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 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.

It has been described in mice models that Primary Myelofibrosis (PMF) with JAK2-V617F mutation has an increased expression of programmed death-ligand 1 (PD-L1) in megakaryocytes leading to cancer immune evasion by inhibiting the T-lymphocytes. To prove this hypothesis, we quantified PD-L1 expression on 29 bone marrow (BM) biopsies. We created a scoring system to quantify PD-L1 expression in megakaryocytes. We obtained 14 BM with JAK2 positive PMF, 5 JAK2 negative PMF and 10 patients with normal BM biopsies. PD-L1 expression was higher in the JAK2 positive group compared to the control group with a score of 212.6 vs 121.1 (t-value 2.05,p-value 0.025). In addition, the score was higher in the PMF group regardless of JAK2 mutational status when compared to the control group with score of 205.9 vs 121.1(t-value 2.12,p-value 0.021). There was no difference in the PD-L1 score between the JAK2 negative vs the control group 187.2 vs 121.1 (t-value 1.02,p-value 0.162). These findings suggest that PMF patients with a JAK2 mutation have a higher PD-L1 expression in megakaryocytes compared to the control group. We postulate that the combination of checkpoint and JAK2 inhibitors may be an active treatment option in JAK2 mutated PMF given the higher PD-L1 expression.

Background/Aim: The present study aimed to develop detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving Atezolizumab plus Bevacizumab (Atez/Bev). Methods: Between September 2020 and January 2023, the patients treated with Atez/Bev were enrolled (n=719, males 577, median age 74 years). Factors involved in overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression-free survival (PFS) were examined retrospectively, and the prognostic ability of the newly system was compared to CRAFITY score using concordance index (c-index) and Akaike Information Criterion (AIC) results. Results: Cox-hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used for IMnunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI-De) scoring. For IMABALI-De scores of 0/1/2/3/4/5, OS was not applicable (NA)/NA/26.11/18.79/14.07/8.32 months (P<0.001; AIC 2788.67, c-index 0.699), while for CRAFITY scores of 0/1/2, OS was 26.11/20.29/11.32 months (p<0.001; AIC 2864.54, c-index 0.606). PFS for those IMABALI-De scores was 21.75/12.89/9.18/8.0/5.0/3.75 months (P<0.001; AIC 5203.32, c-index 0.623) and for the CRAFITY scores was10.32/7.68/3.57 months (p<0.001; AIC 5246.61, c-index 0.574). IMABALI-De score had better AIC and c-index results as compared to CRAFITY score for both OS and PFS. Conclusion: The proposed IMABALI-De score may have a favorable prognostic predictive ability for uHCC patients with Atez/Bev.

NSCLC is a highly prevalent cancer and accounts for 85% of cases of lung cancer. Conventional cancer treatments, such as chemotherapy and radiation, frequently exhibit limited efficacy and notable adverse reactions. Therefore, a drug repurposing method is proposed for effective NSCLC treatment. This study aims to evaluate candidate drugs that are effective for NSCLC at the clinical level using systems biology and network analysis approach. Differentially expressed genes of transcriptomics data were identified using the systems biology and network analysis approach. A network of gene co-expression was developed with the aim of detecting two modules of gene co-expression. Subsequently, the Drug-Gene interaction database was employed to pinpoint potential pharmaceutical agents that target crucial genes within two gene co-expression modules associated with non-small cell lung cancer (NSCLC). The construction of a drug-gene interaction network was facilitated with the utilisation of Cytoscape. Finally, the gene set enrichment analysis was done to validate candidate drugs. Unlike previous research on repositioning drugs for NSCLC, which uses a gene co-expression network, this project is the first to research both gene co-expression and co-occurrence networks. And the co-occurrence network also accounts for differentially expressed genes in cancer cells and their adjacent normal cells. Drugs exhibiting elevated gene regulation and gene affinity within the drug-gene interaction network are deemed noteworthy for the efficacious management of non-small cell lung cancer (NSCLC). According to this discourse, NSCLC genes exert a high degree of regulation over medications such as vincristine, fluorouracil, methotrexate, clotrimazole, etoposide, tamoxifen, sorafenib, doxorubicin, and pazopanib. Hence, there is a possibility of repurposing these drugs for the treatment of non-small cell lung cancer. Key words: Non-small cell lung cancer (NSCLC), drug repurposing, network analysis, drug-gene interaction, therapeutics

