Anti-Angiogenic Effect of Orally Available Pemetrexed for Metronomic Chemotherapy

Metronomic chemotherapy (MCT) is defined as the frequent administration of low-dose chemotherapeutics, without long drug-free periods, with the exertion of antitumor activity exclusively through anti-angiogenic mechanisms. In this study, we have developed an orally available formulation of pemetrexed (PMX) for MCT. PMX was first complexed ionically with Nα-deoxycholyl-l-lysyl-methylester (DCK) as the permeation enhancer. This was followed by dispersion with poloxamer 188 and Labrasol to form the solid oral formulation of PMX (PMX/DCK-OP). PMX/DCK-OP exhibited a 10.6-fold increase in permeability across a Caco-2 cell monolayer compared to PMX alone. This resulted in a 70-fold increase in the oral bioavailability of PMX/DCK-OP in mice over oral PMX alone. In the A549 xenograft model, tumor volume was reduced by 51.1% in the PMX/DCK-OP treated group compared to only 32.8% in the maximum tolerated dose (MTD)-treated group. Furthermore, PMX/DCK-OP exhibited a significant anti-angiogenic effect on the A549 xenograft mice when compared to the MTD-treated group, as indicated by microvessel density quantification for CD-31. In addition, PMX/DCK-OP enhanced the release of an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), into both the blood circulation and the tumor microenvironment. Therefore, due to its oral route of administration, PMX/DCK-OP appears to be a better alternative to the conventional treatment of PMX.

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Metronomic Chemotherapy: A Systematic Review of the Literature and Clinical Experience

Journal of Oncology ◽

10.1155/2019/5483791 ◽

2019 ◽

Vol 2019 ◽

pp. 1-31 ◽

Cited By ~ 19

Author(s):

Cem Simsek ◽

Ece Esin ◽

Suayib Yalcin

Keyword(s):

Clinical Studies ◽

Lower Cost ◽

Metronomic Chemotherapy ◽

Maximum Tolerated Dose ◽

Cancer Management ◽

The Past ◽

Promising Therapeutic Approach ◽

Treatment Models ◽

Dose Dense ◽

Preclinical And Clinical Studies

Metronomic chemotherapy, continuous and dose-dense administration of chemotherapeutic drugs with lowered doses, is being evaluated for substituting, augmenting, or appending conventional maximum tolerated dose regimens, with preclinical and clinical studies for the past few decades. To date, the principle mechanisms of its action include impeding tumoral angiogenesis and modulation of hosts’ immune system, affecting directly tumor cells, their progenitors, and neighboring stromal cells. Its better toxicity profile, lower cost, and easier use are main advantages over conventional therapies. The evidence of metronomic chemotherapy for personalized medicine is growing, starting with unfit elderly patients and also for palliative treatment. The literature reviewed in this article mainly demonstrates that metronomic chemotherapy is advantageous for selected patients and for certain types of malignancies, which make it a promising therapeutic approach for filling in the gaps. More clinical studies are needed to establish a solidified role for metronomic chemotherapy with other treatment models in modern cancer management.

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A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3101 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3101-3101

Author(s):

Ying Cheng ◽

Ying Liu ◽

Jinhua Xu ◽

Jing Zhu ◽

Ying Wang ◽

...

Keyword(s):

Partial Response ◽

Phase I ◽

Solid Tumors ◽

Renal Cancer ◽

Phase I Study ◽

Angiogenesis Inhibitor ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Open Label ◽

Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

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Upregulated Talin1 Synergistically Boosts β-estradiol-induced Proliferation and Pro-angiogenesis of Eutopic and Ectopic Endometrial Stromal Cells in Adenomyosis

10.21203/rs.3.rs-181716/v1 ◽

2021 ◽

Author(s):

Yi-yi Wang ◽

Hua Duan ◽

Sha Wang ◽

Yong-jun Quan ◽

Jun-hua Huang ◽

...

