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Rambam Maimonides Medical Journal Jul 2021The objective of this study was to retrospectively review clinical data, management protocols, and clinical outcomes of patients with fibromatoses of head and neck...
OBJECTIVE
The objective of this study was to retrospectively review clinical data, management protocols, and clinical outcomes of patients with fibromatoses of head and neck region treated at our tertiary care center.
METHODS
We retrospectively reviewed the medical records of 11 patients with confirmed histopathological diagnosis of fibromatosis registered in the Department of Head and Neck Surgery at Tata Memorial Centre, India, between 2009 and 2019. Various clinical and pathological features and treatment modalities were evaluated.
RESULTS
Age at diagnosis ranged between 18 and 74 years, with a median age of 36 years. The female-to-male ratio was 5:6. Supraclavicular fossa (n=4) was the most common subsite of origin in the neck (n=8). The lateral (n=2) and posterior cervical regions (n=2) were other common neck subsites. Less commonly involved sites were the mandible (n=1), maxilla (n=1), and thyroid (n=1). A total of eight patients underwent surgery at other centers before being referred to us for further management. Out of a total 11 patients, nine patients had unresectable disease at presentation. Six of the patients with unresectable disease received a combination of weekly doses of vinblastine 6 mg/m and methotrexate 30 mg/m for a median duration of 6 months (range 6-18 months) followed by hormonal therapy with tamoxifen. Three patients received metronomic chemotherapy followed by hormonal therapy. One treatment-naive patient with fibromatosis of posterior cervical (suboccipital) region underwent R2 resection (excision of bulk of the tumor with preservation of critical structures) at our center along with adjuvant radiotherapy. One pregnant patient reported to us after undergoing surgery outside and defaulting radiotherapy. During median follow-up of 29 months (range 1-77 months), six patients had stable disease, and four patients had disease reduction. Disease progression was seen in one patient. The two-year progression-free survival (PFS) was 90% (95% CI 70%-100%).
CONCLUSION
Gross residual resection (R2) was the mainstay of surgical treatment in our series, as obtaining clear surgical margins is seldom possible in these locally aggressive tumors. Radiotherapy, chemotherapy, and hormonal therapy are the other preferred and more conservative treatment modalities. The goal of surgery should be preserving function with minimal or no morbidity. As fibromatoses in the head and neck region are extremely rare, their treatment awaits the development of standard treatment protocols.
PubMed: 34270403
DOI: 10.5041/RMMJ.10444 -
Cancers Jul 2022Triple-negative breast cancer-defined by the absence of oestrogen/progesterone receptors and human epidermal growth factor receptor 2 expression-is a complex and... (Review)
Review
Triple-negative breast cancer-defined by the absence of oestrogen/progesterone receptors and human epidermal growth factor receptor 2 expression-is a complex and heterogeneous type of tumour characterised by poor prognosis, aggressive behaviour and lack of effective therapeutic strategies. The identification of new biomarkers and molecular signatures is leading to development of new therapeutic strategies including immunotherapy, targeted therapy and antibody-drug conjugates (ADCs). Against a background where chemotherapy has always been considered the standard of care, evolution towards a precision medicine approach could improve TNBC clinical practice in a complex scenario, with many therapeutic options and new drugs. The aim of this review was to focus on emerging therapeutic targets and their related specific therapy, discussing available and emerging drugs, underlining differences in approval by American and European regulatory authorities and showing the future perspective in the large number of ongoing clinical trials.
PubMed: 35954393
DOI: 10.3390/cancers14153729 -
EMBO Molecular Medicine Sep 2020Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically...
Conventional maximum-tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment-free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia-inducible factor (HIF)-1α and (HIF)-2α (hereafter referred to as HIFα). Instead, frequent low-dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre-clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11-gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra-metastatic tumor microenvironment.
Topics: Breast Neoplasms; Female; Humans; Lung Neoplasms; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 32686360
DOI: 10.15252/emmm.201911416 -
Clinical and Experimental Medicine Feb 2021Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a...
