Further Reduction In Tumor Size Research Articles

Successful anti-PD-1 therapy in metastatic endometrial cancer with microsatellite instability: a case report

High efficacy of anti-PD-1 therapy has been shown in malignant tumors with mismatch repair deficiency. According to the literature review, mismatch repair deficiency is determined in 20–40 % of all endometrial cancer cases and up to 48 % of its endometrioid subtype. We report the short review of the recent literature and the case of durable partial response on pembrolizumab immunotherapy in a patient with a metastatic endometrioid adenocarcinoma with MMR-deficiency progressed on 2 chemotherapy lines. Partial response was achieved after 6th course, treatment was stopped after 8th course. Patient is on follow-up without any anticancer treatment for 11 months. Partial response lasts for 13 months, with further reduction in tumor size. The treatment was well tolerated without adverse events.

The ribosome inhibiting protein riproximin shows antineoplastic activity in experimental pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all malignancy types. To improve the survival of patients with PDAC, the development of novel anticancer agents is warranted. Riproximin (Rpx) is a newly identified plant lectin, which was isolated from Ximenia americana. The ribosome inactivating protein of type II exhibits potent anticancer activity as recently demonstrated. The rat PDAC cell line ASML was used for in vitro and in vivo studies. The antiproliferative effect of Rpx was assessed using an MTT assay. The modulation of proteins involved in apoptosis was evaluated using western blotting. Tumor-bearing nude rats were treated with Rpx, gemcitabine (GEM) or dinaline (DIN) as single agents, or a combination of Rpx with GEM, or DIN. Rpx was administered intraperitoneally at doses of 1.7–5.4 µg/kg, three times/week, GEM was administered intravenously (50 mg/kg/week) and DIN perorally (10 mg/kg, 5 times/week). Rpx inhibited ASML cell proliferation at IC50-values of 0.8–172 pM, caused apoptosis and reduced tumor growth significantly by 90% (P<0.05). The survival rate of rats was significantly increased (21.8 days for Rpx treated vs. 17.6 days for control rats; P=0.05). Higher doses of Rpx caused no further reduction in tumor size when compared with the low dose of Rpx or a combination of Rpx with GEM, or DIN. The standard drug GEM alone was less effective compared with Rpx. In addition, DIN was ineffective, and in combination, reduced the activity of Rpx. These results suggest that Rpx has an evident potential for use in pancreatic cancer treatment. Further experiments are required in order to elucidate its affinity for certain cancer cells and to optimize the combination therapy with other antineoplastic agents.

Fatal hemorrhage in a patient with advanced soft tissue sarcoma following radiation and pazopanib treatment: A case report.

A 71-year-old Japanese woman presented to the Department of Neurosurgery of Keio University School of Medicine (Tokyo, Japan) with a leiomyosarcoma originating in the infratemporal fossa and an 85-mm metastasis to the right lung. Since the pulmonary lesion was associated with risk of airway obstruction, radiation therapy (50 Gy/20 fractions) was administered to the patient, which resulted in remarkable tumor shrinkage. Subsequently, the patient was administered 800 mg/day pazopanib for 10 weeks, which resulted in further reduction in tumor size. However, the patient succumbed to a massive hemorrhage of sudden onset. Three possible explanations for the fatal hemorrhage are: i) adverse reaction to pazopanib; ii) side effects of radiation; and iii) remarkable tumor shrinkage. As a result, it may be proposed that the synergic effects of the aforementioned hypotheses may have been responsible for the bleeding observed in the present case. Therefore, clinicians should be alert to the possibility of this adverse event. In the present study, the first case of mortality due to massive hemorrhage following remarkable tumor shrinkage induced by radiation therapy and subsequent pazopanib treatment is reported.

Dose-Modified Ifosfamide, Epirubicin, and Etoposide is a Safe and Effective Salvage Therapy with High Peripheral Blood Stem Cell Mobilization Capacity for Poorly Mobilized Hodgkin's Lymphoma and Non-Hodgkin's Lymphoma Patients.

