Δευτέρα 4 Ιανουαρίου 2021

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Αυστραλία
Ιαπωνία
Νέα Ζηλανδία
Ρουάντα
Σιγκαπούρη
Νότια Κορέα
Ταϊλάνδη
Κίνα, με την επιφύλαξη επιβεβαίωσης αμοιβαιότητας



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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
Telephone consultation 11855 int 1193,

Relapsed and refractory primary CNS lymphoma

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Abstract

Background

Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management.

Methods

We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded.

Results

During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2–88.5) months and median PFS was 11.0 (0.2–73.9) months. At diagnosis (r2 = 0.85, p < 0.001), first relapse (r2 = 0.69, p < 0.001), multiple relapses (r2 = 0.97, p < 0.001) PFS was highly correlated with OS. In contrast, there was no correlation between the duration of subsequent progression-free intervals. No difference in PFS or OS was seen between CSF or intraocular relapse and parenchymal relapse. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7%. Consolidation with autologous stem cell transplant (ASCT) was associated with longer PFS compared to either no consolidation (p = 0.01) and trended to longer PFS when compared to other consolidation strategies (p =  ;0.06). OS was similarly improved in patients consolidated with ASCT compared with no consolidation (p = 0.04), but not compared with other consolidation (p = 0.22). Although patients receiving ASCT were younger, KPS, sex, and number of recurrences were similar between consolidation groups. A multivariate analysis confirmed an independent effect of consolidation group on PFS (p = 0.01), but not OS.

Conclusions

PFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.

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MRI-guided stereotactic radiation therapy for hepatocellular carcinoma: a feasible and safe innovative treatment approach

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Abstract

Purpose

Hepatocellular carcinoma (HCC) in early stages benefits from local ablative treatments such as radiofrequency ablation (RFA) or transarterial chemoembolization (TACE). In this context, radiotherapy (RT) has shown promising results but has not been thoroughly evaluated. Magnetic resonance-guided RT (MRgRT) may represent a paradigm shifting improvement in stereotactic body radiotherapy (SBRT) for liver tumors.

Methods

We retrospectively evaluated HCC patients treated on a hybrid low-tesla MRgRT unit. A total biologically effective dose (BED) > 100 Gy was delivered in 5 consecutive fractions, respecting the appropriate organs-at-risk constraints. Hybrid MR scans were used for treatment planning and cine MR was used for delivery gating. Patients were followed up for toxicity and treatment–response assessment.

Results

Ten patients were enrolled, with a total of 12 lesions. All the lesions were irradiated with no interruptions. Six patients had already performed previous local therapies. Median follow-up after SBRT was 6.5 months (1–25). Two cases of acute toxicity were reported (G ≤ 2 according to CTCAE v4.0). At the time of the analysis, 90% of the population presented local control. Child–Pugh before and after treatment remained unchanged in all but one patient.

Conclusion

MRgRT is a feasible and safe option showing favorable toxicity profile for HCC treatment.

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Efficacy of clobazam as add-on therapy in brain tumor-related epilepsy

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Abstract

Purpose

Brain tumor-related epilepsy (TRE) is often resistant to currently available antiepileptic medications (AEDs). Clobazam was initially approved as adjunctive AED for patients with Lennox Gastaut syndrome but has been used in TRE, despite limited evidence in this context. This observational study aims to examine the effect of clobazam on seizure frequency on patients who have a primary CNS tumor and continued seizures despite their current AEDs.

Methods

A retrospective review of patients with histologically-confirmed primary brain tumors seen in the neuro-oncology interdisciplinary clinic from April 2016–2019 was completed, and patients on clobazam were identified. Response to clobazam was defined as a greater than 50% reduction in seizure frequency. Additional data including patient and tumor characteristics, treatment course, tolerability, AEDs used prior to addition of clobazam, and AEDs concomitantly used with clobazam were collected.

Results

A total of 35 patients with TRE on clobazam were identified, with 2 patients unable to tolerate the medication due to side effects. Of the 33 remaining patients, a total of 31 (93.9%) of patients were deemed responders. Ten patients (30.3%) were seizure free within 6 months of clobazam initiation and 21 (63.6%) reported a significant reduction in seizure frequency. This reduction also allowed several patients to modify concurrent AEDs.

Conclusions

Clobazam is an effective agent to use as add-on AED in TRE, with 94% of patients showing a significant response within 6 months. Furthermore, the addition of clobazam may yield a reduction in polypharmacy, as concomitant AEDs can be reduced and potentially withdrawn.

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Motor deficits at presentation and predictors of overall survival in central nervous system lymphomas

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Abstract

Purpose

Central nervous system lymphomas (CNSL) can present with motor and non-motor symptoms. In many central nervous system tumors, motor deficits are associated with significant morbidity and functional impairment, and correlate with worse prognosis. CNSLs however, often exhibit remarkable response to chemotherapy and radiotherapy with corresponding symptom improvement. We investigate the survival outcomes and trajectories of motor and functional recovery in a cohort of patients presenting with and without initial motor deficits.

Methods

Patients who underwent biopsy and with a histologically confirmed CNSL between 2008 and 2019 were retrospectively identified. Baseline demographic variables, comorbidities, presenting symptoms, histological type, neuroimaging features (location and number of lesions), and treatment administered (pre- and post-operative steroid use and chemotherapy regime) were recorded. Dates of death were obtained from the National Registry of Births and Deaths. Motor power and performance status at admission, 1 month and 6 months were determined.