Metronomic chemotherapy has shown promising antitumor activity in a number of malignancies. We previously reported a phase II clinical trial of metronomic UFT (a 5-fluorouracil prodrug; 100 mg/twice per day p.o.) and cyclophosphamide (CTX; 500 mg/m i.v. bolus on day 1 and then 50 mg/day p.o.) plus celecoxib (200 mg/twice a day p.o.) in 38 patients with advanced refractory gastrointestinal tumors. The mechanisms of action of metronomic chemotherapy include inhibition of angiogenesis, direct cytotoxic effects on cancer cells, and, at least for drugs such as CTX, activation of the immune system. To further evaluate the latter, we carried out an immune system multiplex 14-cytokine profiling of plasma samples that were available (for day 0, day 28, and day 56) from 31 of the 38 patients in the above-noted clinical trial. Our results show that pre-treatment plasma-level cutoffs of interferon gamma (> 12.84 pg/ml), sCD40L (< 2168 pg/ml), interferon alpha 2 (> 55.11 pg/ml), and IL-17a (< 15.1 pg/ml) were predictive markers for those patients with better progression-free survival (p < .05 for each cytokine). After 28 days of metronomic therapy, the plasma levels of sCD40L, IL-17a, and IL-6 (< 130 pg/ml) could serve as predictors of improved progression-free survival, as could levels interferon gamma and sCD40L after 56 days of therapy. We observed minimal changes in cytokine profiles, from baseline, as a consequence of the metronomic therapy, with the exception of an elevation of IL-6 and IL-8 levels 28 days (and 56 days) after treatment started (p < 0.05). Our results indicate that a selective cytokine elevation involves IL-6 and IL-8, following metronomic chemotherapy administration. In addition, interferon gamma and sCD40L may be potential biomarkers for gastrointestinal cancer patients that are likely to benefit from metronomic chemotherapy. Our study contributes to our understanding of the mechanisms of action of metronomic chemotherapy, and the cytokine profiling we describe may guide future selection of gastrointestinal cancer patients for UFT/CTX/celecoxib combination metronomic chemotherapy.
Topics: Administration, Metronomic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cytokines; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Prognosis; Survival Rate
PubMed: 33048259
DOI: 10.1007/s10238-020-00666-9 -
Indian Journal of Cancer 2023Ovarian cancer is a leading cause of death from gynecological cancer in the world and in India. This study aims to evaluate the efficacy and toxicity profile of oral... (Observational Study)
Observational Study
BACKGROUND
Ovarian cancer is a leading cause of death from gynecological cancer in the world and in India. This study aims to evaluate the efficacy and toxicity profile of oral metronomic chemotherapy (MCT) in the form of etoposide, cyclophosphamide, and tamoxifen in recurrent and metastatic ovarian cancer.
METHODS
This was a retrospective observational study that included those post-treatment patients who had the recurrent or metastatic disease after completion of treatment in 2018 at Regional Cancer Centre, Bikaner, Rajasthan. Forty patients who were unfit for further intensive intravenous chemotherapy were included. The oral MCT constituted etoposide, cyclophosphamide, and tamoxifen. Descriptive statistics and Kaplan-Meier analyses were performed. Progression-free survival (PFS) and overall survival (OS) were assessed.
RESULTS
Forty women with a median age of 62 (range: 35-80) years were enrolled in the study to receive oral MCT. The Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) was 0-1 in 28 patients and 2-3 in 12 patients. The best clinical response rate post-oral MCT was seen in the first 4 months. Objective response was observed in 24 (60%) of patients in the form of stable disease (19, 47.5%) and partial response (5, 12.5%). Disease progression was observed in 10 (25%) of patients. The median follow-up was 6.4 months (4.5-9.2 months). The median estimated OS was 6.5 months. The median estimated PFS was 3.7 months. Nineteen (47.5%) patients had grade-I/II mucositis. Grade-III/IV mucositis were observed in 9 (22.5%) patients. Thirty-seven (92.5%) patients died at the end of the study at 1 year. Dose reduction was required in 15 (37.5%) patients.
CONCLUSION
Oral MCT was found to be an effective and well-tolerated regime with good symptomatic control and low-moderate toxicity profile in patients with relapsed and metastatic ovarian cancer. However, 22% of patients showed grade-III/IV thrombocytopenia.
Topics: Humans; Female; Adult; Middle Aged; Aged; Aged, 80 and over; Carcinoma, Ovarian Epithelial; Retrospective Studies; Etoposide; Mucositis; Administration, Metronomic; India; Cyclophosphamide; Ovarian Neoplasms; Tamoxifen; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37530237
DOI: 10.4103/ijc.IJC_143_20 -
Frontiers in Oncology 2022Predicting patient responses to chemotherapy regimens is a major challenge in cancer treatment. Experimental model systems coupled with quantitative mathematical models...
