A case of non-palpating breast cancer with huge lymph node metastasis

We report a case of non-palpating breast cancer with huge lymph node metastasis. The patient was a 58-year-old woman who had a huge tumor at her right armpit. The tumor was 4 cm in diameter. Aspiration biopsy cytology for the tumor was performed. The diagnosis is Class V. Mammography showed an ill-defined mass at her right breast. Ultrasonography revealed a low echoic mass at the C area of her right breast. A core needle biopsy for the breast tumor led to a diagnosis of an invasive ductal carcinoma positive for estrogen receptor and progesterone receptor, and negative for HER2/neu protein expression. She received 4 cycles of CEF (E: 60 mg/tri-weekly) plus 12 cycles of paclitaxe (l80 mg/weekly). After chemotherapy, she received muscle preserving mastectomy plus axillary lymph nodes dissection. In histopathology, there were no carcinoma cells in resected breast tissue and resected lymph nodes. Therefore, the effect of chemotherapy was diagnosed as a pathological complete response. After operation, she was administered aromatase inhibitor. The patient has been well and remained disease-free during a follow-up period of 6 years.     

The combined effect of Paclitaxel and toremifene therapy for estrogen receptor positive and aromatase inhibitor resistant metastatic breast cancer

Multidrug resistance proteins such as P-glycoprotein (P-gp) are potential targets for improving the efficacy of paclitaxel (PTX), a mitotic inhibitor used in cancer chemotherapy. The selective estrogen receptor modulator toremifene (TOR) moderate P-gp was related to a drug resistance in vitro. A comparison of PTX alone with PTX+TOR in hormone-receptor-positive metastatic breast cancer patients (MBC) was conducted to determine the therapeutic value of adding TOR to a PTX regiment. Thirteen MBC patients received 80 mg/m2 PTX weekly (PTX group) and 14 MBC patients received the same weekly dose of PTX plus 120 mg/day TOR daily (PTX+TOR group). All 27 patients were repeatedly treated with a combination of PTX and TOR as long as disease progression or unmanageable severe adverse events were defined. The PTX group was compared with PTX+TOR group with respect to best overall response, response rate, clinical benefit rate, time to progression, adverse events and toxic profile of PTX and TOR. No significant difference in response rate was observed between the PTX group and the PTX+TOR group. However, clinical benefit rate and time to progression improved significantly in the PTX+TOR group in comparison with the PTX group. TOR did not significantly enhance the adverse events of PTX. These results suggested that combined treatment of PTX and TOR for MBC patients improves a patient response over PTX alone.     

Cross-resistance to ouabain in a murine leukemia cell variant selected for cis-dichlorodiammineplatinum(II) resistance

A murine leukemic cell line (R1.1) variant (R1.1/CDDPR-E8) resistant to cis-dichlorodiammineplatinum(II)(CDDP) was also found to be resistant to ouabain, a postulated specific inhibitor of sodium-potassium ATPase. The variant established by the culture of parental cells in step by step increasing concentrations of CDDP, exhibited 11-fold higher resistance to CDDP than the parental R1.1 cells. The present study suggests that a mutational change leading to an alteration in cell membrane characteristics associated with ouabain has also changed the sensitivity of cells against CDDP. Alternatively, the present data may indicate that the cytotoxicity of CDDP is closely linked to its effects on cell membrane.     

Photodynamic therapy using nanoparticle loaded with indocyanine green for experimental peritoneal dissemination of gastric cancer

Although there have been multiple advances in the development of novel anticancer agents and operative procedures, prognosis of patients with advanced gastric cancer remains poor, especially in patients with peritoneal metastasis. In this study, we established nanoparticles loaded with indocyanine green (ICG) derivatives: ICG loaded lactosomes (ICGm) and investigated the diagnostic and therapeutic value of photodynamic therapy (PDT) using ICGm for experimental peritoneal dissemination of gastric cancer. Experimental peritoneal disseminated xenografts of human gastric cancer were established in nude mice. Three weeks after intraperitoneal injection of the cancer cells, either ICGm (ICGm‐treated mice) or ICG solution (ICG‐treated mice) was injected through the tail vein. Forty‐eight hours after injection of the photosensitizer, in vivo and ex vivo imaging was carried out. For PDT, 48 h after injection of the photosensitizer, other mice were irradiated through the abdominal wall, and the body weight and survival rate were monitored. In vivo imaging revealed that peritoneal tumors were visualized through the abdominal wall in ICGm‐treated mice, whereas only non‐specific fluorescence was observed in ICG‐treated mice. The PDT reduced the total weight of the disseminated nodules and significantly improved weight loss and survival rate in ICGm‐treated mice. In conclusion, ICGm can be used as a novel diagnostic and therapeutic nanodevice in peritoneal dissemination of gastric cancer.     