Keyword(s):

Cell Proliferation ◽

Stromal Cells ◽

Stromal Cell ◽

Intervention Group ◽

Xenograft Model ◽

Treated Group ◽

Endometrial Stromal Cells ◽

Growth And Survival ◽

Human Carcinomas

Abstract Adenomyosis (ADS) is an estrogen-dependent gynecological disease with unspecified etiopathogenesis. Local hyperestrogenism may serve a central role in contributing the origin of ADS. Talin1 is mostly identified to be overexpressed and involved in the progression of numerous human carcinomas through mediating cell proliferation, adhesion and motility. Whether Talin1 exerts an oncogenic role in the development of ADS and presents an extra impact on the efficacy of estrogen, no relevant data are available yet. Here we demonstrated that the adenomyotic eutopic and ectopic endometrial stromal cells (ADS_Eu_ESC and ADS_Ec_ESC) treated with β-estradiol (β-E2) presented stronger proliferative and proangiogenetic capacities, accompanied by increased expression of PCNA, Ki67, VEGFB and ANGPTL4 proteins, compared with the controls. Meanwhile, these promoting effects were abrogated in the presence of Fulvestrant (ICI 182780, an estrogen-receptor antagonist). Aberrantly Upregulation of Talin1 mRNA and protein level was observed in ADS endometrial specimens and stromal cells. Through performing functional experiments in vitro, we further determined that merely overexpression of Talin1 (OV-Talin1) also enhanced ADS stromal cell proliferation and pro-angiogenesis, while the most pronounced facilitating effects were found in the co-intervention group of Talin1 overexpression plus β-E2 treatment. Results from the xenograft model showed that the hypodermic endometrial lesions from the co-treatment group with OV-Talin1 and β-E2 had the highest mean weight and volume, compared with that of individual OV-Talin1 or β-E2 treatment. The expression levels of PCNA, Ki67, VEGFB and ANGPTL4 in the lesions were correspondingly elevated most significantly in the co-treated group. Our findings unveiled that abnormally overexpressed Talin1 cooperated with E2 in stimulating ADS endometrial stromal cell proliferation and neovascularization, synergistically promoting the growth and survival of ectopic lesions. These results may be beneficial to provide a new insight for clarifying the pathogenesis of ADS.

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Abstract 3310: Human Peripheral Blood-derived CD31 + Cells Have Robust Angio-vasculogenic Properties And Enhance Recovery Following Hindlimb Ischemia

Circulation ◽

10.1161/circ.116.suppl_16.ii_745-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Sung-Whan Kim ◽

Hyun-Jai Cho ◽

Ji Yoon Lee ◽

Yong Jin Choi ◽

Young-sup Yoon

Keyword(s):

Peripheral Blood ◽

Network Formation ◽

Therapeutic Potential ◽

Human Peripheral Blood ◽

Therapeutic Option ◽

Fold Increase ◽

Treated Group ◽

Circulating Endothelial Cells ◽

Hindlimb Ischemia ◽

Murine Bone Marrow

Background: Recently, we reported that murine bone marrow derived CD31 + cells have hemangioblastic activities. In this study, we hypothesized that human peripheral blood derived CD31 + cells (hCD31 + ) have robust angio-vasculogenic potential and can induce therapeutic neovascularization in hindlimb ischemia. Methods and Results: hCD31 + cells were isolated using a magnetic bead separation technique. By FACS analysis, we confirmed that more than 98% of hCD31 + cells are positive for CD45, suggesting that hCD31 + cells are not circulating endothelial cells. In endothelial progenitor cell (EPC) culture assay, hCD31 + cells almost exclusively gave rise to EPCs and produced significantly higher colony forming activity than hCD31 - cells (n=5, each) (25.2 ± 2.2 vs. 3.6 ± 0.5/mm 2 , P<0.01). In the matrigel tube formation assay, coculturing HUVEC with hCD31 + cells revealed that hCD31 + cells robustly contributed to network formation with HUVECs suggestive of angio-vasculogenic activity. Real-time PCR showed that hCD31 + cells express higher levels of angiogenic genes (fold increase: angiopoietin-1, 5.6 ± 0.8; HGF, 2.7 ± 0.6; VEGF-A, 3.8 ± 0.5; FGF-2, 2.0 ± 0.5) and lower levels of inflammatory genes (fold decrease: Interferonγ, 13.2 ± 2.5; TNFα, 2.3 ± 0.9) than hCD31 − cells. To investigate therapeutic potential, we surgically induced hindlimb ischemia in athymic nude mice, and injected hCD31 + cells, hCD31 − cells and PBS into the ischemic limbs (n=9, each). The hCD31 + treated group showed a higher limb salvage rate than other groups [total salvage/tip necrosis/amputation; hCD31 + cells 5/4/0, hCD31 − cells 2/5/2, PBS control 0/5/4] (P<0.01). At 14 days, perfusion ratio and capillary density were significantly higher in the hCD31 + treated group compared to the hCD31 − and PBS treated groups. Histologic analysis demonstrated that a fraction of injected DiI-labeled hCD31 + cells exhibit endothelial phenotypes during the follow-up period of 8 weeks. Conclusion: The present study demonstrated that hCD31 + cells have robust angio-vasculogenic potential with low inflammatory activity, and enhanced post-ischemia recovery. These data suggested that hCD31 + cell transplantation may represent a novel therapeutic option for treating ischemic cardiovascular diseases.

