Conventional cancer treatments face the challenge of therapeutic resistance, which causes poor treatment outcomes. The use of combination therapies can improve treatment results in patients and is one of the solutions to overcome this challenge. Chemotherapy is one of the conventional treatments that, due to the non-targeted and lack of specificity in targeting cancer cells, can cause serious complications in the short and long-term for patients by damaging healthy cells. Also, the employment of a wide range of strategies for chemotherapy resistance by cancer cells, metastasis, and cancer recurrence create serious problems to achieve the desired results of chemotherapy. Accordingly, targeted therapies can be used as a combination treatment with chemotherapy to both cause less damage to healthy cells, which as a result, they reduce the side effects of chemotherapy, and by targeting the factors that cause therapeutic challenges, can improve the results of chemotherapy in patients. Small molecules are one of the main targeted therapies that can be used for diverse targets in cancer treatment due to their penetration ability and characteristics. However, small molecules in cancer treatment are facing obstacles that a better understanding of cancer biology, as well as the mechanisms and factors involved in chemotherapy resistance, can lead to the improvement of this type of major targeted therapy. In this review article, at first, the challenges that lead to not achieving the desired results in chemotherapy and how cancer cells can be resistant to chemotherapy are examined, and at the end, research areas are suggested that more focusing on them, can lead to the improvement of the results of using targeted small molecules as an adjunctive treatment for chemotherapy in the conditions of chemotherapy resistance and metastasis of cancer cells.
Background: As the ongoing public health crisis from Coronavirus Disease 2019 (COVID-19) pandemic puts strains on current models of cancer care, many health care centers had to adapt to minimize the risk of exposure and infection. The effects of the COVID-19 pandemic in a comprehensive cancer center were determined. Purpose: To measure the impact of the COVID-19 pandemic on care delivery at a comprehensive cancer center. Methods: The number of on-site and telehealth visits (TH) were obtained from scheduling software. Multiple factors including total visits, telehealth visits, screenings for cancer diagnosis, and cancer treatments were tracked from two years before the pandemic onset through 2022. The length of stay (LOS) and Case Mix Index (CMI) were calculated using hospital database. Results: In the third quarter of FY 2020, telehealth visits (TH) represented a fifth of total patient encounters. Cancer treatments, such as chemotherapy, radiation therapy, and surgery, decreased during the pandemic with number of surgeries being most affected (23% decrease in 2020 compared to the previous fiscal year). The average length of stay (LOS) was also longer with less discharges per given time during the pandemic. The increased LOS was related to increased severity of patient illnesses since CMI was higher. Screening mammograms decreased to a nadir of 58% in 2021 as compared to those screened in pre-pandemic fiscal years. Conclusions : The COVID-19 pandemic impacted many aspects of care, such as treatment and screenings. Many of these factors had to be postponed due to the fear of acquiring COVID-19 and access to care. The findings presented implicate that the delays and changes in cancer care during the pandemic resulted in less screening and treatment of more advanced disease.
Doxorubicin, a first-line anticancer drug for osteosarcoma treatment, has been the subject of recent research exploring the mechanisms behind its chemoresistance and its ability to enhance cell migration at sublethal concentrations. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase and zinc-dependent endopeptidase, is well-known for degrading the extracellular matrix and promoting cancer metastasis. Our previous work demonstrated that nuclear MMP-2 regulates ribosomal RNA transcription via histone clipping, thereby controlling gene expression. Additionally, MMP-2 activity is regulated by the non-receptor tyrosine kinase and oncogene, Src, which plays a crucial role in cell adhesion, invasion, and metastasis. Src kinase is primarily regulated by two endogenous inhibitors: C-terminal Src kinase (Csk) and Csk homologous kinase (CHK/MATK). In this study, we reveal that the MMP-2 gene acts as an upstream regulator of Src kinase activity by suppressing its endogenous inhibitor, CHK/MATK, in osteosarcoma cells. We also show that enhanced osteosarcoma cell migration which is induced by sublethal concentrations of doxorubicin can be overcome by inactivating the MMP-2 gene or overexpressing CHK/MATK. Our findings highlight the MMP-2 gene as a promising additional target for combating cancer cell migration and metastasis. This is due to its impact on the gene and protein expression of the tumor suppressor CHK/MATK in osteosarcoma. By targeting the MMP-2 gene, we can potentially enhance the effectiveness of doxorubicin treatment and reduce chemoresistance in osteosarcoma.
