Serum biomarkers for personalization of nanotherapeutics-based therapy in different tumor and organ microenvironments.

Enhanced permeation and retention (EPR) effect, the mechanism by which nanotherapeutics accumulate in tumors, varies in patients based on differences in the tumor and organ microenvironment. Surrogate biomarkers for the EPR effect will aid in selecting patients who will accumulate higher amounts of nanotherapeutics and show better therapeutic efficacy. Our data suggest that the differences in the vascular permeability and pegylated liposomal doxorubicin (PLD) accumulation are tumor type as well as organ-specific and significantly correlated with the relative ratio of MMP-9 to TIMP-1 in the circulation, supporting development of these molecules as biomarkers for the personalization of nanoparticle-based therapy.

Transrectal robotic natural orifice translumenal endoscopic surgery (NOTES) applied to intestinal anastomosis in a porcine intestine model.

BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES) is a minimally invasive operation using devices such as flexible endoscopes and linear or circular staplers. Nevertheless, hand-sewn anastomosis in NOTES remains challenging. This study aimed to investigate the feasibility of transrectal robotic NOTES requiring intracorporeal small intestinal anastomosis and closure of the rectal anterior wall incision in a relevant human model. METHODS: The authors developed a flexible rectal proctoscope with a diameter of 43 mm for transrectal robotic NOTES. Small intestinal anastomosis was performed in a porcine intestinal transrectal NOTES model using two robotic arms and a camera inserted through the proctoscope and a rectal anterior wall incision. The quality of transrectal small intestinal anastomosis using the da Vinci surgical system (transrectal robotic NOTES group) was compared with that of transabdominal anastomosis using the da Vinci surgical system (transabdominal robot-assisted surgery group) and transrectal anastomosis using traditional transanal endoscopic microsurgery (TEM) instruments (TEM NOTES group). The quality of transrectal rectal anterior wall suturing in the transrectal robotic NOTES group was compared with that of the TEM NOTES group and the open surgical instruments group (open group). RESULTS: Robotic intracorporeal suturing was performed successfully in the porcine intestine model. During small intestinal anastomosis, burst pressure in the transrectal robotic NOTES group (67.7 ± 29.3 mmHg) was similar to that in the transabdominal robot-assisted surgery group (73.3 ± 18.2 mmHg) but significantly higher than in the TEM NOTES group (20.3 ± 24.0 mmHg; p < 0.01). During rectal anterior wall suturing, the burst pressure did not differ significantly between the transrectal robotic NOTES group (149.9 ± 81.1 mmHg) and the open group (195.0 ± 60.5 mmHg). CONCLUSIONS: The preliminary safety and efficacy of transrectal robotic NOTES was established. Further studies are required to determine the practical feasibility of this procedure.

LINE-1 methylation shows little intra-patient heterogeneity in primary and synchronous metastatic colorectal cancer.

BACKGROUND: Long interspersed nucleotide element 1 (LINE-1) hypomethylation is suggested to play a role in the progression of colorectal cancer (CRC). To assess intra-patient heterogeneity of LINE-1 methylation in CRC and to understand its biological relevance in invasion and metastasis, we evaluated the LINE-1 methylation at multiple tumor sites. In addition, the influence of stromal cell content on the measurement of LINE-1 methylation in tumor tissue was analyzed. METHODS: Formalin-fixed paraffin-embedded primary tumor tissue was obtained from 48 CRC patients. Matched adjacent normal colon tissue, lymph node metastases and distant metastases were obtained from 12, 18 and 7 of these patients, respectively. Three different areas were microdissected from each primary tumor and included the tumor center and invasive front. Normal mucosal and stromal cells were also microdissected for comparison with the tumor cells. The microdissected samples were compared in LINE-1 methylation level measured by multicolor MethyLight assay. The assay results were also compared between microdissected and macrodissected tissue samples. RESULTS: LINE-1 methylation within primary tumors showed no significant intra-tumoral heterogeneity, with the tumor center and invasive front showing identical methylation levels. Moreover, no difference in LINE-1 methylation was observed between the primary tumor and lymph node and distant metastases from the same patient. Tumor cells showed significantly less LINE-1 methylation compared to adjacent stromal and normal mucosal epithelial cells. Consequently, LINE-1 methylation was significantly lower in microdissected samples compared to macrodissected samples. A trend for less LINE-1 methylation was also observed in more advanced stages of CRC. CONCLUSIONS: LINE-1 methylation shows little intra-patient tumor heterogeneity, indicating the suitability of its use for molecular diagnosis in CRC. The methylation is relatively stable during CRC progression, leading us to propose a new concept for the association between LINE-1 methylation and disease stage.