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Development of orally bioavailable prodrugs of fulvestrant for the treatment of metastatic/advanced breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13027 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13027-e13027

Author(s):

Parva Purohit ◽

Pathik Brahmkshatriya ◽

Vishalgiri Goswami

Keyword(s):

Breast Cancer ◽

Oral Delivery ◽

Tumor Volume ◽

Estrogen Therapy ◽

Xenograft Model ◽

Fold Increase ◽

Tumor Growth Inhibition ◽

Pharmacokinetic Studies ◽

Hormone Receptor Positive ◽

Mcf 7

e13027 Background: Fulvestrant, a potent, selective estrogen receptor degrader, is a primary drug of choice for treating advanced metastatic hormone receptor-positive breast cancer in postmenopausal women following anti-estrogen therapy. However, the existing therapy limits to inconvenient intramuscular injections due to low solubility, weak permeation, high metabolism, and poor pharmacokinetics profile. Additionally, it takes 30 days to reach maximal steady-state plasma concentration, limiting clinical efficacy. To overcome these issues, we modulated physicochemical properties of fulvestrant, enabling its oral delivery to improve bioavailability. Methods: Structurally diverse pro-moieties were appended on fulvestrant to improve solubility and ADME profile. Thermodynamic solubility, plasma/liver microsomal stability, and Caco-2 permeability studies were performed to identify lead molecules. Pharmacokinetic studies were performed for selected molecules in mice. Antitumor activity of once-daily oral dose of three molecules was evaluated in female nude mice using the MCF-7 xenograft model. The efficacy of lead molecules was compared with subcutaneously administered faslodex in terms of percentage tumor growth inhibition. Results: Several prodrugs of fulvestrant were synthesized and evaluated for their intrinsic properties suitable for increasing bioavailability of fulvestrant. Remarkable improvements (̃500 to 2000-fold increase) were achieved in solubility and permeability. The PoC established an increase in systemic plasma exposure of fulvestrant upon oral administration of prodrugs in mice with enhanced bioavailability (1.5-8.7-fold) as compared to fulvestrant given subcutaneously (Table). Herewith, we report the identification of KSHN001022, KSHN001075, and KSHN001126, the prodrugs of fulvestrant, which showed enhanced efficacy with better tumor volume reduction (̃48-88% regression in tumor volume) as compared to that of fulvestrant (78%) in the estrogen-dependent MCF-7 xenograft model. Conclusions: KSHN001 lead candidates demonstrated significantly higher bioavailability, hence, provides a novel strategy to deliver fulvestrant orally to pursue the potential benefits in patients with advanced metastatic disease.[Table: see text]

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Identification of the c-kit ligand: end of the road for understanding aplastic anemia in steel mutant mice?

Blood ◽

10.1182/blood.v78.6.1428.1428 ◽

1991 ◽

Vol 78 (6) ◽

pp. 1428-1431 ◽

Cited By ~ 3

Author(s):

K Pantel ◽

J Boertman ◽

A Nakeff

Keyword(s):

Fold Increase ◽

Treated Group ◽

Negative Control ◽

The Road ◽

Kit Ligand ◽

Normal Littermate ◽

Hematopoietic Recovery ◽

Complete Restoration ◽

Stem And Progenitor Cells ◽

Marrow Cellularity

Abstract We here report the initiation of hematopoietic recovery in congenitally hypoplastic S1/S1d mice by the cytotoxic ablation of cells bearing the natural killer (NK) phenotype (NK 1.1+). The most striking finding was the early several-fold increase in the cycling fraction of stem and progenitor cells (with the exception of progenitors committed to megakaryocytopoiesis) in the anti-NK 1.1+ antibody-treated group. This increase resulted in an early, complete restoration of total marrow cellularity to the normal (+/+) littermate level. Our data suggest that NK 1.1+ cells exert functions critical to the negative control of hematopoietic cell proliferation in S1/S1d mice.

