• Biomolecules & Therapeutics
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• v.30 no.4
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• pp.368-379
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• 2022

Hyaluronic acid (HA), a ligand of CD44, accumulates in some types of tumors and is responsible for tumor progression. The nuclear factor erythroid 2-like 2 (NRF2) regulates cytoprotective genes and drug transporters, which promotes therapy resistance in tumors. Previously, we showed that high levels of CD44 are associated with NRF2 activation in cancer stem like-cells. Herein, we demonstrate that HA production was increased in doxorubicin-resistant breast cancer MCF7 cells (MCF7-DR) via the upregulation of HA synthase-2 (HAS2). HA incubation increased NRF2, aldo-keto reductase 1C1 (AKR1C1), and multidrug resistance gene 1 (MDR1) levels. Silencing of HAS2 or CD44 suppressed NRF2 signaling in MCF7-DR, which was accompanied by increased doxorubicin sensitivity. The treatment with a HAS2 inhibitor, 4-methylumbelliferone (4-MU), decreased NRF2, AKR1C1, and MDR1 levels in MCF7-DR. Subsequently, 4-MU treatment inhibited sphere formation and doxorubicin resistance in MCF7-DR. The Cancer Genome Atlas (TCGA) data analysis across 32 types of tumors indicates the amplification of HAS2 gene is a common genetic alteration and is negatively correlated with the overall survival rate. In addition, high HAS2 mRNA levels are associated with increased NRF2 signaling and poor clinical outcome in breast cancer patients. Collectively, these indicate that HAS2 elevation contributes to chemoresistance and sphere formation capacity of drug-resistant MCF7 cells by activating CD44/NRF2 signaling, suggesting a potential benefit of HAS2 inhibition.

• Radiation Oncology Journal
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• v.20 no.4
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• pp.309-315
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• 2002

Purpose : To evaluate the result of conservative management on recurrence, survival and prognostic factors of patient with operable breast cancer. Materials and Methods : Fifty three patients, treated for localized breast cancer by lumpectomy or quadrantectomy followed by radiotherapy between January 1985 and December 1996, were retrospectively studied. All patients followed up for at least five years. Their median age was 43 years $(range\;24\~72)$. The tumor stages were as follows : T1 in 30 patients, T2 in 21, Tis in 2. Thirty-eight patients had negative and 15 had positive axillary nodes. The histological types were 42 infiltrating ductal, 2 infiltrating lobular, and 2 intraductal carcinomas with 7 other histologies. The tumor locations were the outer quadrant in 38 breasts, the inner quadrant in 13 and central in 2. Radiation doses of $46\~50\;Gy$ were given to the entire breast areas with additional doses of 14-18 Gy delivered to the tumor bed areas. Results : The overall five and 10 yea actuarial and disease free survivals were $94.3\%\;and\;92.4\%,\;91.2\%\;and\;81\%$, respectively. The overall five year survivals were $100\%$ in stage I and IIa, and $66.7\%$ in stage IIb and IIIa tumors. Seven patients failed either locally or distantly. Incidence of local failure and distant metastasis for the first failure were $7.5\%\;and\;5.7\%$, respectively. Local recurrence appeared within 2 years of treatment at the primary site and after more than 8 years outside of primary lesion, whereas distant metastasis appeared between 2 and 6 years following treatment. The overall recurrences were high at a young age (< or = 35 years), with 5 out of 12 (2 local, 3 distant), and in T2 lesions with 5 out of 21 (1 local, 3 distant, and 1 in both). Distant metastasis was high in the positive axillary lymph node group with 4 out of 15 $(26.6\%)$. A high incidence in the axillary node was noted at a young age with 7 out of 12 $(58.3\%)$ and in T2 lesions with 8 out of 21 $(38.4\%)$. A young age, positive axillary node and large tumor size were all related with poor survival. Conclusion : Based on this study, lumpectomy or quadrantectomy, followed by radiation appears to be an adequate therapeutic method in operable breast cancer. A long term follow-up is necessary because a recurrence of breast can occur long time after treatment. The poor prognostic group, especially young patients with an aggressive biological behavior needs more effective treatment modalities to improve their survival.

