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The Oncologist Dec 2023Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer...
BACKGROUND
Preclinical models suggest synergy between anti-angiogenesis therapy, mammalian target of rapamycin (mTOR), and histone deacetylase inhibitors to promote anticancer activity.
METHODS
This phase I study enrolled 47 patients between April 2012 and 2018 and determined safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) when combining bevacizumab, temsirolimus, and valproic acid in patients with advanced cancer.
RESULTS
Median age of enrolled patients was 56 years. Patients were heavily pretreated with a median of 4 lines of prior therapy. Forty-five patients (95.7%) experienced one or more treatment-related adverse events (TRAEs). Grade 3 TRAEs were lymphopenia (14.9%), thrombocytopenia (8.5%), and mucositis (6.4%). Grade 4 TRAEs included lymphopenia (2.1%) and CNS cerebrovascular ischemia (2.1%). Six patients developed DLTs across 10 dose levels with grade 3 infection, rash, mucositis, bowel perforation, elevated lipase, and grade 4 cerebrovascular ischemia. The MTD was dose level 9 (bevacizumab 5 mg/kg days 1 and 15 intravenously (IV) plus temsirolimus 25 mg days 1, 8, 15, and 22 IV and valproic acid 5 mg/kg on days 1-7 and 15-21 per orally (PO)). Objective response rate (ORR) was 7.9% with confirmed partial response (PRs) in 3 patients (one each in parotid gland, ovarian, and vaginal cancers). Stable disease (SD) ≥+6 months was seen in 5 patients (13.1%). Clinical benefit state (CBR: PR + SD ≥+6 months) was 21%.
CONCLUSION
Combination therapy with bevacizumab, temsirolimus, and valproic acid was feasible, but there were numerous toxicities, which will require careful management for future clinical development (ClinicalTrials.gov Identifier: NCT01552434).
Topics: Female; Humans; Middle Aged; Bevacizumab; Valproic Acid; Mucositis; Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Thrombocytopenia; Lymphopenia; Ischemia; Maximum Tolerated Dose
PubMed: 37311055
DOI: 10.1093/oncolo/oyad158 -
Molecules (Basel, Switzerland) Sep 2023Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer and has a poor prognosis. As standardized TNBC treatment regimens cause drug resistance...
Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer and has a poor prognosis. As standardized TNBC treatment regimens cause drug resistance and tumor recurrence, the development of new TNBC treatment strategies is urgently required. Bufotalin is a bufadienolide isolated from the skin and parotid venom glands of the toad , and has several pharmacological properties, including antiviral, anti-inflammatory, and anticancer activities. However, the anticancer effect and underlying molecular mechanisms of action of bufotalin in TNBC have not been fully studied. In the current study, we investigated the effects of bufotalin on the growth and metastasis of MDA-MB-231 and HCC1937 TNBC cells. Bufotalin potently inhibited the proliferation of both TNBC cell lines by promoting cell cycle arrest and caspase-mediated apoptosis. Furthermore, bufotalin effectively suppressed the migration and invasion of both TNBC cell lines by regulating the expression of key epithelial-mesenchymal transition (EMT) biomarkers, matrix metalloproteinases (MMPs), and integrin α6. Notably, the anticancer effect of bufotalin in TNBC cells was associated with the downregulation of the signal transducer and activator of the transcription 3 (STAT3) signaling pathway. Collectively, our results suggest that the natural compound bufotalin may exert antiproliferative and antimetastatic activities in TNBC cells by modulating the apoptotic pathway and the STAT3/EMT axis.
Topics: Humans; Triple Negative Breast Neoplasms; Epithelial-Mesenchymal Transition; Neoplasm Recurrence, Local; Apoptosis; Bufanolides; Cell Proliferation; Cell Line, Tumor; Cell Movement; STAT3 Transcription Factor
PubMed: 37836626
DOI: 10.3390/molecules28196783 -
JAMA Otolaryngology-- Head & Neck... Feb 2024Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence.
IMPORTANCE
Postoperative radiation therapy for close surgical margins in low- to intermediate-grade salivary carcinomas lacks multi-institutional supportive evidence.
OBJECTIVE
To evaluate the oncologic outcomes for low- and intermediate-grade salivary carcinomas with close and positive margins.
DESIGN, SETTING, AND PARTICIPANTS
The American Head and Neck Society Salivary Gland Section conducted a retrospective cohort study from 2010 to 2019 at 41 centers. Margins were classified as R0 (negative), R1 (microscopically positive), or R2 (macroscopically positive). R0 margins were subclassified into clear (>1 mm) or close (≤1 mm). Data analysis was performed from June to October 2023.
