Anticancer treatment efficacy is limited by the development of refractory tumor cells characterized by increased expression and activity of mechanisms promoting survival, proliferation, and ...metastatic spread. The present review summarizes the current literature regarding the use of the anthelmintic mebendazole (MBZ) as a repurposed drug in oncology with a focus on cells resistant to approved therapies, including so called "cancer stem cells". Mebendazole meets many of the characteristics desirable for a repurposed drug: good and proven toxicity profile, pharmacokinetics allowing to reach therapeutic concentrations at disease site, ease of administration and low price. Several in vitro studies suggest that MBZ inhibits a wide range of factors involved in tumor progression such as tubulin polymerization, angiogenesis, pro-survival pathways, matrix metalloproteinases, and multi-drug resistance protein transporters. Mebendazole not only exhibits direct cytotoxic activity, but also synergizes with ionizing radiations and different chemotherapeutic agents and stimulates antitumoral immune response. In vivo, MBZ treatment as a single agent or in combination with chemotherapy led to the reduction or complete arrest of tumor growth, marked decrease of metastatic spread, and improvement of survival. Further investigations are warranted to confirm the clinical anti-neoplastic activity of MBZ and its safety in combination with other drugs in a clinical setting.
Adenoid cystic carcinoma (ACC) of salivary gland is a slowly growing tumor showing a propensity for delayed recurrence, with decreased survival rates. The identification of poor prognosis patients ...may help in defining molecular-based targeted strategies in this rare disease orphan of new treatments. Through a gene expression microarray-based approach followed by GSE functional analysis the expression profile of 46 primary untreated ACC samples and of ACC (h-TERT) tumor cells was analyzed. Patients who experienced early relapse showed enrichment in proliferation-related gene sets, including the G2-M checkpoint, E2F and myc targets, and in gene sets related to IFN signaling and aberrant proteostasis (FDR < 0.1), indicating increased mitotic and transcriptional activity in aggressive ACC. Similar functions were enriched in ACC samples classified by immunohistochemical staining as p63-negative, which exhibited increased protein burden and activation of pro-survival stress response pathways compared to p63-positive tumors. Compared to ACC tissues, ACC (h-TERT) cells share transcriptional features of aggressive p63-negative tumors. These data suggest association of specific pathway alterations with histopathological features of ACC, as recapitulated by p63 testing in patient prognostic stratification, anticipating new avenues for therapeutic intervention.
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F-fluciclovine (
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F-FACBC) is a radiotracer already studied for prostate cancer, and its potential role in brain tumors (such as glioma) is not yet well investigated despite promising results. ...The aim of this review is to evaluate the possible diagnostic role of
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F-FACBC PET/CT or PET/MRI in patients with gliomas and glioblastomas. A comprehensive literature search of the PubMed/MEDLINE, Scopus, Embase, and Cochrane library databases was conducted to find the relevant published articles about the diagnostic performance of FACBC PET/CT or PET/MRI in patients affected by glioma and/or glioblastoma. Seven papers were included in the systematic review. From the analyses of the selected studies, the following main findings were obtained: glioma and glioblastoma are FACBC-avid tumors with a detection rate of about 100%; FACBC PET has high-diagnostic accuracy in defining tumor extent, volumes, and satellite lesions better than MR; compared to methionine, FACBC has similar accuracy but better tumor-to-background contrast; FACBC uptake may help to discriminate between low-grade and high-grade glioma. Radiolabelled fluciclovine (
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F-FACBC) imaging seems to be useful in analyzing glioma/glioblastoma. Further studies enrolling a wider population are needed to clarify the real clinical and diagnostic role of
18
F-FACBC in this setting and its possible position in the diagnostic flowchart.