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CHARACTERIZATION OF DISORDERS OF PLATELET-VESSEL WALL INTERACTION IN AN AGGREGOMETER INCORPORATING BLOOD FLOW PAST AN ENDOTHELIAL CELL MONOLAYER

10.1055/s-0038-1644537 ◽

1987 ◽

Author(s):

E F Grabowski ◽

K McKenny

Keyword(s):

Endothelial Cell ◽

Cell Monolayer ◽

Fold Increase ◽

Flow Chamber ◽

Fluorescent Label ◽

Endothelial Cell Monolayer ◽

Flowing Blood ◽

Normal States ◽

Wall Interaction

Epi-fluorescence videomicroscopy permits real-time imaging of platelet (plt) adhesion-aggregation to a defined microinjury site of an endothelial cell monolayer (ECM) exposed to flowing blood. The fluorescent label is the TAB murine monoclonal antibody (courtesy of Dr. R.P. McEver) directed against human pit cp HB, together with a fluorescein-conjugated goat F(ab')2 against murine immunoglobulin. The combination assures specificity for pit membranes, yet leaves pit function intact. Bovine aortic ECM, grown on rectangular cover glasses, comprise one wall of a flow chamber mounted on a vertical microscope stage. A 6-0 sterile suture, drawn across the ECM in a direction transverse to flow, creates microinjuries of width 70 ± 15 (mean ± SD). Pit deposition is virtually absent upon intact and confluent regions of the ECM. On microinjury sites and at a shear rate of 270 sec-1, however, computer-enhanced images show pit adherence, aggregation, and embolization. Pretreatment of the ECM with 1.0 mMFC lysine acetyl salicylate, further, leads to a three-fold increase in aggregate length. ECM products inhibitable by aspirin, therefore, modulate adhesion-aggregation in disease and normal states under physiologic flow conditions. The Table shows that nercent coverage of the injury area, and mean aggregate length readily discriminate normal, post-aspirin, and von Willebrand's (vWD's) bloods. Aggregate length is reduced in vWD's blood to a greater degree (p<0.01) than by oral aspirin, while the latter is associated with a paradoxic increase (p<0.01) in single plt adhesion.

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Uracil-ftorafur: an oral fluoropyrimidine active in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.10.3461 ◽

1998 ◽

Vol 16 (10) ◽

pp. 3461-3475 ◽

Cited By ~ 42

Author(s):

A Sulkes ◽

S E Benner ◽

R M Canetta

Keyword(s):

Colorectal Cancer ◽

Single Agent ◽

Objective Response ◽

Response Rates ◽

The United States ◽

Maximum Tolerated Dose ◽

Oral Route ◽

Western World ◽

Oral Fluoropyrimidine ◽

Hand Foot Syndrome

PURPOSE AND DESIGN This review describes the early clinical development of uracil-ftorafur (UFT), an oral fluoropyrimidine, designed in 1978 by adding uracil to ftorafur. The review focuses on the treatment of colorectal cancer and summarizes the Japanese experience and the phase I and II trials performed in the United States and Europe. RESULTS Clinical trials of UFT published in the Western world have included 581 patients with colorectal cancer. UFT has been administered in these trials as a single agent or biomodulated by leucovorin (LV). UFT was administered daily in split doses for periods that ranged from 14 to 28 days. The activity of oral UFT in large-bowel cancer when administered with oral LV (approximately 50 mg/dose) has resulted in objective response rates of approximately 40%. Response rates of approximately 25% (range, 17% to 39%) were reported when UFT was administered as a single agent or with lower doses of LV. The highest dose-intensities of UFT are achieved with 28-day schedules of administration. The maximum-tolerated dose (MTD) of UFT with this schedule, when administered concomitantly with oral LV 150 mg daily, is 300 mg/m2 daily. The dose-limiting toxicity (DLT) of UFT has generally been diarrhea. Other commonly described toxicities include nausea and vomiting, fatigue, and stomatitis. Myelosuppression occurs infrequently. Typically, hand-foot syndrome and neurologic toxicity are lacking. CONCLUSION UFT is a fluoropyrimidine active in colorectal cancer. The oral route of administration and improved safety profile represent important advantages over both conventional and infusional fluorouracil (5-FU) regimens.