OLFM4, LY6D and S100A7 as potent markers for distant metastasis in estrogen receptor‐positive breast carcinoma

Metastatic breast cancer is a highly lethal disease, and it is very important to evaluate the biomarkers associated with distant metastasis. However, molecular features of distant metastasis remain largely unknown in breast cancer. Estrogens play an important role in the progression of breast cancer and the majority of stage IV breast carcinomas express estrogen receptor (ER). Therefore, in this study, we examined molecular markers associated with distant metastasis in ER‐positive breast carcinoma by microarray and immunohistochemistry. When we examined the gene expression profile of ER‐positive stage IV breast carcinoma tissues (n = 7) comparing ER‐positive stage I‐III cases (n = 11) by microarray analysis, we newly identified OLFM4, LY6D and S100A7, which were closely associated with the distant metastasis. Subsequently, we performed immunohistochemistry for OLFM4, LY6D and S100A7 in 168 ER‐positive breast carcinomas. OLFM4, LY6D and S100A7 immunoreactivities were significantly associated with stage, pathological T factor, distant metastasis and Ki67 status in the ER‐positive breast carcinomas. Moreover, these immunoreactivities were significantly associated with a worse prognostic factor for distant metastasis‐free and breast cancer‐specific survival in ER‐positive stage I‐III breast cancer patients. However, when we performed immunohistochemistry for OLFM4, LY6D and S100A7 in 40 ER‐negative breast carcinomas, these immunoreactivities were not generally associated with the clinicopathological factors examined, including distant metastasis and prognosis of patients, in this study. These results suggest that OLFM4, LY6D and S100A7 immunoreactivity are associated with an aggressive phenotype of ER‐positive breast carcinoma, and these are potent markers for distant metastasis of ER‐positive breast cancer patients.     

Potential of a glucagon‐like peptide‐1 receptor/glucose‐dependent insulinotropic polypeptide receptor/glucagon receptor triagonist for the treatment of obesity and type 2 diabetes

Triagonists of GLP‐1R/ GIPR /GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus result in weight loss and glycemic control in obese T2D animal models.