Background : Metaplastic Breast Cancer (MpBC) is an exceedingly rare entity, accounting for less than 1% of all malignant breast tumours. Predominantly triple-negative, they are notorious for their chemoresistance, high rates of recurrence and decreased disease-free survival (DFS). All this contributes significantly to BC mortality and results in poor prognostic implications. Limited evidence has led to a lacuna of specific treatment guidelines for this entity and hence remains an uncharted territory for clinicians. Case : We report a case of left-sided low-grade metaplastic triple negative T3N2aM0 BC treated with neoadjuvant chemotherapy, primary surgery, and adjuvant radiotherapy, presently in remission. Conclusion : Limited experience in management of this pathological entity warrants the need for more research on it, with a special focus on targeted therapy. Discussing possibilities of a tailored approach, rather than a one-size-fits-all approach may aid in paving the path for the future of MpBC treatment.

Cancer is one of the leading causes of morbidity and mortality, worldwide. Little information is available for the temporal trends of cancer in the Mediterranean region, including Cyprus. We aimed to analyze cancer incidence trends overall and by sex for the period 2004-2017 regarding the five most common cancer sites for the population of Cyprus. Data were obtained from the nationwide cancer registry dataset that included 27,017 total cancer cases in Cyprus (2004-2017). We estimated the crude, sex-, and age-specific, as well as age-standardized (ASR) cancer incidence rates and we analyzed the time trends of ASR using the joinpoint regression program. For the general population (0-85+ years of age), the most common cancer sites in descending order, were breast, prostate, lung, colorectal, and thyroid cancer. During the study period, breast and thyroid cancer ASR presented a significantly increasing temporal trend. Lung cancer ASRs seemed to stabilize (no increase or decrease) during the more recent years (2009 onwards) for both sexes; a similar pattern was observed for colorectal cancer in males. The ASRs of prostate cancer in men were in steady decline from 2012 onwards and the same was observed for the female ASRs of colorectal cancer from 2007 onwards. The colorectal cancer ASR temporal patterns overall, during the whole study period appeared unchanged. This temporal analysis would feed into cancer surveillance and control programs that focus on prevention, early detection, and treatment, particularly for cancer sites of higher mortality rates or those with temporally increasing trends.

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: In high income countries, retinoblastoma is curable in more than 95% of cases, whereas in low-income countries, mortality remains high, especially when the diagnosis is made late or the treatment is discontinued. The aim of this work was to determine the factors associated with adherence to the treatment of retinoblastoma in the Ivory Coast and the Democratic Republic of Congo (DRC). Procedure: A retroprospective cohort study was carried out. Data were collected from patient folders and follow-up records of parents. Results: A total of 175 children with retinoblastoma were registered from January 2013 to December 2015. Seventy-six children (43%) were 5 years old and above. Care costs were covered by families in 86.9% of cases. Chemotherapy refusal was recorded in 39 cases (22.3%), and enucleation refusal was recorded in 79 cases (45.1%). After 36 months of follow-up, we recorded 16.6% deaths, 27.4% treatment dropouts, and 18.3% loss to follow-up after treatment. The commonest cause for enucleation refusal was fear of infirmity, while chemotherapy refusal and absconding treatment were due to financial constraints. Conclusion: Poor adherence to retinoblastoma management was due to financial constraints, and a lack of knowledge of the disease and its treatment. Family psychosocial support is needed to improve this condition.

