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Molecular Cancer Therapeutics Dec 2023Integrin beta-6, a component of the heterodimeric adhesion receptor alpha-v/beta-6, is overexpressed in numerous solid tumors. Its expression has been shown by multiple...
Integrin beta-6, a component of the heterodimeric adhesion receptor alpha-v/beta-6, is overexpressed in numerous solid tumors. Its expression has been shown by multiple investigators to be a negative prognostic indicator in diverse cancers including colorectal, non-small cell lung, gastric, and cervical. We developed SGN-B6A as an antibody-drug conjugate (ADC) directed to integrin beta-6 to deliver the clinically validated payload monomethyl auristatin E (MMAE) to cancer cells. The antibody component of SGN-B6A is specific for integrin beta-6 and does not bind other alpha-v family members. In preclinical studies, this ADC has demonstrated activity in vivo in models derived from non-small cell lung, pancreatic, pharyngeal, and bladder carcinomas spanning a range of antigen expression levels. In nonclinical toxicology studies in cynomolgus monkeys, doses of up to 5 mg/kg weekly for four doses or 6 mg/kg every 3 weeks for two doses were tolerated. Hematologic toxicities typical of MMAE ADCs were dose limiting, and no significant target-mediated toxicity was observed. A phase I first-in-human study is in progress to evaluate the safety and antitumor activity of SGN-B6A in a variety of solid tumors known to express integrin beta-6 (NCT04389632).
Topics: Humans; Immunoconjugates; Antineoplastic Agents; Prognosis; Integrins; Carcinoma; Cell Line, Tumor
PubMed: 37619980
DOI: 10.1158/1535-7163.MCT-22-0817 -
Cureus Apr 2024During the COVID-19 pandemic, excess deaths including cancer have become a concern in Japan, which has a rapidly aging population. Thus, this study aimed to evaluate...
During the COVID-19 pandemic, excess deaths including cancer have become a concern in Japan, which has a rapidly aging population. Thus, this study aimed to evaluate how age-adjusted mortality rates (AMRs) for different types of cancer in Japan changed during the COVID-19 pandemic (2020-2022). Official statistics from Japan were used to compare observed annual and monthly AMRs with predicted rates based on pre-pandemic (2010-2019) figures using logistic regression analysis. No significant excess mortality was observed during the first year of the pandemic (2020). However, some excess cancer mortalities were observed in 2021 after mass vaccination with the first and second vaccine doses, and significant excess mortalities were observed for all cancers and some specific types of cancer (including ovarian cancer, leukemia, prostate cancer, lip/oral/pharyngeal cancer, pancreatic cancer, and breast cancer) after mass vaccination with the third dose in 2022. AMRs for the four cancers with the most deaths (lung, colorectal, stomach, and liver) showed a decreasing trend until the first year of the pandemic in 2020, but the rate of decrease slowed in 2021 and 2022. This study discusses possible explanations for these increases in age-adjusted cancer mortality rates.
PubMed: 38721172
DOI: 10.7759/cureus.57860 -
The Lancet. Oncology May 2024Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of... (Randomized Controlled Trial)
Randomized Controlled Trial
Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.
BACKGROUND
Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC.
METHODS
In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting.
FINDINGS
Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis).
INTERPRETATION
Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches.
FUNDING
Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
Topics: Humans; Antibodies, Monoclonal, Humanized; Double-Blind Method; Chemoradiotherapy; Male; Squamous Cell Carcinoma of Head and Neck; Female; Middle Aged; Aged; Head and Neck Neoplasms; Antineoplastic Agents, Immunological; Progression-Free Survival; Adult
PubMed: 38561010
DOI: 10.1016/S1470-2045(24)00100-1 -
Medical Archives (Sarajevo, Bosnia and... 2024Chordoma is a rare malignant neoplasm that predominantly arises from the axial skeleton, but can also develop in unusual locations. However, there are also rare cases of...
BACKGROUND
Chordoma is a rare malignant neoplasm that predominantly arises from the axial skeleton, but can also develop in unusual locations. However, there are also rare cases of "NOS" chordoma involving the oropharyx and epithelial-myoepithelial carcinoma of the parotid gland in the same patient. According to contemporary research, chordoma is a rare malignant neoplasm that arises from the embryonic remnants of the notochord. and typically involves the clivus, sacrococcygeal bones or vertebrae. Studies have shown that the incidence of chordoma has been estimated to be one per one million people per year. Chordoma can occur at any age, but most commonly it is diagnosed in the 40-60 year old age group with the male predominance.
OBJECTIVE
The aim of this article was to review the case of a 74-year-old female patient with epithelial-myoepithelial carcinoma of the parotid gland and a case of "NOS" chordoma involving the oropharyx.
METHODS
Diagnostic methods were used to examine a female patient with two primary malignant tumors: CT neck scan, CT of paranasal sinuses, ultrasound examination, scintigraphy and operative finding.
CASE PRESENTZATION
Due to the anatomy complexity, complete resection of the tumor through a transoral-transpharyngeal approach was not possible. Intraoperative palpation of the mass revealed well defined submucosal lesion 20x43x46mm beginning at the level of the oro- and hypopharynx and extending superiorly to the nasopharynx, and posteriorly into the spinal canal and intervertebral foramen causing near complete occlusion of the oro and hypopharynx. The patient also underwent extracapsular dissection of the parotid tumor. Postoperative palliative radiotherapy was performed.
CONCLUSION
Surgical treatment remains the mainstay of treatment for EMC and radiation is imperative for patients who refuse surgery and for those with advanced or inoperable diseases.
Topics: Humans; Male; Female; Aged; Adult; Middle Aged; Chordoma; Oropharynx; Spine; Carcinoma
PubMed: 38481587
DOI: 10.5455/medarh.2024.78.68-70