Using the geriatric nutritional risk index to predict outcomes in older patients with remnant gastric cancer after gastrectomy: a retrospective multicenter study in Japan.

PURPOSE: This study investigated the prognostic value of the geriatric nutritional risk index (GNRI) in patients undergoing curative gastrectomy for remnant gastric cancer (RGC). METHODS: This multicenter retrospective study included 105 patients with RGC of ≥ 65 years of age who underwent curative gastrectomy at 10 institutions in Japan between January 2000 and December 2016. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) were analyzed. RESULTS: Receiver operating curve analyses indicated that the optimal cutoff value of the GNRI for OS was 95.4. Patients were categorized into high and low GNRI groups based on the optimal GNRI cutoff value. The GNRI was significantly correlated with body mass index (p < 0.001), amount of bleeding (p = 0.021), Clavien-Dindo grade 5 postoperative complications (p = 0.040), death caused by primary disease (p = 0.010), and death caused by other diseases (p = 0.002). The OS and DSS were significantly worse in the low GNRI group. A low GNRI and T3 or deeper tumor invasion were independent prognostic factors for OS and DSS. CONCLUSIONS: The GNRI is a promising predictor of both short- and long-term outcomes in older patients with RGC.

Repurposing of the Cardiovascular Drug Statin for the Treatment of Cancers: Efficacy of Statin-Dipyridamole Combination Treatment in Melanoma Cell Lines.

Metastatic melanoma has a very poor prognosis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, are cholesterol-lowering agents with a potential for cancer treatment. The inhibition of HMGCR by statins, however, induces feedback, which paradoxically upregulates HMGCR expression via sterol regulatory element-binding protein-2 (SREBP2). Dipyridamole, an antiplatelet agent, is known to inhibit SREBP2 upregulation. We aimed to demonstrate the efficacy of statin-dipyridamole combination treatment in both human and spontaneously occurring canine melanoma cell lines. The half maximal inhibitory concentration (IC50) of atorvastatin showed a 68-92% reduction when combined with dipyridamole, compared with that of atorvastatin alone. In some melanoma cell lines, cell proliferation was suppressed to almost zero by the combination treatment (≥3 µM atorvastatin). Finally, the BRAF inhibitor, vemurafenib, further potentiated the effects of the combined statin-dipyridamole treatment in BRAF V600E mutation-bearing human melanoma cell lines. In conclusion, the inexpensive and frequently prescribed statin-dipyridamole combination therapy may lead to new developments in the treatment of melanoma and may potentiate the effects of vemurafenib for the targeted therapy of BRAF V600E-mutation bearing melanoma patients. The concordance between the data from canine and human melanoma cell lines reinforces this possibility.

In vitro evaluation of the efficacy of photodynamic therapy using 5-ALA on homologous feline mammary tumors in 2D and 3D culture conditions and a mouse subcutaneous model with 3D cultured cells.

BACKGROUND: Numerous studies have shown that photodynamic therapy (PDT) has a therapeutic effect on mammary tumor cells, with 5-aminolevulinic acid (5-ALA-HCL) being a commonly used photosensitizer for PDT. Feline mammary tumors (FMTs) are relatively common. However, the cytotoxic and antitumor effects of 5-ALA-PDT on FMTs have not been clarified. To this end, we evaluated the therapeutic effect of 5-ALA-PDT on FMTs through in vitro experiments using an FMT FKR cell line established for this study. METHODS: We performed 5-ALA-PDT in 2D-cultured FKR-A (adherent cells) and 3D-cultured FKR-S (spheroid cells) cells and performed a series of studies to evaluate the cell viability and determine the protoporphyrin IX (PpIX) content in the cells as well as the expression levels of mRNAs associated with PpIX production and release. An in vivo study was performed to assess the effectiveness of 5-ALA-PDT. RESULTS: There was a significant difference in the concentration of PpIX in FMT cells under different incubation culture modes (2D versus 3D culture). The concentration of PpIX in FMT cells was correlated with the differences in cell culture (2D and 3D) as well as the expression levels of genes such as PEPT1, PEPT2, FECH, and HO-1. CONCLUSIONS: In the in vitro study, 5-ALA-PDT had a stronger inhibitory effect on 3D-cultured FKR-S cells, which resemble the internal environment of organisms more closely. We also observed a significant inhibitory effect of 5-ALA-PDT on FMT cells in vivo. To our knowledge, this is the first study on 5-ALA-PDT for FMTs under both 2D and 3D conditions.