• YAKHAK HOEJI
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• v.55 no.1
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• pp.16-21
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• 2011

HER-2 (Human Epidermal Growth Factor Receptor-2) is a protein giving higher aggressiveness in human breast cancers. Trastuzumab is a monoclonal antibody that targets HER-2 and is known to extend survival across all stages of HER2-positive breast cancer. In this study, we attempted to development of a quantitative ELISA (Enzyme-Linked ImmunoSorbent Assay) for evaluating anti HER-2 antibodies using human HER-2 recombinant proteins to support antibody producing processes and pharmacokinetic studies. We established direct or indirect ELISA method for the trastuzumab-like protein combined human recombinant HER-2. The ELISA method will prove to be great value in quantitating anti-HER-2 antibodies levels for developing anticancer antibodies.

• Journal of Pathology and Translational Medicine
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• v.52 no.6
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• pp.369-377
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• 2018

Background: Chemokine receptor CXC chemokine receptor type 4 (CXCR4) and its ligand CXC motif chemokine 12 (CXCL12; stromal cell-derived factor-1) are implicated in tumor growth, metastasis, and tumor cell-microenvironment interaction. A number of studies have reported that increased CXCR4 expression is associated with worse prognosis in triple-negative breast cancer (TNBC), but its prognostic significance has not been studied in TNBC patients treated with adjuvant chemotherapy. Methods: Two hundred eighty-three TNBC patients who received adjuvant chemotherapy were retrospectively analyzed. Tissue microarray was constructed from formalin-fixed, paraffin-embedded tumor tissue and immunohistochemistry for CXCR4 and CXCL12 was performed. Expression of each marker was compared with clinicopathologic characteristics and outcome. Results: High cytoplasmic CXCR4 expression was associated with younger age (p=.008), higher histologic grade (p=.007) and lower pathologic stage (p=.045), while high CXCL12 expression was related to larger tumor size (p=.045), positive lymph node metastasis (p=.005), and higher pathologic stage (p=.017). The patients with high cytoplasmic CXCR4 experienced lower distant recurrence (p=.006) and better recurrence-free survival (RFS) (log-rank p=.020) after adjuvant chemotherapy. Cytoplasmic CXCR4 expression remained an independent factor of distant recurrence (p=.019) and RFS (p=.038) after multivariate analysis. Conclusions: High cytoplasmic CXCR4 expression was associated with lower distant recurrence and better RFS in TNBC patients treated with adjuvant chemotherapy. This is the first study to correlate high CXCR4 expression to better TNBC prognosis, and the underlying mechanism needs to be elucidated in further studies.

• Brain Tumor Research and Treatment
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• v.6 no.2
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• pp.54-59
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• 2018

Background Leptomeningeal metastasis (LM) is an uncommon, but devastating complication of advanced cancer and has no standard treatment. Herein, we analyzed the clinical characteristics and outcomes of patients with solid tumors who were diagnosed with LM. Methods Between January 2007 and December 2017, we retrospectively analyzed the medical records of patients with solid tumors who were diagnosed with LM. Results A total of 58 patients were enrolled in this study. The median age of patients was 51 years (range, 27-72 years), and 62.1% had a poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) (>2). The common types of primary tumor were breast cancer (39.7%), gastric cancer (25.9%), and non-small cell lung cancer (20.7%). Forty-two patients (72.4%) were diagnosed with LM by MRI of the brain and/or spine and cerebrospinal fluid (CSF) analysis, 14 were diagnosed by CSF analysis alone, and 2 were diagnosed by MRI alone. Treatments for LM were performed in 53 patients (91.4%), and best supportive care was provided for 5 patients (8.6%). Intrathecal chemotherapy, radiotherapy, and systemic chemotherapy were administered in 43 (74.1%), 17 (29.3%), and 24 (41.4%) patients, respectively. The median overall survival of the entire cohort was 2.4 months (95% confidence interval, 1.0-3.7). In the analysis of prognostic factors for survival, a good ECOG PS (${\leq}2$), administration of systemic chemotherapy after LM diagnosis, and a prior history of brain radiation were associated with prolonged survival. Conclusion Although the prognosis of LM in patients with solid tumors is poor, systemic chemotherapy might improve survival in selected patients with a good PS.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3357-3362
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• 2013