MAIN OUTCOMES AND MEASURES
Main outcomes were risk factors for local recurrence.
RESULTS
A total of 865 patients (median [IQR] age at surgery, 56 [43-66] years; 553 female individuals [64%] and 312 male individuals [36%]) were included. Of these, 801 (93%) had parotid carcinoma and 64 (7%) had submandibular gland carcinoma, and 748 (86%) had low-grade tumors and 117 (14%) had intermediate-grade tumors, with the following surgical margins: R0 in 673 (78%), R1 in 168 (19%), and R2 in 24 (3%). Close margins were found in 395 of 499 patients with R0 margins (79%), for whom margin distances were measured. A total of 305 patients (35%) underwent postoperative radiation therapy. Of all 865 patients, 35 (4%) had local recurrence with a median (IQR) follow-up of 35.3 (13.9-59.1) months. In patients with close margins as the sole risk factor for recurrence, the local recurrence rates were similar between those who underwent postoperative radiation therapy (0 of 46) or observation (4 of 165 [2%]). Patients with clear margins (n = 104) had no recurrences. The local recurrence rate in patients with R1 or R2 margins was better in those irradiated (2 of 128 [2%]) compared to observed (13 of 64 [20%]) (hazard ratio [HR], 0.05; 95% CI, 0.01-0.24). Multivariable analysis for local recurrence found the following independent factors: age at diagnosis (HR for a 10-year increase in age, 1.33; 95% CI, 1.06-1.67), R1 vs R0 (HR, 5.21; 95% CI, 2.58-10.54), lymphovascular invasion (HR, 4.47; 95% CI, 1.43-13.99), and postoperative radiation therapy (HR, 0.10; 95% CI, 0.04-0.29). The 3-year local recurrence-free survivals for the study population were 96% vs 97% in the close margin group.
CONCLUSIONS AND RELEVANCE
In this cohort study of patients with low- and intermediate-grade major salivary gland carcinoma, postoperative radiation therapy for positive margins was associated with decreased risk of local recurrence. In isolation from other risk factors for local recurrence, select patients with close surgical margins (≤1 mm) may safely be considered for observation.
Topics: Humans; Male; Female; Infant; Adult; Middle Aged; Aged; Retrospective Studies; Cohort Studies; Margins of Excision; Carcinoma; Salivary Gland Neoplasms
PubMed: 38095911
DOI: 10.1001/jamaoto.2023.3952 -
Auris, Nasus, Larynx Dec 2023Sialocele that develops after parotid surgery often prolongs the treatment period and stresses both the surgeon and patient. The extent of surgery and tumor size are...
OBJECTIVE
Sialocele that develops after parotid surgery often prolongs the treatment period and stresses both the surgeon and patient. The extent of surgery and tumor size are known to be associated with sialocele occurrence. We investigated the incidence of post-parotidectomy sialocele and the associated risk factors, with a focus on tumor size.
METHODS
We retrospectively reviewed the medical records of 172 patients who underwent parotidectomy between January 2013 and May 2020 at Haeundae Paik Hospital, Inje University of Korea. We stratified patients into those with and without sialocele (fluid collection in the operative bed). We compared clinical data, patient demographics, and surgical details; we identified risk factors for sialocele development after parotid surgery.
RESULTS
Seventeen patients were diagnosed with post-parotidectomy sialocele (9.88%; 17/172). Univariate logistic regression revealed that the male sex, deep lobe tumor location, and large tumor size were significantly associated with postoperative sialocele (p = 0.015, 0.009, and 0.016, respectively). We subjected these parameters to multivariate analyses; the odds ratios were 3.70, 3.58, and 2.34, respectively. Receiver operating characteristic curve analyses showed that a tumor size > 2.50 cm was the optimal cutoff in terms of predicting post-parotidectomy sialocele.
CONCLUSION
Male sex, a tumor in the deep lobe, and large tumor size were strongly associated with increased risk for sialocele after parotidectomy. Tumor size > 2.50 cm serves as the cutoff identifying patients likely to experience sialocele after parotid surgery.