Comparison of the anticancer effects of various statins on canine oral melanoma cells.

Canine oral melanoma is a highly malignant cancer with a poor prognosis. Statins, commonly used drugs for treating dyslipidemia, exhibit pleiotropic anticancer effects and marked anti-proliferative effects against melanoma cells. The anticancer effects among statins vary; in human cancers, lipophilic statins have shown stronger anticancer effects compared with hydrophilic statins. However, data on the differences in the effects of various statins on canine cancer cells are lacking, hence the optimal statins for treating canine melanoma remain unknown. Therefore, this study aimed to clarify the most effective statin by comparing the anticancer effects of hydrophilic rosuvastatin and lipophilic atorvastatin, simvastatin, fluvastatin and pitavastatin on three canine oral melanoma cell lines. Time-dependent measurement of cell confluence showed that lipophilic statins had a stronger anti-proliferative effect on all cell lines than hydrophilic rosuvastatin. Quantification of lactate dehydrogenase release, an indicator of cytotoxicity, showed that lipophilic statins more effectively induced cell death than hydrophilic rosuvastatin. Lipophilic statins affected both inhibition of cell proliferation and induction of cell death. The anticancer effects of statins on canine oral melanoma cells differed in the following ascending order of IC50 values: pitavastatin < fluvastatin = simvastatin < atorvastatin < rosuvastatin. The required concentration of pitavastatin was approximately 1/20th that of rosuvastatin. Among the statins used in this study, pitavastatin had the highest anticancer effect. Our results suggest lipophilic pitavastatin as the optimal statin for treating canine oral melanoma.

Vascular-targeted photodynamic therapy with glucose-conjugated chlorin e6 for dogs with spontaneously occurring tumours.

BACKGROUND: Photodynamic therapy (PDT) using photosensitisers is a minimally invasive treatment for malignant tumours. However, ideal photosensitisers are not yet established. Recently, we developed a new photosensitiser, glucose-conjugated chlorin e6 (G-Ce6). OBJECTIVES: To evaluate the clinical efficacy of vascular-targeted PDT (VTP), a type of PDT utilising a short drug-light interval, using G-Ce6 to treat spontaneously occurring tumours in dogs. METHODS: Five dogs with spontaneously occurring tumours (malignant melanoma: three; haemangiopericytoma: two; and squamous cell carcinoma: one) were subjected to VTP. These dogs were intravenously injected with G-Ce6 at doses of 1-3 mg/kg 5 min before laser irradiation. Tumours were superficially or interstitially irradiated using a 677-nm diode laser. RESULTS: Repeated VTP decreased tumour size, yielding complete remission in three dogs. Complications such as oedema surrounding normal tissues and fistulae were observed, and the oedema was self-limiting. The fistula was cured by debriding the necrotic tissues formed after VTP. CONCLUSIONS: Our findings demonstrate that VTP using G-Ce6 had antitumour effects in dogs with spontaneously occurring tumours.

Impact of Frailty and Sarcopenia on Short- and Long-Term Outcomes in Elderly Patients Undergoing Radical Gastrectomy for Gastric Cancer.

