Anti-cancer activity of amorphous curcumin preparation in patient-derived colorectal cancer organoids.

Despite its adverse effects, chemotherapy is generally used for the treatment of colorectal cancer (CRC). Development of supplement preparations targeting cancer stem cells (CSCs) that cause distant metastasis and drug resistance is required. Although curcumin is known to have anti-tumor, hepatoprotective, and hypoglycemic-like actions, its low water solubility, oral absorption, and bioavailability impede its therapeutic uses. Patient-derived organoid cultures can recapitulate heterogeneity, epithelial structures, and molecular imprints of their parental tissues. In the present study, anti-carcinogenic properties of amorphous curcumin (AC), a compound with improved solubility and bioavailability, were evaluated against human CRC organoids. Treatment with AC inhibited the cell viability of CRC organoids in a concentration-dependent manner. AC arrested the cell cycle of CRC organoids and induced apoptosis. AC inhibited phosphorylation of ERK. Expression of downstream signals of ERK, namely c-MYC and cyclin-D1, were inhibited. Expressions of CSC markers, CD44, LGR5, and CD133, were declined in the AC-treated CRC organoids. The combinational treatment of CRC organoids with AC and anti-cancer drugs, oxaliplatin, 5-FU, or irinotecan showed a synergistic activity. In vivo, AC decreased the tumor growth of CRC organoids in mice with the induction of necrotic lesions. In conclusion, AC diminished the cell viability of CRC organoids through the inhibition of proliferation-related signals and CSC marker expression in addition to arresting the cell cycle. Collectively, these data suggest the value of AC as a promising supplement that could be used in combination with anti-cancer drugs to prevent the recurrence and metastasis of CRC.

[A Resected Case of Advanced Lower Rectal Cancer with Neoadjuvant Chemotherapy by FOLFOXIRI plus Cetuximab].

Although the current standard of care for patients with lower rectal cancer in Japan includes total mesorectal resection with lateral lymph node dissection, postoperative local and distant recurrence rates are high. Multidisciplinary treatment is important to improve the prognosis. A man in his 30s was diagnosed with lower rectal cancer due to bloody stool and referred to our department. He was diagnosed as cT3N3M0, cStage Ⅲc with right obturator lymph node metastasis. Four courses of neoadjuvant chemotherapy(NAC)with FOLFOXIRI plus cetuximab were performed. Because Grade 3 neutropenia was observed in the first cycle(CTCAE v5.0), pegfilgrastim was administered in the second and subsequent cycles, and NAC was completed without dose reduction. The patient underwent laparoscopy-assisted intersphincteric rectal resection and D3+rtLD2 dissection. Histopathological resection margins were negative, and the resection was R0. Lymph node metastasis was found only in No. 263d-rt, and the pathological diagnosis was ypT3N3M0, pStage Ⅲc. Histological evaluation of response to treatment was Grade 2. The postoperative course was good and the patient was discharged on postoperative day 15. The patient received 8 courses of adjuvant chemotherapy with mFOLFOX6 from the 7th postoperative week and is alive and recurrence-free 6 months after surgery.

Long-Term Clinical and Angiographic Outcomes After Implantation of New-Generation Drug-Eluting Stents for Patients on Maintenance Hemodialysis.

Prior research has revealed poorer clinical outcomes after drug-eluting stent (DES) implantation for hemodialysis patients. This study aims to investigate the long-term clinical and angiographic outcomes after new-generation DES implantation for hemodialysis patients.We retrospectively enrolled 91 consecutive patients (118 lesions) who underwent successful new-generation DES (everolimus-, zotarolimus-, and biolimus-eluting stents) implantation for the first time. We measured the serum calcium and phosphorus levels in the blood samples obtained just before hemodialysis. The follow-up period of clinical events was, at least, 1.5 years. In this study, major adverse cardiac and cerebrovascular events (MACCE) and clinically driven target lesion revascularization were reported in 36 (39.6%) and 11 (12.1%) patients, respectively. The prevalence of peripheral artery disease was significantly higher in the MACCE group (41.7% versus 14.5%, P = 0.006). The serum calcium level was significantly higher in the MACCE group (9.34 ± 0.92 mg/dL versus 8.77 ± 0.88 mg/dL; P = 0.004). The multivariate Cox proportional hazards model revealed that the serum calcium level (hazard ratio, 1.86; 95% confidence interval [CI]: 1.26-2.77; P = 0.002), suboptimal (over 55 mg2/dL2) calcium-phosphorus product (hazard ratio, 3.27; 95% CI: 1.41-7.61; P = 0.006) and the coexistence of peripheral artery disease (hazard ratio, 3.15; 95% CI: 1.49-6.65; P = 0.003) were independent predictors of MACCE.For hemodialysis patients, MACCE remains a frequent occurrence after new-generation DES implantation and is associated with calcium-phosphate metabolism and peripheral artery disease.