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Amelioration of ferric nitrilotriacetate-induced hepatotoxicity in Wistar rats by diallylsulfide

Human & Experimental Toxicology ◽

10.1177/0960327115583362 ◽

2015 ◽

Vol 35 (3) ◽

pp. 259-266 ◽

Cited By ~ 5

Author(s):

S Ansar ◽

M Iqbal

Keyword(s):

Lipid Peroxidation ◽

Corn Oil ◽

Tissue Injury ◽

Fold Increase ◽

Treated Group ◽

Pharmaceutical Products ◽

Albino Rats ◽

Ferric Nitrilotriacetate ◽

Hepatic Lipid Peroxidation ◽

Hydrogen Peroxide Generation

Garlic contains diallylsulfide (DAS) and other structurally related compounds that are widely believed to be active agents in preventing cancer. This study shows the effect of DAS (a phenolic antioxidant used in foods, cosmetics, and pharmaceutical products) on ferric nitrilotriacetate (Fe-NTA)-induced hepatotoxicity in rats. Male albino rats of Wistar strain weighing 125–150 g were given a single dose of Fe-NTA (9 mg kg−1 body weight, intraperitoneally) after 1 week of treatment with 100 and 200 mg kg−1 DAS in corn oil respectively administered through the gavage. Fe-NTA administration led to 2.5-fold increase in the values of both alanine transaminase and aspartate aminotransferase, respectively, and 3.2-fold increase in the activity of lactate dehydrogenase, microsomal lipid peroxidation to approximately 2.0-fold compared to saline-treated control. The activities of glutathione (GSH) and other antioxidant enzymes decreased to a range of 2.2–2.5-fold. These changes were reversed significantly ( p < 0.001) in animals receiving a pretreatment of DAS. DAS protected against hepatic lipid peroxidation, hydrogen peroxide generation, preserved GSH levels, and GSH metabolizing enzymes to 60–80% as compared to Fe-NTA alone-treated group. Present data suggest that DAS can ameliorate the toxic effects of Fe-NTA and suppress oxidant-induced tissue injury and hepatotoxicity in rats.

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Metastatic feline mammary cancer: prognostic factors, outcome and comparison of different treatment modalities – a retrospective multicentre study

Journal of Feline Medicine and Surgery ◽

10.1177/1098612x20964416 ◽

2020 ◽

pp. 1098612X2096441

Author(s):

Gonçalo Petrucci ◽

Joaquim Henriques ◽

Hugo Gregório ◽

Gonçalo Vicente ◽

Justina Prada ◽

...

Keyword(s):

Metastatic Disease ◽

Adjuvant Treatment ◽

Imaging Techniques ◽

Treatment Options ◽

Clinical Signs ◽

Stage Iv ◽

Metronomic Chemotherapy ◽

Maximum Tolerated Dose ◽

Treatment Modalities ◽

Number Of Patients

Objectives Although feline mammary carcinomas (FMCs) are highly metastatic, the literature and treatment options pertaining to advanced tumours are scarce. This study aimed to investigate the clinical outcome of metastatic FMC with or without adjuvant treatment. Methods The medical records of 73 cats with metastatic FMC (stage 4) were reviewed and included in this study. Metastatic disease was detected by distinct imaging techniques (radiography, ultrasound and CT) and confirmed by cytology and/or histopathology. Cats with adjuvant chemotherapy treatment (n = 34) were divided into three groups: group 1 (n = 9) cats receiving maximum tolerated dose chemotherapy; group 2 (n = 15) cats receiving metronomic chemotherapy; and group 3 (n = 10) cats treated with toceranib phosphate. The study endpoints were time to progression (TTP) and tumour-specific survival (TSS). Treatment-related toxicity was evaluated according to the Veterinary Co-operative Oncology Group’s Common Terminology Criteria for Adverse Events version 1.1 (VCOG-CTCAE). Results Overall mean TTP and TSS were 23 and 44 days, respectively. Cats with clinical signs at the time of diagnosis had a lower TSS (14 days) than asymptomatic cats (120 days; P <0.001). Cats with pleural effusion had a lower TSS (16 days) than cats without ( P <0.001). Median TSS was 58, 75 and 63 in groups 1, 2 and 3, respectively ( P = 0.197). Toxicity was observed in 66.7%, 20% and 30% of cats in groups 1, 2 and 3, respectively. Conclusions and relevance To the best of our knowledge, this study includes the highest number of patients with metastatic FMC assessed. Despite the overall poor prognosis, some cats survived >6 months, indicating that adjuvant treatment may be an option to consider in metastatic disease. More studies are warranted for better understanding and management of stage IV patients.

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