Objective: Immunochemotherapy has become a new treatment for advanced esophageal squamous cell carcinoma (ESCC). We aimed to study the clinical efficacy and toxicity of immunochemotherapy based on PD-1/PD-L1 compared with chemotherapy alone in the treatment of advanced ESCC, focusing on analyzing the influence of PD-L1 expression level. Methods: Randomized controlled trials comparing PD-1/PD-L1 based immunochemotherapy wirh chemotherapy alone for advanced ESCC were included. We extracted efficacy data [objective response rate (ORR), disease control rate (DCR), overall survival (OS) rate, progression-free survival (PFS) rate] and safety data (treatment-related adverse events, treatment-related mortality) and performed meta-analyses. Results: 5 articles were included. Compared with chemotherapy alone, the ORR and DCR of immunochemotherapy increased by 2.05 times and 1.54 times, respectively. Overall, patients receiving immunochemotherapy had a significant long-term survival advantage [OS: hazard ratio (HR)=0.68, 95% hazard ratio (CI) 0.61-0.75; PFS: HR=0.62, 95%CI 0.55, 0.70, respectively]. Even with PD-L1 tumor proportion score <1%, immunochemotherapy also showed a significant survival advantage [OS: HR=0.65, 95%CI 0.46-0.93; PFS: HR=0.56, 95%CI 0.46-0.69, respectively]. However, for PD-L1 combined positive score (CPS)<1, the survival advantage of immunochemotherapy was not significant [OS: HR=0.89, 95%CI 0.42-1.90; PFS: HR=0.71, 95%CI 0.47-1.08, respectively]. The toxicity of immunochemotherapy was higher than that of chemotherapy alone, but there was no statistical difference in treatment-related mortality (odds ratio=1.11, 95%CI 0.67-1.83). Conclusions: In this study, PD-1/PD-L1 based immunochemotherapy significantly could improve survival outcomes in patients with advanced ESCC. For patients with CPS<1, the survival advantage of immunochemotherapy was not significant. The toxicity of immunochemotherapy was acceptable.
Background Malignant brain tumors are among the most threatening diseases of the central nervous system, and despite increasingly updated treatments, the prognosis has not been improved. Tumor treating fields (TTFields) are an emerging approach in cancer treatment using intermediate-frequency and low-intensity electric field, and can lead to development of novel therapeutic options. Recent findings A series of biological processes induced by TTFields to exert anti-cancer effects have been identified, and applications of TTFields in oncology have been increasingly reported. This review addresses the mechanisms of TTFields and recent advances in the application of TTFields therapy in malignant brain tumors, especially in glioblastoma (GBM). Conclusions As a novel therapeutic strategies, TTFields have shown promising results in many clinical trials, especially in GBM, and continue to evolve. A growing number of patients with malignant brain tumors are being enrolled in ongoing clinical studies demonstrating that TTFields-based combination therapies can improve treatment outcomes.