The human skeleton is the most common organ to be affected by metastatic cancer and bone metastases are a major cause of cancer morbidity. The five most frequent cancers in Malaysia among males includes prostate whereas breast cancer is among those in females, both being associated with skeletal lesions. Bone metastases weaken bone structure, causing a range of symptoms and complications thus developing skeletal-related events (SRE). Patients with SRE may require palliative radiotherapy or surgery to bone for pain, having hypercalcaemia, pathologic fractures, and spinal cord compression. These complications contribute to a decline in patient healthrelated quality of life. The multidimensional assessment of health-related quality of life for those patients is important other than considering a beneficial treatment impact on patient survival, since the side effects of treatment and disease symptoms can significantly impact health-related quality of life. Cancer treatment could contribute to significant financial implications for the healthcare system. Therefore, it is essential to assess the health-related quality of life and treatment cost, among prostate and breast cancer patients in countries like Malaysia to rationalized cost-effective way for budget allocation or utilization of health care resources, hence helping in providing more personalized treatment for cancer patients.

• Genomics & Informatics
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• v.14 no.4
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• pp.205-210
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• 2016

Interleukin-10 (IL10) plays an important role in initiating and maintaining an appropriate immune response to non-Hodgkin lymphoma (NHL). Previous studies have revealed that the transcription of IL10 mRNA and its protein expression may be infl uenced by several single-nucleotide polymorphisms in the promoter and intron regions, including rs1800896, rs1800871, and rs1800872. However, the impact of polymorphisms of the IL10 gene on NHL prognosis has not been fully elucidated. Here, we investigated the association between IL10 polymorphisms and NHL prognosis. This study involved 112 NHL patients treated at the National Cancer Center, Korea. The median age was 57 years, and 70 patients (62.5%) were men. Clinical characteristics, including age, performance status, stage, and extra-nodal involvement, as well as cell lineage and International Prognostic Index (IPI), were evaluated. A total of four polymorphisms in IL10 with heterozygous alleles were analyzed for hazard ratios of overall survival (OS) and progression-free survival (PFS) using Cox proportional hazards regression analysis. Diffuse large B-cell lymphoma was the most common histologic type (n = 83), followed by T-cell lymphoma (n = 18), mantle cell lymphoma (n = 6), and others (n = 5). Cell lineage, IPI, and extra-nodal involvement were predictors of prognosis. In the additive genetic model results for each IL10 polymorphism, the rs1800871 and rs1800872 polymorphisms represented a marginal association with OS (p = 0.09 and p = 0.06) and PFS (p = 0.05 and p = 0.08) in B-cell lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). These findings suggest that IL10 polymorphisms might be prognostic indicators for patients with B-cell NHL treated with R-CHOP.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3711-3717
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• 2013

Background: To assess the efficacy and tolerability of Cisplatin plus Gemcitabine combination in patients with brain metastases (BM) from breast cancer (BC). Materials and Methods: Eighteen BC patients with BM who were treated with Cisplatin plus Gemcitabine regimen between 2003-2011 were evaluated. Results: A median of 6 cycles of this regimen were received, in fifteen patients (83.3%) as first-line chemotherapy, in 2 as second-line and in 1 as third-line after diagnosis of BM. Dose reduction was performed in 11 (61.1%) patients; major reasons were neutropenia and leukopenia. Grade III neutropenia and Grade II trombocytopenia rates were 33.3% and 16.7% respectively. Overall response rate (ORR; complete+partial response rate) was 33.4% (n=6) for the entire study population; triple negative patients achieved an 66.6% ORR while hormone receptor (HR) positive patients had 25% and HER2 positive patients 12.5%. Median progression-free survival was 5.6 months (2.4-8.8 months, 95%CI) and longer in patients with triple negative breast cancer (TNBC) (median 7.4 months, 95%CI, 2.4-12.3 months) than the patients with other subtypes (median 5 months for HER2 positive and 3.6 months for HR positive patients). Median PFS of the patients with TNBC who received this regimen as first-line was 9.2 months (5.2-13.2 months, 95%CI). Conclusions: Cisplatin plus Gemcitabine may be a treatment option for patients with BM from breast cancer. Longer PFS and higher response rates are results that support the usage of this regimen especially for the triple negative subtype. However, further prospective and randomized trials are clearly required to provide more exact information.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.13
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• pp.5297-5304
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• 2015