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 and Aims: Progesterone therapy is a relatively inexpensive treatment option for endometrial and breast cancers, with few side effects. Two signaling pathways usually mediate the physiological effects of progesterone, namely genomic and non-genomic actions. Genomic action occurs slowly via the nuclear progesterone receptor (PR), whereas the membrane progesterone receptor (mPR) induces rapid non-genomic action. We investigated the effects of progesterone and various PR agonists on ovarian cancer cells. Methods: PR expression of six serous ovarian cancer cell lines was examined by western blotting, and mPR expression was examined by RT-qPCR. PR-negative and mPR-positive ovarian cancer cells were exposed to progesterone and seven types of PR agonists (medroxyprogesterone acetate [MPA], dehydroepiandrosterone, dienogest, levonorgestrel, drospirenone, pregnenolone, and allopregnanolone) at 10–400 μM, and viable cell counts after exposure for 30 min were measured using the water soluble tetrazolium (WST-1) assay. Ovarian cancer cell lines were exposed to 100 μM progesterone, and the expression of BAX, a pro-apoptotic protein, after 1-5 min was examined by western blotting. Results: Western blotting detected no PR expression in the six serous ovarian cancer cell lines. In contrast, RT-qPCR detected mPR expression in all six serous ovarian cancer cell lines. Progesterone and MPA induced cell death in all tested ovarian cancer cell lines in a concentration-dependent manner, whereas no effect was observed for other PR agonists. Western blotting revealed that pro-apoptotic protein BAX expression occurred 1 min after exposure to progesterone, suggesting that the cytocidal effects are mediated by rapid non-genomic action. Conclusions: MPA, like progesterone exhibited a rapid cytocidal effect on PR-negative ovarian cancer cells through non-genomic action. Progesterone and MPA could be novel treatment modalities for ovarian cancer. Keywords: genomics, medroxyprogesterone acetate, ovarian cancer, progesterone, progesterone receptor

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.

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.

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.

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.

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.

Background: Preoperative serum CA19-9 and histology grade could reflect the biological characteristics of pancreatic ductal adenocarcinoma (PDAC). This study aims to explore the combined effect of preoperative CA19-9 and histology grade on the prognosis of patients with PDAC. Methods: A total of 612 patients with PDAC undergoing curative pancreatectomy were retrospectively enrolled. A biological risk model was established based on preoperative CA19-9 and histology grade. Prognostic significance of the biological risk was evaluated. Results: 360 (58.8%) patients had preoperative CA19-9>112 U/ml and 348 (56.9%) patients had high histology grade. Biological risk based on preoperative CA19-9 and histology grade was independently associated with survival of PDAC patients. The biological risk was incorporated into the eighth edition of the TNM staging system and a modified TNM (mTNM) staging system was developed. The ROC curves showed that the area under curve(AUC) of the mTNM staging system was significantly greater than that of the TNM staging system. Conclusion: Biological risk based on preoperative CA19-9 and histology grade was an independent prognostic factors for patients with PDAC. Incorporating the biological risk into the TNM staging system could improve the the accuracy of the TNM staging system in predicting prognosis of PDAC.

Background Tumor deposits (TD) are considered as Extranodal Extension (ENE) in the AJCC 8th edition of Head and Neck Squamous Cell Carcinoma (HNSCC) TNM staging. Methods We analyzed TDs in patients with HNSCC who underwent surgery and adjuvant radiotherapy ± chemotherapy. Overall Survival (OS) and progression rate were compared to patients with ENE. Results ENE was detected in 50 patients, while TDs in 21. Based on the presence of ENE alone or TDs, the mean time to progression was significant (p<0.005). OS at three years was 55.7% for the whole study group, 60.4% in ENE and 38.4% in TDs. OS difference between the N2a-ENE, N3b-ENE, and the TDs ± ENE group was significant (p=0.05). The hazard ratio between ECs and TDs was Exp (B) 2.296 (p= 0.027). Conclusions The prognostic implication of TDs represents an independent risk factor, and a separate classification might be required.