Adenoid cystic carcinoma (ACC) is a rare malignancy characterized by high incidence of relapse. When relapsing, ACC has an indolent but relentless behaviour, thus leading to a poor long-term ...prognosis. The treatment of choice of relapsing ACC remains surgery followed by radiotherapy, whenever feasible. Therapeutic weapons are limited to systemic drugs. The most widely used chemotherapy regimen is the combination of cisplatin and doxorubicin, however with low response rate and not long lasting; there is also a lack of alternatives for second line therapies in case of disease progression. Therefore, a more comprehensive strategy aimed at identifying at preclinical level the most promising drugs or combination is clearly needed. In this study, the cytotoxic effects of two standard chemotherapy drugs, cisplatin and doxorubicin, and of five targeted therapy-drugs was tested in vitro, on an h-TERT immortalized ACC cell line, and in vivo, on zebrafish embryos with ACC tumoral cell xenograft. Then, combinations of one standard chemotherapy drug plus one targeted therapy drug were also evaluated, in order to find the best treatment strategy for ACC. Data obtained demonstrated that both vorinostat and olaparib significantly increased the standard chemotherapy cytotoxic effects, suggesting new interesting therapeutic options for ACC.
Stereotactic radiosurgery (SRS) is an effective treatment option for multiple brain metastases (BMs). Modern mono-isocentric techniques allow the delivery of multiple stereotactic courses, in the ...event of intracranial failure. Nevertheless, limited data on effectiveness and toxicity have been reported in comparison to WBRT. Aim of this retrospective matched-pair analysis was to compare patients affected by limited BMs treated with multiple SRS courses using a mono-isocentric, non-coplanar technique (HyperArc™, Varian Medical System) to upfront WBRT. One hundred and two patients accounting for 677 BMs were treated with HyperArc™. In case of further intracranial progression, 44 treatment courses of 201 metastases in 19 patients, were treated by subsequent HyperArc™ courses. This population was matched with 38 patients treated with WBRT. The median BMs number was 4 (range 2–10) for HyperArc™ and 5 (range 2–10) for WBRT. Overall survival (OS) and toxicity were evaluated. The median follow-up was 9 months (range 3–40 months). The median OS was not reached (range 5–22 months) for HyperArc™ patients and 8 months (range 3–40 months) for WBRT patients, while the 1-year OS was 77% and 34.6% for HyperArc™ and WBRT, respectively (p = 0.001; HR 4.77, 95% CI 1.62–14.00). There was one case of radionecrosis. HyperArc™ is an effective and safe technique for the treatment of multiple BMs. In selected cases of intracranial oligorecurrence, further subsequent courses can be safely delivered with the same technical approach. Moreover, in patients with a limited number of BMs, SRS showed an improved survival outcome when compared to WBRT.
Purpose
Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) has been shown to increase survival rates in oligometastatic disease (OMD), but local control of colorectal ...metastases remains poor. We aimed to explore the natural course of oligometastatic colorectal cancer and to investigate how SBRT of lung metastases can delay the progression to polymetastatic disease (PMD).
Methods
107 lung oligometastases in 38 patients were treated with SBRT at a single institution. The median number of treated lesions was 2 (range 1–5). Time to PMD (ttPMD) was defined as the time from SBRT to the occurrence of >5 new metastases. Genetic biomarkers such as
EGFR, KRAS, NRAS, BRAF
, and microsatellite instability were investigated as predictive factors for response rates.
Results
Median follow-up was 28 months. At median follow-up, 7 patients were free from disease and 31 had progression: 18 patients had sequential oligometastatic disease (SOMD) and 13 polymetastatic progression. All SOMD cases received a second SBRT course. Median progression-free survival (PFS) was 7 months (range 4–9 months); median ttPMD was 25.8 months (range 12–39 months) with 1‑ and 2‑year PFS rates of 62.5% and 53.4%, respectively. 1‑ and 2‑year local PFS (LPFS) rates were 91.5% and 80%, respectively. At univariate analysis,
BRAF
wildtype correlated with better LPFS (
p
= 0.003), SOMD after primary SBRT was associated with longer cancer-specific survival (
p
= 0.031). Median overall survival (OS) was 39.5 months (range 26–64 months) and 2‑year OS was 71.1%.
Conclusion
The present results support local ablative treatment of lung metastases using SBRT in oligometastatic colorectal cancer patients, as it can delay the transition to PMD. Patients who progressed as SOMD maintained a survival advantage compared to those who developed PMD.
Purpose
To evaluate tolerance and biochemical control rates of salvage external beam radiotherapy (EBRT) in patients with local relapse from prostate cancer (PC) after high-intensity focused ...ultrasound (HIFU) as primary treatment.