Background: The Pakistan Atomic Energy Commission Cancer Registry (PAECCR) program has made availability of a common cancer incidence database possible in Pakistan. The cancer incidence data from nuclear medicine and oncology institutes were gathered and presented. Materials and Methods: The cancer incidence data for the last 30 years (1984-2014) are included to describe a data set of male and female patients. The data analysis concerning occurrence, trends of common cancers in male and female patients, stage-wise distribution, and mortality/follow-up cases is also incorporated for the last 10 years (2004-2014). Results: The total population of provincial capital Lahore is 9,800,000. The total number of cancer cases was 80,390 (males 32,156, females 48,134). The crude incidence rates in PAECCR areas were 580.8/$10^5$ during 2010 to 885.4/$10^5$ in 2014 (males 354.1/$10^5$, females 530.1/$10^5$). The cancer incidence rates for head and neck (15.70%), brain tumors (10.5%), and non-Hodgkin lymphoma (NHL, 9.53%) were found to be the highest in male patients, whereas breast cancer (46.7%), ovary tumors (6.80%), and cervix (6.31%) cancer incidence rates were observed to be the most common in female patients. The age range distribution of diagnosed and treated patients in conjunction with the percentage contribution of cancer patients from 15 different cities of Punjab province treated at the Institute of Nuclear Medicine and Oncology, Lahore are also included. Leukemia was found to be the most common cancer for the age group of 1-12 years. It has been identified that the maximum number of diagnosed cases were found in the age range of 51-60 years for males and 41-50 years for female cancer patients. Conclusions: Overall cancer incidence of the thirty years demonstrated that head and neck and breast cancers in males and in females respectively are the most common cancers in Punjab province in Pakistan, at rates almost the highest in Asia, requiring especial attention. The incidence of brain, NHL, and prostate cancers among males and ovarian and cervix cancers among females have increased rapidly. These data from a major population of Punjab province should be helpful for implementation of appropriate planning, prevention and cancer control measures and for determination of risk factors within the country.

• Korean journal of aerospace and environmental medicine
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• v.31 no.2
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• pp.57-59
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• 2021

For nonsmall cell lung cancer (NSCLC), surgery is indicated only for stage 3 as a curative measure. Even so, there is a high risk of recurrence following stage 3 lung cancer surgery, a third (33.9%) of patients experienced a cancer recurrence mostly within 2 years after surgery. The median survival time for all stages reaches only 21.9 months. For people undergoing surgery for stage 3A NSCLC, a pre-operative course of (neoadjuvant chemotherapy) can improve survival times, by improving the resectability and lowering the risk of recurrence. Pleural metastases are frequently associated with tumors of the lung and breast. Chest radiographs and computed tomography scans of pleural metastases can present as an effusion or smooth or nodular pleural thickening. In the absence of irregular or nodular pleural thickening, it is difficult to distinguish a benign from a malignant pleural effusion. To treat lung cancer, tyrosine kinase inhibitors (TKIs) recently have been used to cope with genetic mutations, apart from cytotoxic anticancer drugs. Compared to cytotoxic drugs, they are effective, have fewer side effects, and are easy to administer. Airman must have no cancer disease to apply for Class-I medical certification. Specifically, if previously operated on cancer, the cancer should not remain in the body at present, and the disease free state should persist at least one year after all kinds of anti-cancer treatments including adjuvant chemotherapy are completed. Here, this case deals with a 41-year-old pilot who has ATP license who had stage 3A NSCLC. The pilot underwent curative lung cancer surgery (lobectomy) a year ago and showed suspicious pleural metastasis at the time of his application for certification and was still using an unauthorized TKI agent alectinib (Alecensa; Roche, Basel, Switzerland).