First-line Gemcitabine Versus Treatment of Physician's Choice for Metastatic Breast Cancer: A Prospective Cohort Study.

BACKGROUND/AIM: This study aimed to investigate the efficacy of first-line gemcitabine monotherapy for metastatic breast cancer (MBC) and its effect on health-related quality of life (HRQoL) compared with treatment of physician's choice (TPC). PATIENTS AND METHODS: We enrolled 96 patients into the first-line gemcitabine group (n=47) or other treatment of physician's choice (TPC) group (n=49) from May 2010 to April 2013. HRQoL was evaluated every 4 weeks. RESULTS: There was no significant difference in the median time to treatment failure (5.3 vs. 4.6 months, hazard ratio=0.87, p=0.546) and the incidence rates of grade 3/4 haematological toxicity (10.6% vs. 8.1%, p=0.677) and grade 3/4 non-haematological toxicity (4.2% vs. 8.1%, p=0.429) between the gemcitabine and TPC groups. Changes in HRQoL from baseline to 12 weeks were not significantly different. CONCLUSION: Gemcitabine achieves similar efficacy and HRQoL benefit to other chemotherapy and can be used as first-line treatment for MBC.

Negative feedback regulation of calcineurin-dependent Prz1 transcription factor by the CaMKK-CaMK1 axis in fission yeast.

Calcium signals trigger the translocation of the Prz1 transcription factor from the cytoplasm to the nucleus. The process is regulated by the calcium-activated phosphatase calcineurin, which activates Prz1 thereby maintaining active transcription during calcium signalling. When calcium signalling ceases, Prz1 is inactivated by phosphorylation and exported to the cytoplasm. In budding yeast and mammalian cells, different kinases have been reported to counter calcineurin activity and regulate nuclear export. Here, we show that the Ca(2+)/calmodulin-dependent kinase Cmk1 is first phosphorylated and activated by the newly identified kinase CaMKK2 homologue, Ckk2, in response to Ca(2+). Then, active Cmk1 binds, phosphorylates and inactivates Prz1 transcription activity whilst at the same time cmk1 expression is enhanced by Prz1 in response to Ca(2+). Furthermore, Cdc25 phosphatase is also phosphorylated by Cmk1, inducing cell cycle arrest in response to an increase in Ca(2+). Moreover, cmk1 deletion shows a high tolerance to chronic exposure to Ca(2+), due to the lack of cell cycle inhibition and elevated Prz1 activity. This work reveals that Cmk1 kinase activated by the newly identified Ckk2 counteracts calcineurin function by negatively regulating Prz1 activity which in turn is involved in activating cmk1 gene transcription. These results are the first insights into Cmk1 and Ckk2 function in Schizosaccharomyces pombe.

Breast cancer manifested by hematologic disorders.

Breast cancer is the most common type of cancer in women. However, it is very rarely manifested as hematologic disorders. A 35-year-old woman was admitted because of disseminated intravascular coagulation. Examinations revealed the presence of breast cancer in her left breast; therefore, paclitaxel was administered weekly. Although disseminated intravascular coagulation was controlled, pulmonary dysfunction due to lymphangitis carcinomatosa suddenly occurred 10 weeks after treatment. Pulmonary dysfunction was effectively treated with epirubicin and cyclophosphamide. Twenty-three weeks after treatment, the patient developed liver dysfunction accompanied with jaundice due to progressive metastatic lesions in the liver; liver dysfunction improved after the administration of vinorelbine. Subsequently, because of the recurrence of pulmonary dysfunction, rechallenge with epirubicin and cyclophosphamide was performed and was effective; however, this therapy was discontinued because of its adverse effects. She expired of liver failure 33 weeks after the occurrence of disseminated intravascular coagulation. Metastatic tumors in the bone marrow, lung, and liver showed different sensitivities to different anti-cancer agents. We report a case of breast cancer manifested by hematologic disorders which was treated by a sequential chemotherapy.

The topoisomerase II alpha gene status in primary breast cancer is a predictive marker of the response to anthracycline-based neoadjuvant chemotherapy.

This study aimed at evaluating the usefulness of topoisomerase II alpha (TOP2A) for predicting the effect of anthracycline-based neoadjuvant chemotherapy in breast cancer. The TOP2A status was examined using fluorescent in situ hybridization (FISH) in 14 pre-chemotherapeutic breast cancer tissues, and was also assessed by immunohistochemistry (IHC) in 14 pairs of pre- and post-chemotherapeutic breast cancer specimens. TOP2A gene aberration by IHC tended to show a correlation with pathological responses but this was not statistically significant (p=0.060). On the other hand, the low TOP2A/CEP17 ratio correlated with good pathological responses (p=0.012). TOP2A overexpression was not significantly associated with response (p=0.580). Our results thus suggest that the TOP2A/CEP17 ratio may be a useful predictor of the effects of anthracycline-based neoadjuvant chemotherapy in breast cancer.