Introduction: Monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells that produces a monoclonal protein. To describe the epidemiological and immunochemical characteristics of monoclonal gammopathies diagnosed during a nineteen-year period in a Moroccan teaching hospital was the main objective of this study. Methods: This study was performed from January 2000 to August 2019. It was a retrospective study that included of 545 Moroccan patients with monoclonal gammopathy. Results: The patients who participated in the study, 374 (68.6%) were male and 171(31.4%) were female, with a mean ±SD age of 62.24±13.14 years. The most frequent reasons for admission were bone pain (41,60%), renal failure (19.08%), alteration of the general condition (12.21%) and anemia (10.69). Plasma cell proliferative disorders in our study were as follow, multiple myeloma (MM) (45.65%), Monoclonal gammopathies of undetermined significance (MGUS) (39.05%), Waldenstrom’s macroglobulinemia(5.58%), Lymphoma (2.27%+1.2%), Chronic Lymphocytic Leukemia (2.48%), Plasma cell leukemia (1.86%), Plasmacytoma (0.62%), POEMS syndrome (0.41%), and Amyloidosis (0.84%). The most frequent isotypes in MM were the IgGκ (62) 36.5%, IgGλ(52)30.6%, IgAκ(27)15.9% and the IgAλ (19)11.2%. It is also worthy of note, that Free light chain MM represents 20% of all cases of MM. Conclusions: This is the largest Moroccan cohort, it included 545 patients. The results of this study point to the need for an early diagnosis of monoclonal gammopathies in the Moroccan population
Background: Sinonasal undifferentiated carcinoma (SNUC) is an exceedingly rare head and neck malignancy. No consensus exists on treatment for metastatic disease. Case: A 56-year-old female was diagnosed with SNUC after endorsing sinus congestion, diplopia, and right orbital pain. Initially treated with surgery and radiation, she later developed significant metastatic disease. She demonstrated progression of her hepatic metastases under pembrolizumab therapy. However, the addition of ipilimumab and a COX-2 inhibitor resulted in significant improvement in her lesions as well as an ongoing durable response. Her regimen was complicated by immune-related adverse events successfully treated with steroids.Conclusion: Dual checkpoint inhibition deserves consideration when treating metastatic SNUC, especially after single agent therapy has failed. The positive effect of this treatment may be augmented by IDO1 inhibition.
Background Multiple myeloma (MM) patients have variable responses to mRNA vaccination to COVID-19. Little is known regarding their vaccine-induced antibody levels over time. Methods We monitored spike IgG antibody levels over 24 weeks among a subset of 18 MM patients who showed a full response after two mRNA vaccinations. MM patients had a more rapid decline in antibody levels as compared to 8 healthy controls, with power law half-lives of 72 days (versus 107 days) and exponential half-lives of 37 days (versus 51 days). Results The patients with longer SARS-CoV-2 antibody half-lives were more likely to have undetectable monoclonal protein than those with shorter half-lives, suggesting better disease control may correlate with longer duration of vaccine-induced antibodies. Regardless, by 16 weeks post-second dose of mRNA vaccination, the majority of patients had antibody levels below 250 binding arbitrary units per milliliter, which would be unlikely to contribute significantly to preventing COVID-19. Conclusions Thus, even MM patients who respond adequately to vaccination are likely to require more frequent booster doses than the general population.
Background: Human papillomavirus (HPV) is the causative agent of nearly all forms of cervical cancer, which can arise upon viral integration into the host genome and concurrent loss of viral regulatory gene E2. Gene-based delivery approaches show that E2 reintroduction reduces proliferative capacity and promotes apoptosis in vitro. This work explored if our calcium-dependent protein-based delivery system, TAT-CaM could deliver functional E2 protein directly into cervical cancer cells to limit proliferative capacity and induce cell death. Methods: TAT-CaM and the HPV16 E2 protein containing a CaM-binding sequence (CBS-E2) were expressed and purified from E. coli. Calcium-dependent binding kinetics were verified by Biolayer Interferometry. Equimolar TaT-CaM:CBS-E2 constructs were delivered into the HPV16+ SiHa cell line and uptake verified by confocal microscopy. Proliferative capacity was measured by MTS assay and cell death was measured by release of lactate dehydrogenase. As a control for specificity to HPV+ cells, human microvascular cells (HMECs) were used. Results: TAT-CaM bound CBS-E2 with high affinity in the presence of calcium and rapidly disassociated in its absence. After introduction by TAT-CaM, E2 was detected in cellular interiors by orthogonal projects taken at the depth of the nucleus. In dividing cells, E2 relocalized to regions associated with the mitotic spindle. Cells receiving a single daily dose of CBS-E2 for 4 days showed a significant reduction in metabolic activity at low doses and cell death at high doses compared to controls. This phenotype was retained for 7 days with no further treatments. When subcultured at day 12, treated cells regained their proliferative capacity. Conclusions: Using the TAT-CaM platform, bioactive E2 protein was delivered into living cervical cancer cells, inducing senescence and cell death in a time- and dose-dependent manner. These results suggest that this nucleic acid and virus-free delivery method could be harnessed to develop novel, effective protein therapeutics.