Predicting patient responses to chemotherapy regimens is a major challenge in cancer treatment. Experimental model systems coupled with quantitative mathematical models to calculate optimal dose and frequency of drugs can enable improved chemotherapy regimens. Here we developed a simple approach to track two-dimensional cell colonies composed of chemo-sensitive and resistant cell populations fluorescence microscopy and coupled this to computational model predictions. Specifically, we first developed multiple 4T1 breast cancer cell lines resistant to varying concentrations of doxorubicin, and demonstrated how heterogeneous populations expand in a two-dimensional colony. We subjected cell populations to varied dose and frequency of chemotherapy and measured colony growth. We then built a mathematical model to describe the dynamics of both chemosensitive and chemoresistant populations, where we determined which number of doses can produce the smallest tumor size based on parameters in the system. Finally, using an model we demonstrated multiple doses can decrease overall colony growth as compared to a single dose at the same total dose. In the future, this system can be adapted to optimize dosing strategies in the setting of heterogeneous cell types or patient derived cells with varied chemoresistance.
PubMed: 36505801
DOI: 10.3389/fonc.2022.980770 -
Frontiers in Oncology 2022Leptomeningeal metastases (LM) are rare and catastrophic for metastatic breast cancer (MBC). The prognosis of HER2-positive breast cancer (BC) with LM is extremely poor.... (Review)
Review
Leptomeningeal metastases (LM) are rare and catastrophic for metastatic breast cancer (MBC). The prognosis of HER2-positive breast cancer (BC) with LM is extremely poor. There is no high-quality evidence of treatment regimens in HER2-positive BC with LM yet. Here, we present a case of LM in a 50-year-old woman with HER2-positive BC. Immunohistochemistry revealed invasive ductal carcinoma, estrogen receptor negative, progesterone receptor negative, HER2 3+, P53 positive 80%, and Ki-67 positive 35%. Reported for the first time, the patient was given pyrotinib-targeted therapy (400 mg, oral, every day), metronomic vinorelbine (40 mg, oral, three times a week), and intrathecal methotrexate (10 mg, infrequent and irregular use due to poor compliance) synchronously. The patient received and benefited from the treatment regimen for 16 months. And the quality of life, as self-reported, improved significantly. We also comprehensively summarized all the case reports, observational studies, and clinical trials related to HER2-positive BC with LM in the PubMed database and ClinicalTrials.gov. Intrathecal chemotherapy (methotrexate, cytarabine, thiotepa), intrathecal trastuzumab, whole-brain radiotherapy, and systemic therapy are commonly used treatment options according to a review of the literature and research. Pembrolizumab and trastuzumab deruxtecan (DS-8201) as novel drugs are promising in LM. Furthermore, trastuzumab emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs) such as tucatinib and neratinib have exhibited good efficacy in HER2-positive BC with central nervous system (CNS) metastases and deserve further exploration. In our report, combining pyrotinib-targeted therapy with metronomic chemotherapy is a potential regimen, which has presented satisfactory therapeutic efficacy and also warrants additional investigation in HER2-positive BC with LM.
PubMed: 35251981
DOI: 10.3389/fonc.2022.811919 -
Cancer Research Communications Jul 2023Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and...
UNLABELLED
Prostate cancer is the second leading cause of noncutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiotherapy remain the primary treatment for patients with early-stage prostate cancer (castration-sensitive prostate cancer). Following ADT, many patients ultimately develop metastatic castration-resistant prostate cancer (mCRPC). Standard chemotherapy options for CRPC are docetaxel (DTX) and cabazitaxel, which increase median survival, although the development of resistance is common. Cancer stem-like cells possess mesenchymal phenotypes [epithelial-to-mesenchymal transition (EMT)] and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits prostate cancer growth by interfering with key cancer pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis [(RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq)], and we observed greater expression of several EMT markers, including , , , , , , and in European American and African American aggressive variant prostate cancer (AVPC) subtypes-mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene was also expressed highly in single-cell subclonal populations in mCRPC. Furthermore, metronomic-topotecan single agent and combinations with DTX downregulated these EMT markers as well as CD44 and CD44/CD133 "stem-like" cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single agent or in combination with DTX was potentially effective against invasive prostate cancer spread. Our RNA-seq and scRNA-seq analysis were supported by and studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.
SIGNIFICANCE
The utilization of metronomic-like dosing regimens of topotecan alone and in combination with DTX resulted in the suppression of makers associated with EMT and stem-like cell populations in AVPC models. The identification of molecular signatures and their potential to serve as novel biomarkers for monitoring treatment efficacy and disease progression response to treatment efficacy and disease progression were achieved using bulk RNA-seq and single-cell-omics methodologies.