Feasibility of AC/EC followed by weekly paclitaxel in node-positive breast cancer in Japan.

UNLABELLED: The feasibility and efficacy of adriamycin or epirubicin in combination with cyclophosphamide followed by weekly paclitaxel (AC/EC-weekly PAC) as adjuvant chemotherapy for breast cancer was investigated. PATIENTS AND METHODS: Node-positive breast cancer was treated with AC/ EC-weekly PAC, namely AC at 60/600 mg/m(2) or EC at 90/600 mg/m(2) x4 at three-week intervals, followed by weekly PAC (80 mg/m(2)) x 12, namely four cycles of single weekly administration for three weeks followed by a one-week rest (3 x 4 PAC) or single weekly administration for 12 consecutive weeks (12 PAC). RESULTS: One hundred and three of 109 consecutive patients enrolled were analyzed, of whom 96 (93.2%) completed the regimen. Grade 3/4 neutropenia occurred in 52.4% receiving AC/EC, and 10.9% of 55 receiving 12 PAC but only 2.1% of 48 receiving 3 x 4 PAC. Neuropathy disorders occurred in more than half receiving PAC, which did not improve after one-week rest in 3 x 4 PAC. CONCLUSION: AC/EC-weekly PAC is feasible and without serious complications.

Tumor doubling time and local immune response to hepatic metastases from colorectal cancer.

BACKGROUND AND OBJECTIVES: A number of studies have investigated the role of tumor-infiltrating lymphocytes in cancer, yet the local immune response to hepatic colorectal cancer metastasis remains unclear. As the tumor doubling time (DT) of hepatic colorectal cancer metastases is a good index of tumor growth, we examined the correlation between tumor DT and the local immune response by phenotype in hepatic colorectal cancer metastases. METHODS: Tumor DT and local immune response were examined in 20 patients with hepatic colorectal cancer metastases by analyzing tumor-infiltrating lymphocytes using flow cytometry or immunohistochemical studies. Tumor proliferative activity was also investigated by determining the expression levels of Ki-67 and proliferating cell nuclear antigen (PCNA). RESULTS: Locally abundant populations of CD83(+) dendritic cells (DCs) and CD8(+) T cells were positively related to longer tumor DT (P < 0.05), as were abundant CD8(+) T cells having interferon-gamma-producing potentials (P < 0.05). There was no significant correlation between tumor cell expression levels of Ki-67 or PCNA and tumor DT. CONCLUSIONS: Longer DT tumors have increased local populations of CD8(+) T cells and CD83(+) DCs even in hepatic colorectal cancer metastases.

Contrast harmonic imaging of canine hepatic tumors.

Six adult healthy Beagles were used to investigate the hepatic perfusion dynamics of Levovist, a contrast agent used in contrast harmonic imaging (CHI). In addition, 8 dogs with hepatocellular carcinoma (HCC) and 2 dogs with metastatic hepatic hemangiosarcoma (HSA) were used to characterize both the CHI findings with Levovist. In the Beagles, the start of intravenously injected Levovist into the aorta between the cranial mesenteric and renal arteries and the portal vein at the hepatic hilum were 5.47 +/- 1.52 sec and 16.03 +/- 3.39 sec, respectively. As a characteristic CHI finding in the 8 dogs with HCC, the early arterial phase showed a fine network of blood flow enhanced at the surrounding region and within the tumor in all the 8 dogs (100%), and the post vascular phase demonstrated a defect in the whole tumor and an enhancement of the surrounding hepatic tissues in 7 dogs (87.5%). In the 2 dogs with HSA, characteristic finding in which the early arterial and late vascular phases showed a rim contrast enhancement pattern, and the post vascular phase revealed that the whole tumor lacked contrast enhancement and the surrounding hepatic tissues was clearly enhanced. In dogs, the start of the early arterial and late vascular phases, and the characterizations of the CHI findings in HCC and HSA were suggested to be similar to those in humans. Therefore, CHI is thought to be useful for the diagnosis of HCC and metastatic hepatic HSA in dogs as well as in humans.

[Efficacy of circadian chronotherapy via hepatic arterial infusion].

For hepatectomy after neoadjuvant chemotherapy (NAC), we applied circadian chronotherapy via the hepatic artery for multiple bilobar liver metastases from colorectal cancer. Four patients underwent chronotherapy and 16 patients underwent flat infusion therapy (5 day q 2 weeks, 4 or more courses). We used 2 drugs, (5-fluorouracil (5-FU) and l-leucovorin (l-LV)), and partially added cisplatin (CDDP) in the flat infusion group. The result was a higher response rate (75% vs 37.5%) and lower toxicity (0% vs 31.3%) in the chronotherapy group. Hepatectomy was performed on 12 of the 20 patients. The 5 responders to NAC showed better overall survival (p < 0.05) and lower remnant liver recurrence (p = 0.052) than the 7 non-responders. We therefore conclude that chronotherapy via the hepatic artery prior to hepatectomy may improve the survival of patients with multiple bilobar liver metastases.