A dose modified ifosfamide, epirubicin, and etoposide (IVE) regimen was prospectively assessed for its efficacy in mobilizing peripheral blood stem cells for autologous transplantation. Two patients with Hodgkin's lymphoma and two with non-Hodgkin's lymphoma who were undergoing stem cell therapy were studied. All patients had a history of multiple treatments with insufficient stem cell mobilization. The dose modified IVE regimen consisted of ifosfamide 3 g/m(2) intravenously (IV) administered on days 1-2 in combination with epirubicin 50 mg/m(2) IV on day 1 and etoposide 200 mg/m(2) (100 mg/m(2) in two patients with complete remission) IV on days 1-3. The ifosfamide dosage was reduced to two-thirds of the original protocol. A substantial high yield of CD34(+) cells was achieved when patients were treated with a dose-modified IVE regimen, compared with that during the previous regimen (two with the ifosfamide, carboplatin, and etoposide [ICE] regimen, one with high-dose cyclophosphamide and one with the original IVE regimen). Two patients who had refractory and residual disease received a 200 mg/m(2) dose of etoposide, which resulted in tumor reduction (one patient with complete remission and one with further reduction in tumor size). After the IVE regimen, all four patients had a sufficient yield of CD34(+) cells in total, which was available for stem cell transplantation. Hematological and non-hematological toxicities were comparable in all regimens. This single-center prospective study demonstrated that the dose-modified IVE regimen can be used as a safe treatment with high mobilizing efficacy in heavily pretreated lymphoma patients.

Carfilzomib Overcomes Resistance to Bortezomib in the Human Lagk-1A Multiple Myeloma Xenograft Model

Introduction: We previously demonstrated that when carfilzomib (CFZ) was administered first to SCID mice bearing our human multiple myeloma (MM) xenografts, followed by the addition of melphalan (MEL) at the time of disease progression, a modest further reduction in tumor size was observed compared with continuing CFZ or adding MEL alone. In addition, substitution of single agent bortezomib (BOR) for CFZ showed no anti-MM effects. However, when MEL was administered first and CFZ was added after disease progression, mice treated with the combination showed a reduction in tumor volume compared with mice that discontinued MEL. Mice treated with CFZ alone showed no reduction in tumor size. Throughout the study, there was a trend toward smaller tumors among mice in which MEL was followed by the addition of CFZ when compared to mice in which MEL was continued or discontinued and treated with single-agent CFZ or vehicle alone. In the current study, we evaluated the anti-MM effects of CFZ, MEL and BOR for severe combined immunodeficient (SCID) mice progressing from BOR+MEL treatment using our human MM xenograft model LAGk-1A.Methods: Each SCID mouse was surgically implanted with a 20 – 40 mm3 LAGk-1A tumor piece into the left hind limb muscle. Seven days post-implantation mice were randomized into treatment groups based on human immunoglobulin (Ig) G levels. Carfilzomib stock solution (2 mg/ml) was diluted to 3 mg/kg using 5% dextrose and administered twice weekly on two consecutive days (Sundays and Mondays) via intravenous (i.v.) injection.Bortezomib stock solution (1 mg/ml) was diluted to 0.25 mg/kg using NaCl and administered twice weekly (Sundays and Tuesdays) via i.v. injection.MEL stock solution (3 mg/ml) was diluted to 1 mg/kg using PBS and administered once weekly (Fridays) via intraperitoneal injection. Mice (n = 10/group) were initially treated with the combination of BOR + MEL until tumor progression. Progression was defined as an increase in paraprotein > 25% confirmed on one consecutive assessment. After tumor progression, mice initially treated with BOR + MEL were randomized to continue to receive BOR + MEL, receive MEL only (discontinue BOR), receive BOR only (discontinue MEL), substitute BOR with CFZ, discontinue BOR + MEL and add in CFZ alone, or discontinue treatment altogether. Tumor size was measured using standard calipers and human IgG levels with an ELISA (Bethyl Laboratories, Montgomery, TX). This study was conducted according to protocols approved by the Institutional Animal Care and Use Committee.Results: Following progression from the combination of BOR + MEL among mice bearing LAGk-1A, substitution of these drugs with single agent CFZ alone did not produce a reduction in tumor volume when compared with mice continuing to receive BOR + MEL. However, significantly smaller tumors were observed when mice progressing from BOR + MEL were switched to CFZ + MEL compared with mice continued on BOR alone (P = 0.0044) or animals switched to CFZ alone (P = 0.05). There was a trend throughout the study toward smaller tumors in mice receiving CFZ + MEL when compared to mice continuing on BOR + MEL, receiving BOR, CFZ or vehicle alone or discontinuing BOR + MEL. Following progression from BOR + MEL, similar anti-MM effects were observed on human IgG (paraprotein) levels among animals treated with CFZ + MEL when compared to mice continuing BOR + MEL, receiving BOR alone switching to CFZ alone or discontinuing both BOR and MEL.Conclusions: These in vivo studies using our human MM xenograft model, LAGk-1A, show that SCID mice progressing from initial BOR + MEL treatment show a reduction in MM tumor burden when BOR is replaced with CFZ at the time of disease progression, and these tumors are significantly smaller than among mice continued on BOR + MEL. These studies demonstrate that once tumors progress from BOR + MEL treatment, CFZ can replace BOR and produce anti-tumor effects. A recent clinical trial confirms our preclinical findings and shows that most MM patients refractory to BOR in combination with other agents, including MEL, will respond to the substitution of CFZ for BOR (Berenson et al., Leukemia 2014). DisclosuresNo relevant conflicts of interest to declare.

