The diagnosis of sinonasal tumors is challenging due to a heterogeneous spectrum of various differential diagnoses as well as poorly defined, disputed entities such as sinonasal undifferentiated ...carcinomas (SNUCs). In this study, we apply a machine learning algorithm based on DNA methylation patterns to classify sinonasal tumors with clinical-grade reliability. We further show that sinonasal tumors with SNUC morphology are not as undifferentiated as their current terminology suggests but rather reassigned to four distinct molecular classes defined by epigenetic, mutational and proteomic profiles. This includes two classes with neuroendocrine differentiation, characterized by IDH2 or SMARCA4/ARID1A mutations with an overall favorable clinical course, one class composed of highly aggressive SMARCB1-deficient carcinomas and another class with tumors that represent potentially previously misclassified adenoid cystic carcinomas. Our findings can aid in improving the diagnostic classification of sinonasal tumors and could help to change the current perception of SNUCs.
Chimeric Antigen Receptor-T cells (CAR-T) are considered novel biological agents, designed to selectively attack cancer cells expressing specific antigens, with demonstrated clinical activity in ...patients affected with relapsed/refractory B-cell malignancies. In consideration of their complexity, the use of CAR-T requires dedicated clinical setting and health care practitioners with expertise in the selection, treatment, and management of toxicities and side effects. Such issue appears particularly important when contextualized in the rapid progress of CAR-T cell treatment, translating into a constant need of updating and evolution. Moreover, the clinical grade manufacturing of CAR-T cells is complex and implies articulated regulatory and organizational aspects. The main goal of this review is to summarize and provide an accurate analysis of the clinical, logistic, and regulatory requirements of CAR-T cell centers. Finally, we describe a new occupational figure called "CAR-T specialist" devoted to the establishment and coordination of the required facilities and regulatory landscape in the context of cancer centers.
Abstract Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12–15 months, despite current best treatment based on surgery, ...radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the blood–brain barrier (BBB). As intracerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. This review summarizes the results of the extensive clinical research conducted on intracerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and convection-enhanced delivery (CED) represent the main techniques for intracerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intracerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel® , are the only FDA-approved treatment for intracerebral chemotherapy of MG, but intracavitary delivery of mitoxantrone and radiolabeled antitenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like backflow, are yet to be properly addressed and contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid™ in patients with recurrent GBM.
Diagnoses of primary malignant mesenchymal brain tumors are a challenge for pathologists. Here, we report the case of a 52-year-old man with a primary brain tumor, histologically diagnosed as a ...high-grade glioma, not otherwise specified (NOS). The patient underwent two neurosurgeries in several months, followed by radiotherapy and chemotherapy. We re-examined the tumor samples by methylome profiling. Methylome analysis revealed an epi-signature typical of a primary intracranial sarcoma,
-mutant, an extremely rare tumor. The diagnosis was confirmed by DNA sequencing that revealed a mutation in
exon 25.
mutations were not found in the patient's blood cells, thus excluding an inherited
syndrome. The methylome profile of the
mutant sarcoma was then compared with that of a high-grade glioma, a morphologically similar tumor type. We found that several relevant regions were differentially methylated. Taken together, we report the morphological, epigenetic, and genetic characterization of the sixth described case of an adult primary intracranial sarcoma,
-mutant to-date. Furthermore, this case report underscores the importance of methylome analysis to refine primary brain tumor diagnosis and to avoid misdiagnosis among morphologically similar subtypes.
Sunitinib is the most commonly prescribed drug for advanced renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on-and off-target ...effects, including hand and foot syndrome and fatigue. It was hypothesized that sunitinib-induced fatigue may be related to off target inhibition of the AMPK enzyme, which results in impairment of energy-producing processes at a systemic level. Quercetin is a naturally occurring flavonol with established AMPK-stimulating activity. While clinical use of quercetin is limited by its poor bio-availability, quercetin-3-O-β-d-glucopyranoside, that is isoquercetin, has an improved pharmacokinetic profile. On the grounds of the
stimulatory activity with respect to AMPk, we hypothesized that oral isoquercetin could improve fatigue in kidney cancer patients receiving sunitinib. Given the lack of data on the safety of isoquercetin given concomitantly with sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day). In the 12-patient study cohort included in this study, isoquercetin was administered concomitantly with 50 mg sunitinib for a median 81 days (IQR, 75.5, 86.5). None of the 12 patients required isoquercetin suspension or isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT fatigue score (6.8 points; 95% CI: 2.8-10.8;
= 0.002) and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1-28.8;
< 0.001) after isoquercetin consumption vs. baseline. In this phase I trial, isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events.