Topics: Male; Humans; Docetaxel; Topotecan; Prostatic Neoplasms, Castration-Resistant; Administration, Metronomic; Androgen Antagonists; Epithelial-Mesenchymal Transition; Taxoids; Disease Progression; Carrier Proteins; Microfilament Proteins
PubMed: 37476073
DOI: 10.1158/2767-9764.CRC-22-0427 -
PloS One 2020To investigate the feasibility of using diffusion MRI (dMRI) and dynamic contrast-enhanced (DCE) MRI to evaluate the treatment response of metronomic chemotherapy (MCT)...
PURPOSE
To investigate the feasibility of using diffusion MRI (dMRI) and dynamic contrast-enhanced (DCE) MRI to evaluate the treatment response of metronomic chemotherapy (MCT) in the 4T1 mammary tumor model of locally advanced breast cancer.
METHODS
Twelve Balb/c mice with metastatic breast cancer were divided into treated and untreated (control) groups. The treated group (n = 6) received five treatments of anti-metabolite agent 5-Fluorouracil (5FU) in the span of two weeks. dMRI and DCE-MRI were acquired for both treated and control groups before and after MCT. Immunohistochemically staining and measurements were performed after the post-MRI measurements for comparison.
RESULTS
The control mice had significantly (p<0.005) larger tumors than the MCT treated mice. The DCE-MRI analysis showed a decrease in contrast enhancement for the control group, whereas the MCT mice had a more stable enhancement between the pre-chemo and post-chemo time points. This confirms the antiangiogenic effects of 5FU treatment. Comparing amplitude of enhancement revealed a significantly (p<0.05) higher enhancement in the MCT tumors than in the controls. Moreover, the MCT uptake rate was significantly (p<0.001) slower than the controls. dMRI analysis showed the MCT ADC values were significantly larger than the control group at the post-scan time point.
CONCLUSION
dMRI and DCE-MRI can be used as potential biomarkers for assessing the treatment response of MCT. The MRI and pathology observations suggested that in addition to the cytotoxic effect of cell kills, the MCT with a cytotoxic drug, 5FU, induced changes in the tumor vasculature similar to the anti-angiogenic effect.
Topics: Administration, Metronomic; Animals; Antimetabolites, Antineoplastic; Case-Control Studies; Contrast Media; Diffusion Magnetic Resonance Imaging; Feasibility Studies; Female; Fluorouracil; Longitudinal Studies; Magnetic Resonance Imaging; Mammary Neoplasms, Animal; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Treatment Outcome
PubMed: 33237905
DOI: 10.1371/journal.pone.0241916 -
Journal of B.U.ON. : Official Journal... 2021The purpose of this study was to investigate the efficacy and safety of maintenance therapy of capecitabine metronomic chemotherapy combined with autologous...
PURPOSE
The purpose of this study was to investigate the efficacy and safety of maintenance therapy of capecitabine metronomic chemotherapy combined with autologous cytokine-induced killer (CIK) cell immunotherapy in patients with recurrent metastatic triple-negative breast cancer (mTNBC).
METHODS
The clinical data of 110 patients with recurrent mTNBC were retrospectively analyzed. Among, 55 were treated with maintenance therapy of capecitabine metronomic chemotherapy combined with autologous CIK cell immunotherapy (DC-CIK group), while the rest 55 were treated with simple metronomic chemotherapy (control group).
RESULTS
The ORR of patients in DC-CIK group and control group was 29.1% and 16.4%, and the DCR was 74.5% and 63.6%, respectively. After treatment, the proportions of CD3+ T lymphocytes, CD4+ T lymphocytes and NK cells as well as the CD4/CD8 cell ratio were notably higher in DC-CIK group than those in control group, while the proportion of CD8+ T lymphocytes was notably lower in DC-CIK group than that in control group. Compared with those before treatment, the scores of quality of life evaluated using the FACT-B-V4.0 scale were remarkably improved in both groups after treatment. The score of emotional status and total score were distinctly higher in DC-CIK group than those in control group. Moreover, the follow-up results together with log-rank test revealed that the PFS in DC-CIK group was notably superior to that in control group.
CONCLUSIONS
The maintenance therapy of capecitabine metronomic chemotherapy combined with DC-CIK cell immunotherapy is effective in the treatment of recurrent mTNBC, with tolerable adverse reactions. It can improve the patients' immune function, improve their quality of life, and prolong their PFS. Key words: capecitabine, metronomic chemotherapy, immunotherapy, breast cancer, recurrent and metastatic.
Topics: Administration, Metronomic; Adult; Antimetabolites, Antineoplastic; Capecitabine; Combined Modality Therapy; Cytokine-Induced Killer Cells; Female; Humans; Immunotherapy, Adoptive; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies; Treatment Outcome; Triple Negative Breast Neoplasms
PubMed: 34268928
DOI: No ID Found