Methods
Twenty-four patients presented biochemical failure of PC. Salvage EBRT to the residual prostate was performed with moderate hypofractionation schedule (MHRT) in 28 fractions (
n
= 16) or with extreme hypofractionation schedule (SBRT) in 5 fractions (
n
= 8) by means of image-guided volumetric modulation arc therapy. In case of MHRT, the median dose was 71.4 Gy, whereas in case of SBRT it was 32.5 Gy.
Results
The median follow-up was 28 months. The median PSA nadir was 0.26 ng/mL. In case of MHRT, the median PSA nadir was 0.15 ng/mL and occurred within a median time of 19 months. In case of SBRT, the median PSA nadir was 0.64 ng/mL and occurred within a median time of 8 months. No G3 higher acute or late toxicity after EBRT was observed. Only three patients presented with G2 acute GI toxicity (actinic proctitis). Twelve patients experienced acute G1 GU toxicity: 8/16 of men treated with MHRT and 4/8 of men treated with SBRT. Complete local control of disease was achieved in 23/24 patients (96%).
Conclusions
Our data confirm the feasibility and the low toxicity of salvage EBRT with both schedules of treatment after HIFU failure. The findings of low acute toxicity and good biochemical control rates are encouraging, but a larger number of patients and a longer follow-up are needed to confirm these results.
Objectives
Solitary plasmacytoma (SP) is characterized by a single mass of clonal plasma cells. Definitive RT can result in long-term local control of the SP. Due to the small number of patients and ...narrow range of doses, phase III randomized trials are lacking. The aim of this study is to further support the potential use of RT for the treatment of SP.
Methods
Clinical data of all patients treated for SP at our Institution between 1992 and 2018 were reviewed. A total of 42 consecutive patients were analyzed.
Results
The median follow-up was 84.8 months. Radiation dose did not differ significantly as a function of sex, type of SP (solitary bone plasmacytoma or as extramedullary plasmacytoma), tumor size; conversely differs significantly as a function of age (
p
= 0.04). The 5y-OS and 10y-OS were, respectively, 96 and 91%. Local recurrences developed in 21.4% of patients (9/42). 16 patients progressed to MM (38.1%). The 5y-progression to MM free survival (PMFS) and the 10y-PMFS were, respectively, 68.6 and 61.9%.
Conclusions
Our data confirm that good results are achievable with RT to treat SP, but they don’t allow defining a dose–effect correlation; therefore, it remains uncertain which is the most effective dose and whether lower doses can guarantee adequate disease control.
Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ...ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years; all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III–IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months; 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams’ grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches.
Purpose
To retrospectively review our 20 year experience of multidisciplinary management of non-metastatic ductal prostate cancer (dPC), a rare but aggressive histological subtype of prostate cancer ...whose optimal therapeutic approach is still controversial.
Methods
Histologically confirmed dPC patients undergoing primary, curative treatment radical prostatectomy (RP), external beam radiotherapy (EBRT), and androgen deprivation therapy (ADT) were included, and percentage of ductal and acinar pattern within prostate samples were derived. Survival outcomes were assessed using the subdistribution hazard ratio (SHR) and Fine-and-Gray model.
Results
From January 1997 to December 2016, 81 non-metastatic dPC fitted selection criteria. Compared to surgery alone, SHR for progression-free survival and cancer-specific mortality were 2.8 (95% CI 0.6–13.3) and 1.3 (95% CI 0.1–16.2) for exclusive EBRT, 2.7 (95% CI 0.6–13.0) and 6.5 (95% CI 0.6–69.8) for adjuvant EBRT, 4.9 (95% CI 0.7–35.5) and 5.8 (95% CI 0.5–65.6) for salvage EBRT post-prostatectomy recurrence, and 3.2 (95% CI 0.7–14.0) and 3.9 (95% CI 0.3–44.1) for primary ADT (
P
= 0.558;
P
= 0.181), respectively. Comparing multimodal treatment and monotherapy confirmed the above trends. Local recurrence more typically occurred in pure dPC patients, mixed histology more frequently produced metastatic spread (29.6% relapse in total,
P
= 0.026).
Conclusion
Albeit some limitations affected the study, our findings support the role of local treatment to achieve better disease control and improve quality of life. Different behavior, with typical local growth in pure dPC, higher distant metastatization in the mixed form, might influence treatment response. Given its poor prognosis, we recommend multidisciplinary management of dPC.
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