Topics: Humans; Male; Parotid Neoplasms; Retrospective Studies; Parotid Gland; Cysts; Risk Factors; Salivary Gland Diseases; Postoperative Complications
PubMed: 36922283
DOI: 10.1016/j.anl.2023.02.006 -
La Radiologia Medica Dec 2023Taste alteration (TA) is a frequent acute side effect of radiation treatment in HNSCC patients. Principal aim of our study was to investigate dosimetric parameters in... (Observational Study)
Observational Study
PURPOSE
Taste alteration (TA) is a frequent acute side effect of radiation treatment in HNSCC patients. Principal aim of our study was to investigate dosimetric parameters in relation to patient-assessed taste impairment in a prospective cohort treated with intensity-modulated radiotherapy.
METHODS
All patients with locally advanced HNSCC and amenable to radical treatment were included. Chemotherapy-induced taste alteration scale (CITAS), EORTC QLQ-C30 and QLQ-HN43 questionnaires at baseline (T0), 3 weeks (T1) and 3 months (T2) after radiotherapy conclusion were used to assess taste impairment. Base of tongue, submandibular glands (SG), parotid glands (PG) and taste buds, along with anterior and medium third of the tongue, were considered as organs at risk and thus delineated according to consensus guidelines. The mean dose to the above-mentioned structures was correlated with patient-reported outcomes.
RESULTS
Between September 2019 and November 2020, 33 patients were recruited, 31 of which analyzed. 71% had oropharyngeal carcinoma, mostly HPV-related (60%). All were treated with tomotherapy. 77.4% had concurrent cisplatin. Mean scores of general taste alterations, global health status and dry mouth and sticky saliva were assessed. The mean doses to the anterior third, medium third and base of the tongue were 23.85, 35.50 and 47.67 Gy, respectively. Taste buds received 32.72 Gy; right and left parotid 25 and 23 Gy; right and left submandibular glands 47.8 and 39.4 Gy. At univariate analysis, dysgeusia correlated with SG mean dose (95% CI 0-0.02 p = 0.05) and PG mean dose (95% CI 0-0.02 p = 0.05); dry mouth with mean dose to anterior (95% CI 0.03-1.47 p = 0.04) and medium third (95% CI 0.02-0.93 p = 0.04) of the tongue, to taste buds (95% CI 0.06-0.96 p = 0.03) and to SGs (95% CI 0.06-0.63 p = 0.02); pain mouth with mean dose to taste buds (95% CI 0-0.02 p = 0.04), to SGs (95% CI 0-0.03 p = 0.03) and to base tongue (95% CI 0-0.02 p = 0.02).
CONCLUSIONS
Our analysis supports the influence of dose distribution on the development of TA in HNSCC patients. The contribution of dose to taste buds and tongue subvolumes remains unclear and worthy of further investigation.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Prospective Studies; Dysgeusia; Taste; Head and Neck Neoplasms; Xerostomia; Radiotherapy, Intensity-Modulated; Radiation Dosage; Neoplasms, Squamous Cell; Radiotherapy Dosage
PubMed: 37642816
DOI: 10.1007/s11547-023-01707-5 -
Haemophilia : the Official Journal of... Mar 2024Valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe...
INTRODUCTION
Valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection.
AIM
To assess safety and efficacy of valoctocogene roxaparvovec 5-6 years post-treatment.
METHODS
In a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6 × 10 vg/kg; n = 7) and 5 (4 × 10 vg/kg; n = 6) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported.
RESULTS
No new treatment-related safety signals emerged. During year 6, a participant in the 6 × 10 vg/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25 × 10 per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration-containing cells occurred. During all follow-ups, >90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8 IU/dL (median, 5.6 IU/dL) and 7.6 IU/dL (median, 7.1 IU/dL) for the 6 × 10 and 4 × 10 vg/kg cohorts, respectively, representing proportionally smaller year-over-year declines than earlier timepoints.
CONCLUSIONS
Valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.
Topics: Adult; Humans; Male; Hemophilia A; Factor VIII; Hemorrhage; Hemostatics; Neoplasms; Dependovirus; Recombinant Fusion Proteins
PubMed: 38317480
DOI: 10.1111/hae.14936 -
Phytomedicine : International Journal... May 2024Colorectal cancer (CRC) is one of the commonest cancers worldwide. Metastasis is the most common cause of death in patients with CRC. Arenobufagin is an active component...
BACKGROUND
Colorectal cancer (CRC) is one of the commonest cancers worldwide. Metastasis is the most common cause of death in patients with CRC. Arenobufagin is an active component of bufadienolides, extracted from toad skin and parotid venom. Arenobufagin reportedly inhibits epithelial-to-mesenchymal transition (EMT) and metastasis in various cancers. However, the mechanism through which arenobufagin inhibits CRC metastasis remains unclear.