There is limited and conflicting data regarding loss of immunity in childhood cancer survivors who did not undergo hematopoietic stem cell transplantation. This retrospective study included 28 childhood cancer survivors whose treatment consisted of at least 3 months of chemotherapy. Decreased seropositivity for measles, mumps, rubella, varicella, tetanus, and hepatitis B was found in patients across all categories of malignancy compared to the general population. Results were more pronounced for those with hematological malignancies. This study indicates that pediatric cancer survivors, especially those with hematological malignancies, may have greater loss of protective antibodies from primary vaccinations.
Background: The significant role of red blood cell distribution width (RDW) and D-Dimer as prognostic factors in patients with some blood malignancies has been reported recently. Aim: We designed and performed a meta-analysis to investigate the prognostic roles of RDW and D-Dimer in subjects with diffuse large B-cell lymphoma (DLBCL). Materials and Methods: We systematically reviewed PubMed-Medline, SCOPUS, EMBASE, Web of Science Core Collection, and Google Scholar up to 30 April 2023 to look for publications on prognostic effects of RDW and D-Dimer in DLBCL patients. For investigation of the associations between RDW and D-Dimer with the overall survival (OS) and progression-free survival (PFS) of the DLBCL cases, hazard ratio (HR) with 95% confidence intervals (CIs) was used. Results: We included 13 eligible studies in the present meta-analysis. The results of pooled analysis showed that increased levels of RDW was related to poor OS (HR=2.01, 95% CI: 1.62-2.48, P value<0.01) and poor PFS (HR=1.52, 95% CI: 1.24-1.85, P value<0.01) among the DLBCL patients. On the other hand, a significant relationship was found between increased D-Dimer and poor OS (HR=2.30, 95% CI: 1.03-5.14, P value<0.05) of the DLBCL patients as well. Conclusion: Our finding clearly confirmed that elevated RDW levels and D-Dimer were associated with adverse OS and PFS in DLBCL.
Background: To understand the changing trends in reporting of race and sex as a demographic variable in phase III lung cancer clinical trials published over the last 35 years. Methods: A total of 426 articles reporting results of phase 3 lung cancer clinical trials published from 1984 to 2019 were identified in PubMed. Statistical analysis on trends over time on percentage of minority and female participation were performed. Results: Only 137 (32.2%) of the 426 studies analyzed reported race of participants. Among those studies, we found that the mean participation rate of white participants was significantly higher (82.65%) (p < 0.001). We found a decrease in African American participants and an increase in Asian participants over time. When looking at sex, we found that although the rate of male participation (69.02%) was significantly higher than that of female participation (30.98%), the female participation has improved with time at a rate of 0.65% per year. Conclusions: We found that the reporting and participation of minority races continues to lag that of other demographic factors like sex in phase III clinical trials in lung cancer. Especially in African Americans, where the participation in lung cancer phase III clinical trials has declined despite the rising incidence in lung cancer.