Glioblastoma is the most frequent and aggressive brain cancer in adults. While precision medicine in oncology has produced remarkable progress in several malignancies, treatment of glioblastoma has ...still limited available options and a dismal prognosis. After first-line treatment with surgery followed by radiochemotherapy based on the 2005 STUPP trial, no significant therapeutic advancements have been registered. While waiting that genomic characterization moves from a prognostic/predictive value into therapeutic applications, practical and easy-to-use approaches are eagerly awaited. Medical reports on the role of the ketogenic diet in adult neurological disorders and in glioblastoma suggest that nutritional interventions may condition outcomes and be associated with standard therapies. The acceptable macronutrient distribution of daily calories in a regular diet are 45–65% of daily calories from carbohydrates, 20–35% from fats, and 10–35% from protein. Basically, the ketogenic diet follows an approach based on low carbohydrates/high fat intake. In carbohydrates starvation, body energy derives from fat storage which is used to produce ketones and act as glucose surrogates. The ketogenic diet has several effects: metabolic interference with glucose and insulin and IGF-1 pathways, influence on neurotransmission, reduction of oxidative stress and inflammation, direct effect on gene expression through epigenetic mechanisms. Apart from these central effects working at the synapsis level, recent evidence also suggests a role for microbiome and gut-brain axis induced by a ketogenic diet. This review focuses on rationales supporting the ketogenic diet and clinical studies will be reported, looking at future possible perspectives.
To assess the efficacy and safety of alternative fotemustine administration schedule in elderly patients with recurrent glioblastoma.
Patients aged >65 years with recurrent glioblastoma received ...fotemustine (80 mg/m
; days 1, 15, 30, 45 and 60, and subsequently every 4 weeks). Primary end point was progression-free survival (PFS) rate at 6 months. Main secondary end point was safety.
58 patients were enrolled at two centers. PFS at 6 months was 47% (27 patients) and overall response rate was 29%. Median PFS and survival were 6 and 7 months, respectively, and longer in responders versus nonresponders. No grade 3–4 hematological toxicities occurred.
The alternative fotemustine administration schedule was an effective and safe treatment for recurrent glioblastoma in elderly patients.
Both docetaxel and androgen-receptor-axis-targeted (ARAT) agents are approved in metastatic castration-sensitive prostate cancer (mCSPC) patients. Predictive factors of therapy efficacy are lacking.
...We included articles reporting data about randomized-controlled clinical trials (RCTs) testing an ARAT agent plus ADT vs. ADT. We aimed to obtain pooled estimates of efficacy outcomes and assess differences in pooled estimates of efficacy outcomes between sub-groups.
A total of 5427 mCSPC patients enrolled in five RCTs were evaluable for OS (Overall Survival) and PFS (Progression-free survival). Pooled OS-HR (Hazard Ratio) was 0.66 (95 % CI: 0.60−0.74), while pooled PFS-HR was 0.46 (95 % CI: 0.40−0.53). Combined treatment with docetaxel was associated with differential OS outcomes, while tumor volume according to the CHAARTED criteria and visceral metastasis were associated with differential PFS outcomes.
Our results add evidence that ARAT agents improve OS in mCSPC and discourage their combined use with docetaxel in this setting.
Study Type – Therapy (case series)
Level of Evidence 4
What's known on the subject? and What does the study add?
Metastatic or locally advanced squamous cell carcinoma of the penis (SCCP) is ...generally incurable, but it can be palliated with systemic chemotherapy. Two retrospective studies, involving <10 patients each, showed that cisplatin plus continuous infusion of 5‐fluorouracil (5‐FU) may be effective and well tolerated. Cisplatin, methotrexate and bleomycin, cisplatin and irinotecan and taxanes can also play an important role for patients with locally advanced/metastatic SCCP. Finally, anti‐EGFR therapy may also be effective in advanced SCCP.
Although cisplatin plus continuous infusion of 5‐FU is widely used in clinical practice for palliation of SCCP, toxicity and efficacy data regarding this schedule include a total of 14 patients with SCCP, treated more than two decades ago. In our retrospective study, cisplatin plus continuous infusion of 5‐FU was used for palliative purposes in a homogenous sample of 25 patients with SCCP. Partial responses and stable disease were observed in 8 (32%) and 10 (40%) patients, respectively, with a median progression‐free survival of 20 weeks. Neutropenia was the most important grade 3–4 side effect observed, occurring in 20% of patients. These data provide confirmation that such a combination regimen is moderately effective and well tolerated in patients with SCCP.
OBJECTIVE
•
To investigate the activity and toxicity of 5‐fluorouracil (5‐FU) as a first‐line treatment in metastatic squamous cell carcinoma of the penis (SCCP).
METHODS
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The medical records of 78 patients with SCCP treated between January 2000 and June 2011 at the four participating centres were reviewed.
•
Data regarding patients treated with first‐line 5‐FU were extracted.
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Patients were included in the study if radiological reports were available for determination of response and progression‐free survival (PFS) according to response evaluation criteria in solid tumours (RECIST) 1.1.
RESULTS
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Between January 2000 and June 2011, 25 patients were treated with i.v. cisplatin on day 1 followed by 5‐FU as a continuous 24‐h infusion for 4 days every 3 weeks until disease progression or unacceptable toxicity. Partial responses and stable disease were observed in eight (32%) and 10 (40%) patients, respectively, with a disease control rate of 72%.
•
Severe neutropenia was the most important grade 3–4 side effect observed, occurring in 20% of patients.
•
The median (interquartile range IQR) PFS was 20 (11–20) weeks and the median (IQR) overall survival (OS) was 8 (7–12) months.
CONCLUSION
•
5‐FU is associated with a moderate response rate and is well tolerated in patients with metastatic SCCP.
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