PURPOSE
This study aimed to elucidate the molecular mechanisms by which arenobufagin inhibits CRC metastasis.
METHODS
Wound-healing and transwell assays were used to assess the migration and invasion of CRC cells. The expression of nuclear factor erythroid-2-related factor 2 (Nrf2) in the CRC tissues was assessed using immunohistochemistry. The protein expression levels of c-MYC and Nrf2 were detected by immunoblotting. A mouse model of lung metastasis was used to study the effects of arenobufagin on CRC lung metastasis in vivo.
RESULTS
Arenobufagin observably inhibited the migration and invasion of CRC cells by downregulating c-MYC and inactivating the Nrf2 signaling pathway. Pretreatment with the Nrf2 inhibitor brusatol markedly enhanced arenobufagin-mediated inhibition of migration and invasion, whereas pretreatment with the Nrf2 agonist tert‑butylhydroquinone significantly attenuated arenobufagin-mediated inhibition of migration and invasion of CRC cells. Furthermore, Nrf2 knockdown with short hairpin RNA enhanced the arenobufagin-induced inhibition of the migration and invasion of CRC cells. Importantly, c-MYC acts as an upstream modulator of Nrf2 in CRC cells. c-MYC knockdown markedly enhanced arenobufagin-mediated inhibition of the Nrf2 signaling pathway, cell migration, and invasion. Arenobufagin inhibited CRC lung metastasis in vivo. Together, these findings provide evidence that interruption of the c-MYC/Nrf2 signaling pathway is crucial for arenobufagin-inhibited cell metastasis in CRC.
CONCLUSIONS
Collectively, our findings show that arenobufagin could be used as a potential anticancer agent against CRC metastasis. The arenobufagin-targeted c-MYC/Nrf2 signaling pathway may be a novel chemotherapeutic strategy for treating CRC.
Topics: Animals; Mice; Humans; NF-E2-Related Factor 2; Colorectal Neoplasms; Cell Line, Tumor; Bufanolides; Lung Neoplasms; Epithelial-Mesenchymal Transition; Cell Movement; Gene Expression Regulation, Neoplastic; Cell Proliferation; Neoplasm Metastasis
PubMed: 38452690
DOI: 10.1016/j.phymed.2024.155391 -
Current Medical Imaging Aug 2023Sebaceous lymphadenoma is a rare parotid gland neoplasm. Up to now, there have been several studies that have discussed the imaging manifestations of salivary sebaceous...
INTRODUCTION/BACKGROUND
Sebaceous lymphadenoma is a rare parotid gland neoplasm. Up to now, there have been several studies that have discussed the imaging manifestations of salivary sebaceous lymphadenoma. In this paper, we have reported a case of multiple parotid sebaceous lymphadenoma demonstrated by ultrasound, CT scan, and MRI examinations, including diffusion-weighted imaging. To the best of our knowledge, this report is the first one on DWI findings of sebaceous lymphadenomas, and also the first report on multiple lesions in unilateral parotid gland.
CASE PRESENTATION
A 41-year-old woman presented with a nodule in the left parotid region. The lesion has grown slowly for 2 months and was not associated with any discomfort. Ultrasound, CT scan, and MRI examinations, including diffusion-weighted imaging, showed multiple nodules in the left parotid gland of a 41-year-old woman. These nodules were heterogeneous on CT scan and MRI examinations, and intratumorally multifocal fat and cystic areas were detected. On ultrasound examination images, these lesions were heterogeneous hypoechoic echotexture with multifocal irregular hyperechogenic areas, without significant blood flow. The patient underwent a left parotidectomy. Histopathologic sections showed nests of sebocytes distributed in lymphoid follicles and lymphocyte background, with obvious cystic changes. The patient recovered after receiving left parotidectomy. The microscopy diagnosis was parotid sebaceous lymphadenoma.
CONCLUSION
This case highlights the main imaging feature of parotid sebaceous lymphadenomas, namely an intraparotid heterogeneous nodule containing multifocal fat and cystic areas, and its possible origination from an intraparotid lymph node. This case also indicates that this rare lesion may occur at multiple sites.