BACKGROUND: The impact of frailty and sarcopenia in patients with gastric cancer is unclear. This study aimed to comprehensively examine the impact of frailty and sarcopenia on the short- and long-term outcomes in elderly patients undergoing radical gastrectomy for gastric cancer. METHODS: We retrospectively assessed 246 patients aged ≥ 65 years who underwent radical gastrectomy. Frailty and sarcopenia were assessed using the modified frailty index (mFI) and psoas muscle mass index (PMI), respectively. RESULTS: There were 30 (12.2%) and 60 (24.4%) patients with High-mFI and Low-PMI, respectively. As the age increased, both sexes showed significant correlations with PMI and mFI (r = - 0.238, 0.322, P = 0.003 and 0.002, respectively). High-mFI and Low-PMI did not affect the short-term outcomes. However, High-mFI was an independent risk factor for non-home discharge (P = 0.004) and was a significant predictor of 3- and 5-year overall survival (OS) (HR = 2.76 and 2.26; P = 0.002 and 0.005, respectively) and 1-, 3- and 5-year non-cancer-specific survival (non-CSS) (HR = 4.88, 8.05, and 4.01; P = 0.017, < 0.001, < 0.001, respectively). Low-PMI was a significant predictor of only 5-year OS (HR = 2.03, P = 0.003) and non-CSS (HR = 2.10, P = 0.020). CONCLUSIONS: Frailty is significant predictor of non-home discharge and 1-, 3-, 5-year OS and 3- and 5-year non-CSS. Sarcopenia is a significant predictor of 5-year OS and non-CSS. Preoperative assessment of both frailty and sarcopenia can help surgeons to select adequate treatment strategies for the elderly population.

Gastrotomy approach for removal of an oesophageal foreign body in a dog.

A 9-year-old castrated male Kaninchen dachshund dog weighing 4.18 kg was referred to our institution and presented with occasional vomiting and dysphagia. The radiographic examination revealed a long radiopaque foreign body located throughout the thoracic oesophagus. Endoscopic removal was attempted using laparoscopic forceps but was unsuccessful as the foreign body was too large to be grasped. A gastrotomy was therefore performed, and long paean forceps were gently and blindly inserted into the cardia of the stomach. The bone foreign body was grasped with the long paean forceps under fluoroscopy and withdrawn from the oesophagus while checking with an endoscope. A gastrotomy approach using long forceps, endoscopy and fluoroscopy should be considered for removal of oesophageal foreign bodies from patients in which an endoscopic approach has been unsuccessful.

Comparison of Characterization in Two-Dimensional and Three-Dimensional Canine Mammary Gland Tumor Cell Models.

Background: Canine mammary gland tumors can be used as predictive models for human breast cancer. There are several types of microRNAs common in human breast cancer and canine mammary gland tumors. The functions of microRNAs in canine mammary gland tumors are not well understood. Methods: We compared the characterization of microRNA expression in two-dimensional and three-dimensional canine mammary gland tumor cell models. We evaluated the differences between two- and three-dimensional cultured canine mammary gland tumor SNP cells by assessing microRNA expression levels, morphology, drug sensitivity, and hypoxia. Results: The expression of microRNA-210 in the three-dimensional-SNP cells was 10.19 times higher than that in the two-dimensional-SNP cells. The intracellular concentrations of doxorubicin in the two- and three-dimensional-SNP cells were 0.330 ± 0.013 and 0.290 ± 0.048 nM/mg protein, respectively. The IC50 values of doxorubicin for the two- and three-dimensional-SNP cells were 5.2 and 1.6 µM, respectively. Fluorescence of the hypoxia probe, LOX-1, was observed inside the sphere of three-dimensional-SNP cells without echinomycin but not in two-dimensional-SNP cells. The three-dimensional-SNP cells treated with echinomycin showed weak LOX-1 fluorescence. Conclusion: The present study showed a clear difference in microRNA expression levels in cells cultured in a two-dimensional adherent versus a three-dimensional spheroid model.

The prognostic impact of the lymphocyte-to-C-reactive protein ratio in patients with unresectable or recurrent advanced gastric cancer treated with first- and second-line treatment.