Cabergoline therapy for Macroprolactinoma during pregnancy: A case report

BackgroundWe assessed the safety of Cabergoline therapy during pregnancy in a lady with hyperprolactinemia intolerant to Bromocriptine.Case presentationWe report the case of a 31 year old lady who presented to us with uncontrolled hyperprolactinemia. A pituitary Macroadenoma was demonstrated by MRI. Due to intolerance to Bromocriptine, Cabergoline was started. The patient improved and subsequently conceived. MRI in the second trimester demonstrated further reduction in the tumor size. It was decided to continue Cabergoline throughout pregnancy to ensure further reduction in tumor size until delivery and to hold Cabergoline during postpartum period to allow for an adequate interval of breastfeeding. At 37 weeks of gestation, the patient delivered a healthy baby.ConclusionWe were able to safely treat macroprolactinemia in our patient during pregnancy with cabergoline. This case report contributes to the relatively meager data available which advocates the safety of cabergoline therapy in pregnant hyperprolactinemic patients.

Optimal duration of chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC) in the first- and second-line settings

e19037 Background: No difference in efficacy has been observed between 3 or 4 vs 6 cycles of 1st line CT in patients (pts) with advanced NSCLC. Although longer treatment may improve progression-free survival, this must be weighed against increased toxicity and potential for worse quality of life. There are no prospective, randomized data on the optimal duration of 2nd line CT. The aims of this retrospective study were to (i) confirm the lack of impact of treatment duration on response rate in 1st line NSCLC and (ii) investigate the impact of treatment duration in the 2nd line setting. Methods: Eligible pts had received at least 4 cycles of 1st line (n=95) or 2nd line (n=55) CT for stage IIIB/IV NSCLC in clinical trials of the ATOM group, Udine, Italy, or the National Cancer Institute, Genoa, Italy and achieved stable disease or responded to treatment; trials included one in the elderly, and the addition of biological agents to CT. Response was assessed according to RECIST after alternate CT cycles and tumor dimensions recorded. The proportion of pts achieving a complete or partial response, as well as its timing and any subsequent tumor shrinkage, were analyzed by treatment line. Results: In the 1st line setting, 48 of 95 pts responded; they did so after 2 (29 pts, 61%), 4 (15 pts, 31%) and 6 cycles (4 pts, 8%). In these pts, 16 (55%) and 9 (41%) pts who had responded by the 2nd and 4th cycle respectively and continued on treatment showed further tumor shrinkage; the median further reduction in tumor size was 16% (range 1–52%) and 6% (range 1–11%), respectively. In the 2nd line setting, 12 of 55 pts responded; they did so after 2 (3 pts, 25%), 4 (7 pts, 58%), and 6 cycles (2 pts, 17%). One and two pts who had responded by the 2nd and 4th cycle respectively and continued on treatment showed further tumor shrinkage of 25%, 5% and 24%, respectively. Conclusions: Approximately 90% of CT-naive pts who responded did so by the 4th cycle; most such pts achieved only minor tumor reduction with further CT and did so at the likely expense of increased toxicity. In the 2nd line setting the achievement of response appeared slower. These results support the discontinuation of 1st CT after 4 cycles and suggest the same is true for 2nd line CT. No significant financial relationships to disclose.