[Questionnaire Survey on Adjuvant Chemotherapy for Colorectal Cancer in Yamaguchi Prefecture].

A questionnaire survey on postoperative chemotherapy for colorectal cancer was conducted in 22 hospitals in Yamaguchi Prefecture. Adjuvant chemotherapy was performed in<95% of Stage Ⅲ cancer, and oxaliplatin(OX)combination therapy was selected depending on the risk of recurrence. However, the proportion of OX combination therapy was lower than that in other prefectures, which was 24% in Stage Ⅲa, 44% in Ⅲb, and 76% in Ⅲc. In addition, among the OX combination therapy regimens(FOLFOX or CAPOX), the proportion of FOLFOX administration was higher in Yamaguchi Prefecture than in other prefectures. In Stage Ⅱ, most hospitals set up high-risk factors for recurrence and underwent adjuvant chemotherapy. FU-based monotherapy was selected in 80% of hospitals. A few hospitals decided the requirement of OX combination therapy based on age alone. In Yamaguchi Prefecture, the indication of postoperative adjuvant chemotherapy for colorectal cancer was almost standard; however, the rate of administering OX combination therapy was low.

[A Case of Colorectal Cancer with Peritoneal Dissemination and Liver Metastasis That Responded to Comprehensive Treatment by Chemotherapy and CRS plus HIPEC].

We report a case of colorectal cancer with peritoneal dissemination and liver metastasis that achieved R0 resection by preoperative chemotherapy and CRS plus HIPEC. A 33-year-old man presented with a complaint of abdominal bloating. After further examination, he was diagnosed with transverse colon cancer with peritoneal dissemination and liver metastasis. After 9 courses of preoperative XELOX plus cetuximab and 4 courses of preoperative XELIRI plus bevacizumab, he underwent transverse colon resection, peritoneal resection, and HIPEC(MMC 20mg/4,000mL physiological saline, 40mins). There was little histological evidence of peritoneal dissemination around the region of the primary tumor. Moreover, no tumor cells were found in other peritoneal disseminations or in the liver metastasis. As a result, he was able to undergo curative resection. Colorectal cancer with peritoneal dissemination still has a poor prognosis, but combination therapy with chemotherapy and CRS plus HIPEC is expected to improve prognosis.

[A Case of Borderline Resectable Pancreatic Cancer Responding to Preoperative GEM plus Nab-PTX Combination Chemotherapy].

We report a case of borderline resectable(BR)pancreatic cancer, which was eligible for R0 resection following preoperative chemotherapy with GEM plus nab-PTX. A 77-year-old woman presented with brown urine and clay-colored stool. After further examination, she was diagnosed with obstructive jaundice due to pancreatic head cancer. Because the tumor was in contact with the region attached to the SMA nerve plexus, she was also diagnosed with BR-A pancreatic cancer. After 6 courses of preoperative GEM plus nab-PTX combination chemotherapy, she underwent subtotal stomach-preservingpancreaticoduodenectomy with SMV resection and right semicircular SMA nerve plexus dissection. In the histopathological diagnosis, malignant cells were observed at low levels in both the pancreatic parenchyma and duodenal mucosa. There were no findings of residual malignant cells in the wall of the SMV or in the nerve plexus around the SMA. Since the final diagnosis was pT3,(DU+), pN0, cM0, fStage III , we concluded that the R0 resection as complete. Histological therapeutic evaluation with the Evans classification concluded that the disease was Grade III . GEM plus nab-PTX combination chemotherapy could be considered for preoperative chemotherapy, which may allow R0 resection for BR pancreatic cancer.

Functional characterization of a heavy metal binding protein CdI19 from Arabidopsis.

Heavy metals are potentially highly toxic for organisms. Plants possess the ability to minimize damage but the underlying molecular mechanisms have yet to be detailed. Screening Cd-responsive genes in Arabidopsis, we previously identified a gene encoding a putative metal binding protein CdI19, which, upon introduction into yeast cells, conferred marked toleration of Cd exposure. Here we describe that bacterially expressed CdI19 directly interacts with Cd at its CXXC motif, as revealed by circular dichroism analysis, and that it is exclusively localized at plasma membranes, as revealed by heterologous expression of fusion product with a green fluorescent protein in BY2 cells. Northern blot analyses indicated that CdI19 transcripts were induced not only by Cd, but also by dicationic forms of Hg, Fe and Cu. Histochemical assays using transgenic Arabidopsis expressing the CdI19 promoter::GUS showed CdI19 to be expressed in petiole, hypocotyl, peduncle and vascular bundles in root tissues. Overexpression of the CdI19 cDNA conferred Cd tolerance in transgenic Arabidopsis. These results suggest that CdI19 plays an important role in the maintenance of heavy metal homeostasis and/or in detoxification by endowing plasma membranes with the capacity to serve as an initial barrier against inflow of free heavy metal ions into cells.