Type 2 diabetes, which often accompanies obesity, is one of the major health‐threatening diseases worldwide. Incretin‐based therapies, such as dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, are used for the treatment of type 2 diabetes. The GLP‐1R agonists have been shown to improve glycemic control and reduce bodyweight through its various actions, including glucose‐dependent insulin secretion, suppression of glucagon secretion, and inhibition of gastric emptying and food intake ¹ .Recently, dual agonists of GLP‐1R and glucose‐dependent insulinotropic polypeptide receptor (GIPR), and those of GLP‐1R and glucagon receptor (GCGR) have been developed. One of the dual agonists of GLP‐1R and GIPR, named tirzepatide, has been shown to bind and activate both GLP‐1R and GIPR in vitro and in vivo, its efficacy for the treatment of type 2 diabetes has been proven in a phase III trial, and it has recently been approved by the US Food and Drug Administration ^{2 , 3} . In the phase III trial, once‐weekly injection of trizepatide (5, 10 or 15 mg) for 40 weeks reduced glycated hemoglobin (HbA1c) from baseline by 1.87, 1.89 or 2.07%, respectively, and reduced bodyweight from baseline by 7.0, 7.8 or 9.5 kg, respectively, in type 2 diabetes patients. The most frequent adverse events with trizepatide were gastrointestinal events ³ . In the clinical trial that compared trizepatide (5, 10 or 15 mg) with once‐weekly semaglutide (1 mg) in type 2 diabetes patients, trizepatide showed non‐inferior and superior reductions in HbA1c levels and in bodyweight ⁴ . For both treatments, gastrointestinal events were the most common adverse events ⁴ . The possible additional effects of GIP signaling in type 2 diabetes patients might depend on its augmentation of insulin secretion during hyperglycemic states ⁵ .The dual agonists of GLP‐1R and GCGR specific for mice or monkeys have been developed and were investigated their effects in each species. In obese and diabetic cynomolgus monkeys induced by high‐fat diet feeding, the monkey‐specific dual agonist of GLP‐1R and GCGR reduced total energy intake, decreased bodyweight and improved glucose tolerance ⁶ . However, in another study using obese diabetic monkeys, glycemic control was worse when they were co‐administered with both GLP‐1R and GCGR agonists compared with that treated with an GLP‐1R agonist alone ⁷ . Therefore, the significance of the activation of GCGR signaling has not yet been fully clarified.In 2015, Finan et al. ⁸ created a triagonist that activates GLP‐1R, GIPR and GCGR by selecting amino acids from the three peptide hormones, GLP‐1, GIP and glucagon, and reported that the triagonist reduced bodyweight and improved glucose control in rodent models of obesity and diabetes.More recently, Bossart et al. ⁹ developed a novel GLP‐1R, GIPR and GCGR triagonist, SAR441255. SAR441255 was confirmed to efficiently bind to and stimulate all three receptors in in vitro studies. In a diet‐induced obesity mouse model, subcutaneous injection of SAR441255 (0.3, 1, 3, 10 or 30 μg/kg) showed a dose‐dependent effect on bodyweight (+9.7%, +6.9%, +5.8%, −4.8% and −14.1%, respectively) compared with injection of vehicle (+11.5%). Non‐fasted blood glucose levels were significantly lower in mice treated with SAR441255 at doses of ≥1 μg/kg when compared with vehicle‐treated controls. In obese diabetic cynomolgus monkeys, treatment with SAR441255 (11 μg/kg) or a monkey‐specific GLP‐1R/GCGR dual agonist (4 μg/kg) ⁶ significantly reduced the bodyweight by −12.6% or −8.1%, respectively, and decreased the HbA1c levels by −1.37% or −1.85%, respectively. Fasting plasma glucose and alanine aminotransferase levels were significantly reduced with SAR441255, but not with the dual agonist (Figure 1).Open in a separate windowFigure 1Possible mechanisms of glucagon‐like peptide‐1 receptor (GLP‐1R)/glucose dependent insulinotropic polypeptide receptor (GIPR)/glucagon receptor (GCGR) triagonist in weight loss and glycemic control in obese type 2 diabetes animal models. Triagonists of GLP‐1R/GIPR/GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus resulting in weight loss and glycemic control in obese type 2 diabetes animal models. Potential effects of each receptor signaling that contribute to weight loss and/or better glycemic control are listed below each receptor.To further understand engagement of the different receptors in vivo, receptor occupancy of SAR441255 at the GLP‐1 and the GCG receptors was studied with the use of positron emission tomography imaging after radiotracer administration in lean cynomolgus monkeys. A subcutaneous injection of 11 μg/kg SAR411255 together with radiotracers specific for GLP‐1R and GCGR showed the significant signals of both receptors in the liver and pancreas of monkeys, suggesting the binding of SAR411255 to both receptors existing in these organs. Cardiovascular safety of SAR411255 was further confirmed in lean cynomolgus monkeys.Finally, a phase I study with SAR411255 in lean to overweight healthy participants was carried out to assess the safety, tolerability, pharmacokinetics and pharmacodynamics. After subcutaneous administration, SAR441255 concentration reached the median maximum serum concentration by 3.0–3.5 h, and was eliminated with a mean elimination terminal half‐life of 3.5–6.1 h. After administration of single doses (80 and 150 mg) of SAR441255 in the fasting state, maximal reduction in blood glucose levels were observed at 1 h post‐dose. At this time point, three of six participants who received the 80 mg dose and all six participants who received the 150 mg dose showed hypoglycemia (<70 mg/dL) without any clinical signs or symptoms. No further low blood glucose values were observed in either dose group. Blood glucose levels subsequently returned to baseline levels within 1–2 h. In contrast, fasting insulin and C‐peptide levels were relatively stable, and showed no correlation with the glucose levels. Therefore, the mechanisms of this early phase hypoglycemia have not yet been clarified. After the mixed‐meal test 3 h after the SAR441255 administration (80 and 150 mg), a dose‐dependent reduction in postprandial plasma glucose was observed. Because insulin and C‐peptide levels were also reduced during mixed‐meal test, postprandial plasma glucose reduction was suggested to be due to inhibition of gastric emptying, as observed with GLP‐1R engagement.Gastrointestinal disorders (nausea, vomiting, dry mouth and mouth ulceration) were the most frequent treatment‐emergent adverse events after treatment with SAR441255. All events were mild in severity, and occurred between 3 and 4 h after SAR441255 administration.To clarify the effects of SAR441255 on GIPR and GCGR in humans, specific biomarkers for each receptor were measured. As expected, a biomarker for GIPR activation, C‐telopeptide of cross‐linked type I collagen, which is a marker of bone turnover, was significantly reduced by >50% in participants who received SAR441255 administration (80 and 150 mg). Likely, plasma amino acids levels, which are sensitive biomarkers of GCGR activation, were reduced after SAR441255 administration in these individuals.As aforementioned, the dual agonists of GLP‐1R and GIPR might have comparable or even more stronger effects in reductions of HbA1c and bodyweight in obese type 2 diabetes patients ⁴ ; the significance of the activation of GCGR signaling should be evaluated to confirm the benefits of the triagonists of GLP‐1R, GIPR and GCGR. In this regard, the effects of glucagon to enhance energy expenditure partly through enhancement of fat and glucose oxidation could cover some of the benefits ⁷ , but further investigations should be necessary. In addition, it has recently been reported that GLP‐1R agonists have clinically significant cardiovascular benefits in type 2 diabetes patients ¹ . Therefore, it should be clarified if the dual or triagonists also have comparable cardiovascular benefits, as observed in GLP‐1R agonists in type 2 diabetes patients.Because triagonists have been shown to have better profiles in weight loss and glycemic control in animal models of obese type 2 diabetes compared with GLP‐1R agonists and dual agonists of GLP‐1R and GIPR or GLP‐1R and GCGR ^{8 , 9} , clinical studies that investigate the efficacy in type 2 diabetes patients should be of great interest.     

Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma

In order to identify genomic biomarkers for the outcome of mogamulizumab-containing treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNV)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P=0.024, and CR rate 71%, 40/56; P=0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNV/indels or copy number variations (CNV) such as homozygous deletion; CD28 alterations included SNV, CNV such as amplification, or fusion; CD274 alterations included CNV such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS) (hazard ratio [HR]: 2.330, 95% confidence interval [CI]: 1.183-4.589; HR: 3.191, 95% CI: 1.287-7.911; HR: 3.301, 95% CI: 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR: 0.286, 95% CI: 0.087-0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR: 2.467, 95% CI: 1.197-5.085; HR: 0.155, 95% CI: 0.031-0.778; HR: 14.393, 95% CI: 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.     

Pulmonary varix clearly demonstrated by 3D-CT before pulmonary angiography

Pulmonary varix is a rare and usually asymptomatic localized dilation of a pulmonary vein. This disease should be distinguished from other pulmonary and mediastinal diseases, particularly pulmonary arteriovenous malformations. Herein, we encountered a case of pulmonary varix clearly demonstrated by 3-dimensional reconstructed computed tomography (3D-CT) which proved useful in its diagnosis. The 3D-CT enabled easy understanding of the vascular connections and confirmation of the absence of an inflow pulmonary artery. We also performed angiography which showed findings consistent with those obtained by the 3D-CT, thus confirming the diagnosis of pulmonary varix. After the diagnosis, the patient was followed up for several years without any treatment and she remained asymptomatic. On follow-up CT, the lesion remained unchanged.