PURPOSE: The goal of this study was to determine which markers are the most useful as first- and second-line pre-treatment markers in patients with unresectable or recurrent gastric cancer (URGC). METHODS: This study included 101 URGC patients who were treated with first- and second-line chemotherapy. Several prognostic scores based on nutrition and inflammation were analyzed using a receiver operating characteristic (ROC) analysis to determine the most useful prognostic marker. RESULTS: The lymphocyte-to-C-reactive protein ratio (LCR) had the highest area under the curve for both first- and second-line chemotherapy, according to an ROC analysis. An ROC analysis was used to determine the optimal LCR cut-off for the median survival time before first- and second-line chemotherapy, and patients were divided into high- and low-LCR groups. Patients with a high LCR had a significantly longer survival than those with a low LCR before first- and second-line chemotherapy (p = 0.004, p < 0.001, respectively). A low LCR before both first- and second-line chemotherapy was an independent poor prognostic factor in a multivariate analysis. CONCLUSIONS: URGC patients with a low LCR before both first- and second-line chemotherapy had a significantly worse prognosis than those with a high LCR in this study. Nutritional intervention during chemotherapy induction may lead to a better prognosis.

Impact of gastrectomy on body composition within 1 month in patients with gastric cancer.

PURPOSE: The present study examined the changes in and risk factors for body composition (BC) during the first postoperative month when dynamic biological reactions occur. METHODS: We retrospectively assessed 202 patients who underwent gastrectomy. The BC was assessed using a bioelectrical impedance analysis and evaluated within 1 month preoperatively, 1 week postoperatively, and 1 month postoperatively. Multiple regression analyses were performed to identify predictive factors for BC change. RESULTS: The mean reduction rate in BC at 1 month postoperatively was - 6.0, - 10.5, - 5.6, - 1.1, - 10.1, and + 1.2% for body weight, body fat, skeletal muscle, bone mineral, extracellular water/total body water, and the whole-body phase angle, respectively. A multiple regression analysis revealed that independent risk factors for weight loss were complications, operative time, and type of gastrectomy (P = 0.004, 0.011, 0.015, respectively), and those for skeletal muscle loss were complications and gastrectomy type (P = 0.002, 0.010, respectively). A segmental lean mass analysis revealed that the lower limbs were markedly reduced at 1 week postoperatively (- 8.0%), and these independent risk factors were the female sex and Stage II/III disease (P = 0.008, 0.036, respectively). CONCLUSION: Detailed analyses of BC might help elucidate the mechanisms underlying postoperative physical changes, which might be useful for perioperative management.

A case of malignant melanoma, a possible primary site in the digit, with systemic metastasis in a mini-Rex.

We report a case of systemic metastasis of malignant melanoma in a mini-Rex (Oryctolagus cuniculus). The animal presented with lameness of the right hind limb, swelling of popliteal lymph node, and a black mass on the first digit. Paralysis of hindlimbs and forelimbs, dysuria, and dysphagia progressed over time, and the rabbit died on day 35 from the first visit. At necropsy, many black lesions were observed in multiple organs including the marrow of most bones. Histopathologically, the tumor cells had highly atypical nuclei of various sizes and an abundant eosinophilic cytoplasm, and some cells contained melanin granules. These cells were positive for PNL2 and S-100, melanoma markers, by immunohistochemistry. This is the first report of malignant melanoma in a mini-Rex with severe malignancy and systemic metastasis including the bone marrow.

Post-colostomy internal hernia of the stomach treated with laparoscopic gastropexy: a case report.