Results

We identified 119 patients, of whom 34% presented with focal motor deficits. The median overall survival (OS) was 26.6 months. Those with focal motor deficits had longer OS (median 42.4 months) than those without (median 23.3 months; p = 0.047). In multivariate Cox analysis, age (HR 1.04 per year; p = 0.003), CCI (HR 1.31 per point; p < 0.001), leptomeningeal/ependymal involvement (HR 2.53; p = 0.016), thalamus involvement (HR 0.34; p = 0.019), neutrophil:lymphocyte ratio (HR 1.06 per point; p = 0.034), positive HIV status (HR 5.31; p = 0.003), preoperative steroids use (HR 0.49; p = 0.018), postoperative high-dose steroids (HR 0.26; p < 0.001) and postoperative low-dose steroids (HR 0.28; p = 0.010) were significant predictors of OS. By one month, 43% of surviving patients had full power, increasing to 61% by six months.

Conclusion

A significant proportion of patients with initial motor deficits recovered in motor strength by six months. In our population, those presenting with motor deficits had paradoxically better overall survival.

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Parasympathetic influences in cancer pathogenesis: further insights

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Pancreatic adenocarcinoma: molecular drivers and the role of targeted therapy

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Abstract

Prognosis from pancreatic ductal adenocarcinoma (PDAC) continues to be poor despite the many efforts channeled to improve its management. Although the mainstay treatment is still traditional chemotherapy, recent advances highlighted a promising potential for targeted therapy in the management of this disease. Those advances emphasize the significance of timely genomic profiling of tumor tissue as well as germline testing of patients to identify potential markers of targeted therapy. While targeted therapy is reserved for a relatively small subset of patients with PDAC, ongoing research is uncovering additional markers, and targeted agents, that will hopefully translate to better outcomes for patients.

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Characterization of primary glioma cell lines derived from the patients according to 2016 CNS tumour WHO classification and comparison with their parental tumours

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Abstract

Background

Gliomas represent about 80% of primary brain tumours and about 30% of malignant ones, which today don't have a resolution therapy because of their variability. A valid model for the study of new personalized therapies can be represented by primary cultures from patient's tumour biopsies.

Methods

In this study we consider 12 novel cell lines established from patients' gliomas and immunohistochemically and molecularly characterized according to the newly updated 2016 CNS Tumour WHO classification.

Results

Eight of these lines were glioblastoma cells, two grade III glioma cells (anaplastic astrocytoma and oligo astrocytoma) and two low grade glioma cells (grade II astrocytoma and oligodendroglioma). All cell lines were analysed by immunohistochemistry for specific glioma markers, respectively VIMENTIN, GFAP, IDH1R132, and ATRX. The methylation status of the MGMT gene promoter was also determined in all lines. The comparison of the immunohistochemical characteristics and of the MGMT methylation status of the lines with the tissues of origin shows that the cells in culture maintain the same characteristics.

Conclusions

Human cancer cell lines represent a support in the knowledge of tumour biology and in drug discovery through its facile experimental manipulation.

Trial registration

NCT 04180046.

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Cohesive cancer invasion of the biophysical barrier of smooth muscle

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Abstract

Smooth muscle is found around organs in the digestive, respiratory, and reproductive tracts. Cancers arising in the bladder, prostate, stomach, colon, and other sites progress from low-risk disease to high-risk, lethal metastatic disease characterized by tumor invasion into, within, and through the biophysical barrier of smooth muscle. We consider here the unique biophysical properties of smooth muscle and how cohesive clusters of tumor use mechanosensing cell–cell and cell–ECM (extracellular matrix) adhesion receptors to move through a structured muscle and withstand the biophysical forces to reach distant sites. Understanding integrated mechanosensing features within tumor cluster and smooth muscle and potential triggers within adjacent adipose tissue, such as the unique damage-associated molecular pattern protein (DAMP), eNAMPT (extracellular nicotinamide phosphoribosyltransferase), or visfatin, offers an opportunity to prevent the first steps of invasion and metastasis through the structured muscle.

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Dose adjustment of venetoclax when co-administered with posaconazole: clinical drug–drug interaction predictions using a PBPK approach

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Abstract

Purpose

Venetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically.

Methods

Two physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug–drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios.

Results

The posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range.

Conclusions

The posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD.

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PDLIM2 prevents the malignant phenotype of hepatocellular carcinoma cells by negatively regulating β-catenin

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Implantation of rectosigmoid cancer in a preexisting anal fissure

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Abstract

Colorectal cancer (CRC) rarely spreads by implantation. We report a case of implantation of rectosigmoid cancer in an anal fissure. A 70-year-old woman with a 15-year medical history of anal fissure was referred to our hospital with anal pain of 3-month duration. Colonoscopy revealed a rectosigmoid tumor and a 10-mm submucosal tumor at the anal verge. Biopsy of the rectosigmoid and anal tumors revealed that both were moderately differentiated adenocarcinomas, and abdominoperineal resection (APR) was performed. The anal adenocarcinoma was surrounded by squamous cell epithelium and mainly proliferated in the submucosal and muscular layers. The patient was diagnosed as having rectosigmoid cancer with implantation of cancer in a preexisting anal fissure. The patient remains well 43 months post-surgery with no sign of recurrence. Implantation of CRC in anal fissure is a rare occurrence. Nevertheless, performing adequate anal examination of patients with CRC befor e surgery and during follow-up is necessary. Further, it is important to perform preoperative large bowel examination of patients with benign anal diseases to prevent implantation of CRC.

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