Long interspersed nuclear element-1 hypomethylation is a potential biomarker for the prediction of response to oral fluoropyrimidines in microsatellite stable and CpG island methylator phenotype-negative colorectal cancer.

We investigated the clinical value of methylation of long interspersed nuclear element-1 (LINE-1) for the prognosis of colorectal cancer (CRC) and for the survival benefit from adjuvant chemotherapy with oral fluoropyrimidines. LINE-1 methylation in tumor DNA was measured by quantitative methylation-specific PCR in 155 samples of stage II and stage III CRC. The presence of microsatellite instability and CpG island methylator phenotype (CIMP) were assessed and 131 microsatellite stable/CIMP- cases were selected for survival analysis, of which 77 patients had received postoperative adjuvant chemotherapy with oral fluoropyrimidines. The CRC cell lines were used to investigate possible mechanistic links between LINE-1 methylation and effects of 5-fluorouracil (5-FU). High LINE-1 methylation was a marker for better prognosis in patients treated by surgery alone. Patients with low LINE-1 methylation who were treated with adjuvant chemotherapy survived longer than those treated by surgery alone, suggestive of a survival benefit from the use of oral fluoropyrimidines. In contrast, a survival benefit from chemotherapy was not observed for patients with high LINE-1 methylation. The CRC cell lines treated with 5-FU showed increased expression of LINE-1 mRNA. This was associated with upregulation of the phospho-histone H2A.X in cells with low LINE-1 methylation, but not in cells with high LINE-1 methylation. The 5-FU-mediated induction of phospho-histone H2A.X, a marker of DNA damage, was inhibited by knockdown of LINE-1. These results suggest that LINE-1 methylation is a novel predictive marker for survival benefit from adjuvant chemotherapy with oral fluoropyrimidines in CRC patients. This finding could be important for achieving personalized chemotherapy.

Single incision endoscopic surgery for lumbar hernia.

Single Incision Endoscopic Surgery (SIES) has emerged as a less invasive surgery among laparoscopic surgeries, and this approach for incisional hernia was reported recently. This is the first report of SIES for an incisional lumbar hernia. A 66-year-old Japanese woman was referred to our institution because of a left flank hernia that developed after left iliac crest bone harvesting. A 20-mm incision was created on the left side of the umbilicus and all three trocars (12, 5, and 5 mm) were inserted into the incision. The hernial defect was 14 × 9 cm and was repaired with intraperitoneal onlay mesh and a prosthetic graft. The postoperative course was uneventful. SIES for lumbar hernia offers a safe and effective outcome equivalent compared to laparoscopic surgery. In addition, SIES is less invasive and has a cosmetic benefit.

Single incision laparoscopic surgery (SILS) using cross hand technique.

Single incision laparoscopic surgery (SILS) was developed as a less invasive surgical procedure, but it remains difficult because of its specific skills and left-right reversal of the instruments. Such a difference makes manipulating endoscopic instruments more challenging and increases the risk. In this study, we introduce the cross hand technique allowing the surgeon to manipulate instruments with intuitive movement.

[Breast cancer during pregnancy--a case report].

Pregnancy-associated breast carcinoma is generally defined as cancer that occurs during pregnancy or within 1 year of delivery, although treatment options are the most complicated when the disease is diagnosed during pregnancy. We report the case of a 30-year-old woman who was diagnosed with breast cancer at her 9th week of pregnancy. The patient initially had mastectomy with axillary lymph node dissection. She began adjuvant therapy with 3 courses of epirubicin/cyclophosphamide at 19 weeks of gestation. After delivery of a healthy child, she received one course of epirubicin/cyclophosphamide and 4 courses of docetaxel. Although the data are limited, pregnant patients with cancer can be treated with systemic chemotherapy with minimal risks to the fetus during the second or third trimester. Management of breast cancer during pregnancy requires an interdisciplinary care team and careful consideration of the patient's stage of disease, the gestational age of the fetus, and the preferences of the patient and her family.