BACKGROUND: Internal hernias are formed by the protrusion of internal organs through an aperture formed congenitally or postoperatively. Internal hernias are most commonly associated with the small intestine. Only two cases of a post-sigmoid colostomy internal hernia of the stomach have been reported. This hernia arises from the space between the lifted sigmoid colon and the left abdominal wall. In the two aforementioned cases, treatment comprised suturing of the sigmoid colon to the lateral abdominal wall and changing of the intraperitoneal route to an extraperitoneal one. Herein, we present a very rare case who underwent laparoscopic gastropexy for a post-sigmoid colostomy internal hernia of the stomach. CASE PRESENTATION: Our patient, a 67-year-old woman, was undergoing chemoradiation for rectal cancer and planned to undergo abdominoperineal resection. However, tumor perforation resulted in a high fever and a right gluteal abscess; therefore, a sigmoid colostomy was performed through the intraperitoneal route in the left lower abdomen. One month after the surgery, the patient presented to our emergency room with vomiting, abdominal pain, and abdominal distension. Computed tomography revealed a markedly distended stomach caused by the obstruction of the pylorus secondary to the colostomy; laparoscopic gastropexy was performed subsequently and the postoperative course was uneventful. CONCLUSIONS: This is the first report on the laparoscopic gastropexy treatment of a post-sigmoid colostomy internal hernia of the stomach; our findings may help physicians manage such hernias.

Intracellular delivery and photothermal therapeutic effects of polyhistidine peptide-modified gold nanoparticles.

Gold nanoparticles (AuNPs) are widely used as an agent in photothermal therapy (PTT) against various cancers. However, a drug delivery system (DDS) is required for effective PTT using AuNPs as AuNPs accumulate passively in tumors. In the present study, we used polyhistidine peptide, a novel cell-penetrating peptide, which is efficiently internalized into tumor cells, as a DDS carrier for PTT using AuNPs. Polyhistidine peptide-modified AuNPs are efficiently internalized into RERF-LC-AI human lung squamous cancer cells and localized to the intracellular lysosome, which is based on the nature of the polyhistidine peptide. Furthermore, the polyhistidine peptide-modified AuNPs inhibited proliferation of RERF-LC-AI cells in a polyhistidine peptide modification-dependent manner under 660 nm laser irradiation. Quantitative real-time PCR showed increased expression levels of an apoptosis-related gene (bax) and heat stress-related gene (hsp70) in RERF-LC-AI cells treated with polyhistidine peptide-modified AuNPs and laser. Our findings highlight the efficacy of AuNPs modified with H16 peptide in PTT.

Impact of geriatric nutritional risk index on outcomes after gastrectomy in elderly patients with gastric cancer: a retrospective multicenter study in Japan.

BACKGROUND: Several studies investigated the utility of inflammation and nutritional markers in predicting the prognosis in patients with gastric cancer; however, the markers with the best predictive ability remain unclear. This retrospective study aimed to determine inflammation and nutritional markers that predicted prognosis in elderly patients over 75 years of age undergoing curative gastrectomy for gastric cancer. METHODS: Between January 2005 and December 2015, 497 consecutive elderly gastric cancer patients aged over 75 years underwent curative gastrectomy in 12 institutions. The geriatric nutritional risk index (GNRI), prognostic nutritional index, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and C-reactive protein/albumin ratio were examined as prognostic markers for overall survival (OS) and disease-specific survival (DSS) using area under the curve (AUC) using receiver operating characteristic (ROC) curve analysis. RESULTS: The GNRI had the highest AUC and predictive value for both OS (0.637, p < 0.001) and DSS (AUC 0.645, p < 0.001). The study cohort was categorized into the high and low GNRI groups based on the optimal GNRI cut-off values for OS (97.0) and DSS (95.8) determined with the ROC analysis. For both OS and DSS, there was a significant correlation between the GNRI and several clinicopathological factors including age, body mass index, albumin, American Society of Anesthesiologists physical status score, depth of tumor invasion, lymph node metastasis, lymphatic invasion, pathological stage, operation duration, bleeding, procedure, approach, death due to primary disease, and death due to other disease. The GNRI remained a crucial independent prognostic factor for both OS (Hazard ratio [HR] = 1.905, p < 0.001) and DSS in multivariate analysis (HR = 1.780, p = 0.043). CONCLUSIONS: Among a panel of inflammation and nutritional markers, the GNRI exhibited the best performance as a prognostic factor after curative gastrectomy in elderly patients with gastric cancer, indicating its utility as a simple and promising index for predicting OS and DSS in these patients.