The main differentials in cases of sudden elevation of hepatic enzyme levels during immunochemotherapy are reactivation of hepatitis B virus or drug-induced liver injury. Here, we report a case of acute liver injury caused by hepatitis E virus (HEV) during chemotherapy for malignant lymphoma, wherein the patient was successfully treated and completed chemotherapy. A 57-year-old woman visited her local doctor because she felt light and tired. The patient underwent lower gastrointestinal endoscopy and was diagnosed with a malignant lymphoma of the small intestine (diffuse large B-cell lymphoma). The patient had a history of oral consumption of undercooked pork liver to improve anemia and was diagnosed with acute hepatitis E. Since the patient responded to chemotherapy, she was treated with single-agent ribavirin while continuing chemotherapy, resulting in a sustained virological response. Even during treatment with immunosuppressive drugs, if appropriate treatment for hepatitis E can be administered, the patient can be fully treated without interruption. The patient was able to complete chemotherapy adequately without interruption of treatment, which was a clinically beneficial result.
Background Several good results of clinical trial of nivolumab or involving nivolumab in advanced esophageal squamous cell carcinoma were reported. However, the response rate was still poor. A rare phenomenon called the “abscopal effect” refers to the regression of not only the irradiated tumor but also non-irradiated distant tumors after local radiotherapy. The mechanism is not completely clear, but it is thought that the activation of anti-tumor immunity induced by radiotherapy is the main factor. Case A 66-year-old man with recurred and nivolumab resistant esophageal squamous cell carcinoma in left-side cervical and abdominal para-aortal lymph node metastasis was treated with a total of 40 Gy (10 fractions) of radiotherapy to the left-side cervical lymph node metastasis which caused neck pain as a palliative treatment. Nivolumab was resumed the day after completion of radiotherapy. At 3 months after radiotherapy showed that the irradiated lesion in the left neck had regressed to a scar-like appearance. Notably, the abdominal para-aortal lymph nodes outside the irradiation area, which had previously tended to progress, had also shrunk (abscopal effect). The T cell receptor and B cell receptor (TCR/BCR) repertoire analysis before and after radiotherapy revealed that radiotherapy caused the changes in the TCR/BCR repertoire. Conclusion Changes in the TCR/BCR receptor repertoire repertoires were assumed to be a part of the mechanism of the abscopal effect. The findings in this patient suggest that combination of immune checkpoint inhibitors and radiotherapy can be a promising treatment approach, even for patients with immune checkpoint inhibitors resistant cancer.
Significant racial disparities in prostate cancer incidence and mortality have been reported between African American Men (AAM) who are at increased risk for prostate cancer, and European American Men (EAM). In most of the studies carried out on prostate cancer, this population is underrepresented. With the advancement of genome-wide association studies (GWAS), several genetic predictor models of prostate cancer risk have been elaborated, as well as numerous studies that identify both germline and somatic mutations with clinical utility. Despite significant advances, the AAM population continues to be underrepresented in genomic studies, which can limit their generalizability and potentially widen disparities. Here we outline racial disparities in currently available genomic applications that are used to estimate the risk of individuals developing prostate cancer and to identify personalized oncology treatment strategies. While the incidence and mortality of prostate cancer are different between AAM and EAM. the biological features and differences of prostate tumors in AAM and EAM are still being described. Samples from AAM remain to be unrepresented in different studies. This disparity impacts the available genomic data on prostate cancer. As a result, the disparity can limit the predictive utility of the genomic applications that have been developed and may lead to widening disparities. More studies with substantially higher recruitment and engagement of African American patients are necessary to overcome this disparity.
