag- patients, respectively (p = 0.09). Survival analysis showed a better prognosis, albeit not significant, in u-Ag+ patients. Median hospital stay did not differ among groups (10 vs. 9 days, p = 0.71). Conclusions: The routine use of Streptococcus pneumoniae u-Ag testing helped to better target antibiotic therapy with a final trend of reduction in mortality of u-Ag+ COVID-19 patients having a concomitant pneumococcal infection. Randomized trials on larger cohorts are necessary in order to draw definitive conclusion