Case Report: Ultrasonography and Magnetic Resonance Imaging of Anterior Segment Dysgenesis in a Calf.

This study includes diagnostic efficacy of the antemortem, combined use of ultrasonography and magnetic resonance imaging (MRI) for the diagnosis of anterior segment dysgenesis. A 7-day-old male Holstein calf presented with progressive unilateral exophthalmos associated with enlargement of the right eyeball soon after birth. Ultrasonography of the enlarged right eyeball showed (1) a 2-cm-thick echogenic parenchymal lesion filling the anterior region of the right eyeball, (2) excess accumulation of the anechoic vitreous humor, and (3) absence of the lens structure. Antemortem examination using T2-weighted and fluid-attenuated inversion recovery MRI revealed a thickened, hyperintense anterior lesion and absence of the lens structure. These imaging findings were suggestive of anterior segment dysgenesis. Antemortem imaging showed no abnormalities other than the abnormal structure and size of the right eyeball; therefore, enucleation of the right eye was performed, which allowed intact healing without suppuration. Ocular ultrasonography enhanced the diagnostic accuracy due to the characteristic ultrasonographic findings of a thickened anterior lesion and absence of the lens structure in the eyeball, suggestive of anterior segment dysgenesis.

CA19-9 in combination with P-CRP as a predictive marker of immune-related adverse events in patients with recurrent or unresectable advanced gastric cancer treated with nivolumab.

BACKGROUND: Immune-check point inhibitors (ICPIs) for treatment of cancer patients sometimes induce potentially life-threatening immune-related adverse events (irAEs), which predict ICPIs treatment efficacy. Prediction of irAEs would be useful for management of irAEs and prediction of ICPIs efficacy. This study aimed to determine predictors of irAEs in patients with recurrent or unresectable advanced gastric cancer (RUGC) treated with nivolumab. METHODS: Seventy-eight RUGC patients treated with nivolumab at nine institutions between January 2017 and April 2020 were included in this study. The usefulness of specific blood test results as predictors of irAEs was evaluated. RESULTS: We observed irAEs in 15 (19.2%) patients. The disease control rate was significantly higher in the patients with irAEs than in those without (86.7% vs. 42.9%; P < 0.001). The median progression-free survival was significantly longer for patients with irAEs than for patients without (4.9 vs. 2.6 months; P = 0.018). The median survival time was longer for patients with irAEs than for those without (9.4 vs. 5.8 months; P = 0.041). The receiver operating characteristic (ROC) curves for irAEs indicated that the area under the curve (AUC) of carbohydrate antigen 19-9 (CA19-9) was highest (0.692; P = 0.022), followed by that for the platelet count × serum C-reactive protein (P-CRP) value (0.680; P = 0.032). The AUC for the CA19-9 + P-CRP combination was 0.782, which was more useful than that for either component and significantly associated with overall survival of nivolumab-treated RUGC patients. CONCLUSIONS: The CA19-9 + P-CRP combination was predictive of irAEs and prognosis in RUGC patients.

What is necessary to shorten the operative time in initial introduction of robotic gastrectomy for gastric cancer?