Anti-proliferative effect of the gastrin-release peptide receptor antagonist RC-3095 plus temozolomide in experimental glioblastoma models

Malignant gliomas have a dismal prognosis despite multi-modality treatments like neurosurgical resection, radiation therapy and chemotherapy. Evidence has indicated that gastrin-releasing peptide (GRP) and its receptor (GRPR) play a role in the development of a variety of cancers including gliomas. In the present study, we investigated the effects of RC-3095, a selective GRPR antagonist, alone or in combination with temozolomide (TMZ), a DNA alkylating agent, in in vitro and in vivo experimental rat C6 glioma models. Cellular proliferation was significantly reduced by all treatments with the combined administration of TMZ and RC-3095 being the most effective treatment. In in vivo experiments, the control group displayed the largest tumors (52 +/- 15.5 mm(3)), whereas RC-3095 reduced the tumor size, with the most significant effect at the dose of 0.3 mg/kg (21 +/- 9.7 mm(3)). The combined therapy produced further reduction in tumor size (10 +/- 7.5 mm(3)). Our results show that the combination of RC-3095 with TMZ produced an important reduction in in vitro and in vivo glioma growth therefore making RC-3095 a candidate drug to potentiate the effects of the DNA alkylating agent TMZ in the treatment of glioma.

Intrahepatic chemoembolization in unresectable pediatric liver malignancies

To determine the effectiveness of a new multidisciplinary approach using neoadjuvant intrahepatic chemoembolization (IHCE) and liver transplant (OLTx) in patients with unresectable hepatic tumors who have failed systemic chemotherapy. From November 1989 to April 1998, 14 children (2-15 years old) were treated with 50 courses of intra-arterial chemotherapy. Baseline and post-treatment contrast-enhanced CT and alpha-fetoprotein levels were performed. Seven had hepatoblastoma, and 7 had hepatocellular carcinoma (1 fibrolamellar variant). All patients had subselective hepatic angiography and infusion of cisplatin and/or adriamycin (36 courses were followed by gelfoam embolization). The procedure was repeated every 3-4 weeks based on hepatic function and patency of the hepatic artery. Six of 14 children received orthotopic liver transplants (31 courses of IHC). Pretransplant, 3 of 6 showed a significant decrease in alpha-fetoprotein, while only 1 demonstrated a significant further reduction in tumor size). Three of 6 patients are disease free at this time. Three of 6 patients died of metastatic tumor 6, 38, and 58 months, respectively post-transplant. One of 14 is currently undergoing treatment, has demonstrated a positive response, and is awaiting OLTx. Three of 14 withdrew from the program and died. Four of 14 patients developed an increase in tumor size, developed metastatic disease, and were not transplant candidates. Two hepatic arteries thrombosed, and one child had a small sealed-off gastric ulcer as complications of intrahepatic chemoembolization. The results of intrahepatic chemoembolization are promising and suggest that some children who do not respond to systemic therapy can be eventually cured by a combination of intrahepatic chemoembolization orthotopic liver transplant. Alpha-fetoprotein and cross-sectional imaging appear to be complementary in evaluating tumor response. IHCE does not appear to convert an anatomically unresectable lesion to a candidate for partial hepatectomy.

Radiolabeled antibody therapy for squamous cell carcinoma of the head and neck.

Immunohistochemical staining for ferritin was performed on 11 human head and neck squamous cell carcinomas transplanted in nude mouse xenografts. Seven tumors were found to be positive. Using ferritin as a tumor antigen target, escalating doses of yttrium-90-labeled antiferritin antibodies were injected intravascularly into nude mice that were transplanted with a ferritin-positive human squamous cell carcinoma. Forty-five days after injection, the mean treated tumor size was 25.6% of control in the 100-microCi group, and 20.6% of control in the 200-microCi group. Ninety days after injection the mean tumor size was 27.5% that of control in the 100-microCi group and 31.7% in the 200-microCi group. Higher doses of radiation (300 and 400 microCi per mouse) caused death of most of the animals due to radiation toxicity. Presensitization of the animal, before antibody injection, with a bolus intraperitoneal injection of 7.5 mg of cisplatin per kilogram of body weight, resulted in further reduction in tumor size when compared with antibody alone or cisplatin alone. This study demonstrates that radioimmunotherapy with selected doses of yttrium-90-labeled antiferritin antibodies is effective against human head and neck squamous cell carcinoma xenografts in nude mice.