PubMed: 37622554
DOI: 10.2174/1573405620666230825113417 -
European Journal of Nuclear Medicine... Aug 2023We aimed to compare the diagnostic performance and biodistribution of two similar PET agents, [Ga]Ga-P16-093 and [Ga]Ga-PSMA-11, in the same group of primary prostate... (Clinical Trial)
Clinical Trial
PURPOSE
We aimed to compare the diagnostic performance and biodistribution of two similar PET agents, [Ga]Ga-P16-093 and [Ga]Ga-PSMA-11, in the same group of primary prostate cancer (PCa) patients.
METHODS
Fifty patients with untreated, histologically confirmed PCa by needle biopsy were enrolled. Each patient underwent [Ga]Ga-P16-093 and [Ga]Ga-PSMA-11 PET/CT within a week. In addition to visual analysis, the standardized uptake value (SUV) was measured for semiquantitative comparison and correlation analysis.
RESULTS
[Ga]Ga-P16-093 PET/CT detected more positive tumors than [Ga]Ga-PSMA-11 PET/CT (202 vs. 190, P = 0.002), both for intraprostatic lesions (48 vs. 41, P = 0.016) and metastatic lesions (154 vs. 149, P = 0.125), especially for intraprostatic lesions in low- and intermediate-risk PCa patients (21/23 vs. 15/23, P = 0.031). Furthermore, [Ga]Ga-P16-093 PET/CT exhibited a significantly higher SUVmax for most matched tumors (13.7 ± 10.2 vs. 11.4 ± 8.3, P < 0.001). For normal organs, [Ga]Ga-P16-093 PET/CT showed significantly lower activity in the kidney (SUVmean: 20.1 ± 6.1 vs. 29.3 ± 9.1, P < 0.001) and urinary bladder (SUVmean: 6.5 ± 7.1 vs. 20.9 ± 17.4, P < 0.001), but displayed a higher uptake in the parotid gland (SUVmean: 8.7 ± 2.6 vs. 7.6 ± 2.1, P < 0.001), liver (SUVmean: 7.0 ± 1.9 vs. 3.7 ± 1.3, P < 0.001), and spleen (SUVmean: 8.2 ± 3.0 vs. 5.2 ± 2.2, P < 0.001) than [Ga]Ga-PSMA-11 PET/CT.
CONCLUSION
[Ga]Ga-P16-093 PET/CT demonstrated higher tumor uptake and better tumor detectability than [Ga]Ga-PSMA-11 PET/CT, especially in low- and intermediate-risk PCa patients, which indicated that [Ga]Ga-P16-093 may serve as an alternative agent for detection of PCa.
TRIAL REGISTRATION
Ga-P16-093 and Ga-PSMA-11 PET/CT Imaging in the Same Group of Primary Prostate Cancer Patients (NCT05324332, Registered 12 April 2022, retrospectively registered). URL OF REGISTRY: https://clinicaltrials.gov/ct2/show/NCT05324332 .
Topics: Humans; Male; Edetic Acid; Gallium Radioisotopes; Positron Emission Tomography Computed Tomography; Prospective Studies; Prostatic Neoplasms; Tissue Distribution
PubMed: 37233785
DOI: 10.1007/s00259-023-06283-4 -
Current Opinion in Otolaryngology &... Apr 2024This review critically assesses the current literature and guidelines, aiming to clarify some of the most important factors that impact surgical strategies of head and... (Review)
Review
PURPOSE OF REVIEW
This review critically assesses the current literature and guidelines, aiming to clarify some of the most important factors that impact surgical strategies of head and neck nonmelanoma skin cancers (NMSCs), focusing on squamous, basal, and Merkel cell carcinomas.
RECENT FINDINGS
Recent developments underscore the complexity of treatment for NMSC, particularly in the head and neck region. There is a lack of high-level evidence for the management of these tumors, especially in advanced stages. The need to tailor the extent of surgical margins and parotid/neck management to different histotypes, considering the varying risk factors for recurrence, is beginning to emerge in the literature. Moreover, the role of immunotherapy and targeted therapies for locally advanced disease, alongside traditional treatment options, is progressively growing.
SUMMARY
NMSCs represent a heterogeneous group of malignancies with varying treatment complexities and prognoses. Management of NMSC is evolving towards an increasingly personalized strategy within a multidisciplinary therapeutic framework.
Topics: Humans; Carcinoma, Basal Cell; Skin Neoplasms; Prognosis; Head and Neck Neoplasms; Immunotherapy
PubMed: 38193646
DOI: 10.1097/MOO.0000000000000960