INTRODUCTION: Robotic gastrectomy (RG) is a good alternative to laparoscopic gastrectomy, as it improves treatment outcomes and reduces the burden of technical difficulties; however, prolonged operative time may be a disadvantage. This study aimed to identify measures to shorten the operative time during the initial introduction of RG at an institution. METHODS: We assessed 33 patients with gastric cancer who underwent radical distal gastrectomy with Billroth-I reconstruction and divided them into three groups: laparoscopic distal gastrectomy (LDG), robotic distal gastrectomy in the early phase (RDG-E), and in the late phase (RDG-L). Operative time, six technical steps, and junk time, including the roll-in/roll-out, docking/undocking, and instrument exchange times, were compared among the groups. RESULTS: The median (range) overall operative times of LDG, RDG-E, and RDG-L were 248 (179-323), 304 (249-383), and 263 (220-367) min, respectively, but no significant differences were observed. For each surgical step of RG, RDG-L in suprapancreatic lymph node dissection was significantly shorter than that in RDG-E. The median (range) junk times of LDG, RDG-E, and RDG-L were 16.7 (12.7-26.4), 48.3 (38.6-67.7), and 42.0 (35.4-49.2) min, respectively. Junk time was significantly longer in RDG-L than in LDG (p = 0.003), but not significant between RDG-E and RDG-L. The learning curve effect of overall, console, and junk times were achieved in four cases of RDG. CONCLUSION: Junk time is a major factor in prolonging RDG operative time. However, to reduce the time after initial introduction, measures to promote robot-specific standardization and more effective use of robotic instruments are essential.

Detection of squamous cell carcinoma of presumed pancreatic origin and its metastasis in a spotted seal (Phoca largha) using ultrasonography and computed tomography.

A 21-year-old female spotted seal (Phoca largha), with a swollen abdomen, had a five-month history of anorexia and vomiting. Ultrasonography revealed an extended mass with central necrotic foci in the right cranial abdomen. Computed tomography revealed an abdominal mass with a low-density central lumen and a pulmonary nodular lesion. Cytology of an abdominal specimen collected through fine-needle aspiration indicated a malignant tumor with round, atypical cells with large nuclei. Three days after diagnosis, necropsy revealed a 10-cm large, solid, whitish mass in the pancreatic parenchyma and multiple small nodules in the liver, spleen, mesentery, lungs, and mediastinal lymph nodes. Histopathological analysis showed prolific neoplastic cells with marked atypia and occasional keratinization. Immunohistochemistry revealed that the neoplastic cells were positive for cytokeratin AE1/AE3 antibody. Thus, the seal was diagnosed with squamous cell carcinoma, of presumed pancreatic origin, which had metastasized to multiple organs.

Atorvastatin preferentially inhibits the growth of high ZEB-expressing canine cancer cells.

The epithelial-to-mesenchymal transition (EMT) is fundamental in cancer progression and contributes to the acquisition of malignant properties. The statin class of cholesterol-lowering drugs exhibits pleiotropic anticancer effects in vitro and in vivo, and many epidemiologic studies have reported a correlation between statin use and reduced cancer mortality. We have shown previously that sensitivity to the anti-proliferative effect of statins varies among human cancer cells and statins are more effective against mesenchymal-like cells than epithelial-like ones in human cancers. There have only been few reports on the application of statins to cancer therapy in veterinary medicine, and differences in statin sensitivity among canine cancer cells have not been examined. In this study, we aimed to clarify the correlation between sensitivity to atorvastatin and epithelial/mesenchymal states in 11 canine cancer cell lines derived from mammary gland, squamous cell carcinoma, lung, and melanoma. Sensitivity to atorvastatin varied among canine cancer cells, with IC50 values ranging from 5.92 to 71.5 µM at 48 h, which were higher than the plasma concentrations clinically achieved with statin therapy. Atorvastatin preferentially attenuated the proliferation of mesenchymal-like cells. In particular, highly statin-sensitive cells were characterized by aberrant expression of the ZEB family of EMT-inducing transcription factors. However, ZEB2 silencing in highly sensitive cells did not induce resistance to atorvastatin. Taken together, these results suggest that high expression of ZEB is a characteristic of highly statin-sensitive cells and could be a molecular marker for predicting whether cancers are sensitive to statins, though ZEB itself does not confer statin sensitivity.