Background: The role and mechanism of centromeric protein N (CENPN), which has been associated with the development of various cancer types, are yet unclear in Gastric adenocarcinoma (STAD). Methods: Data from The Cancer Genome Atlas and Genotype Tissue Expression were used to examine the expression of CENPN in STAD and neighboring tissues. Xiantao Academic was used to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis on CENPN. By reviewing TCGA database, the relationship between CENPN expression and immune cell infiltration was assessed. The expression of CENPN in STAD and surrounding tissues was confirmed by immunohistochemical staining, and the correlation between CENPN expression and clinicopathological characteristics was examined. CENPN was depleted in AGS cells with siRNAs, and its impact on proliferation was measured by CCK-8 and EdU assays. Following siRNA transfection, flow cytometry was performed to identify cell cycle and apoptotic alterations in AGS cells. Results: CENPN was highly expressed in STAD tissues. The degree of invasion, TNM stage, and lymph node metastases were all substantially linked with CENPN expression. GO|KEGG Enrichment analysis revealed that CENPN was essential for the cell cycle, DNA replication, chromosomal segregation, and nuclear division, among other important signaling pathways. Further investigation revealed a positive correlation between CENPN expression and Th2 cells and NK CD56dim cells and a negative correlation between CENPN expression and mast cells , pDC cells,NK cells and B cells. When CENPN expression in AGS cells was knocked down, cell proliferation dramatically reduced, and the percentage of cells in the S and G2-M phases decreased significantly. In addition, compared to the control group, the proportion of apoptotic AGS cells significantly increased after downregulating the expression level of CENPN. Conclusion: According to our data, CENPN acts as an oncogene in STAD and may be a viable therapeutic target.
Introduction: Obesity is a major risk factor in the development of endometrial cancer (EC) in young patients of reproductive age. Fertility sparing treatment is a viable option for a select group of patients with early EC, and involves systemic and intra-uterine hormonal therapy. Weight loss has been associated with improved outcomes in this group. Bariatric surgery (BS) has been shown to be the most efficient and durable method of weight loss in obese patients. However, there is a paucity of data studying the benefit of BS as part of fertility sparing treatment. Methods: We present a retrospective case series of five patients who are undergoing fertility sparing treatment for early EC, who also underwent BS for treatment of obesity and related comorbidities. We aim to show early regression of EC for all the patients and also report on the other health benefits of BS. Results: All five patients in the series achieved regression of EC within six months of undergoing BS. They also achieved significant weight loss consistent with previous studies, and three patients who had comorbidities related to obesity had remission of these conditions. One of the patients with EC regression also managed to conceive with IVF. Conclusion: Patients on fertility sparing treatment for early EC who underwent BS was associated with early regression within 6 months, significant weight loss and resolution of comorbidities. BS could be a promising component of fertility sparing treatment. Long term, prospective studies are required to confirm the benefits reported in this case series.
Approximately 5% of colorectal cancers (CRCs) are hereditary. Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of recognized hereditary CRC. Although Iran, a developing country, has a high incidence of CRC, the spectrum of mutations has yet to be thoroughly investigated. Therefore, this study aimed to investigate pathogenic and non-pathogenic variants in MLH1 and MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS). In the present study, 25 peripheral blood samples were collected from patients with sLS and high microsatellite instability (MSI-H). After DNA extraction, all samples underwent polymerase chain reaction (PCR) and Sanger sequencing to identify the variants in the exons of MLH1 and MSH2 genes. The identified variants were interpreted using prediction tools, including SIFT, CADD, PolyPhen, PROVEAN, REVEL, MetaLR, and Mutational Assessor. In our study population, 13 variants were found in the MLH1 gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants and 3 of the 8 MSH2 variants were novel, whereas the remaining variants were previously reported or available in databases. In addition, some patients with sLS did not have variants in the exons of the MLH1 and MSH2 genes. The variants detected in the MLH1 and MSH2 genes had specific characteristics regarding the number, area of occurrence, and their relationship with demographic and clinicopathologic features. We identified two novel pathogenic/likely pathogenic variants in these two genes. Overall, our results suggest that analysis of MLH1 and MSH2 genes alone is insufficient in the Iranian population, and more comprehensive tests are recommended for detecting LS.