Field carcinogenesis and biological significance of the potential of the bystander effect: carcinogenesis, therapeutic response, and tissue regeneration.

The "bystander effect" is a transmission phenomenon mediating communication from target to non-target cells, as well as cell-to-cell interactions between neighboring and distantly located cells. In this narrative review, we describe the fundamental and clinical significance of the bystander effect with respect to cell-to-cell interactions in carcinogenesis, therapeutic response, and tissue regeneration. In carcinogenesis, the bystander effect mediates communications between tumor microenvironments and non-malignant epithelial cells and has been suggested to impact heterogeneous tumorigenic cells in tumors and cancerized fields. In therapeutic response, the bystander effect mediates communications between drug-sensitive and drug-resistant cells and may transmit both drug efficacy and resistance. Therefore, control of therapeutic response transmission via the bystander effect might offer a promising future cancer treatment. Finally, in tissue regeneration, circulating cells and stromal cells may differentiate into various cells for the purpose of tissue regeneration under direction of the bystander effect arising from surrounding cells in a defective space. We hope that the findings we present will promote the development of innovative cancer therapies and tissue regeneration methodologies from the viewpoint of cell-to-cell interactions through the bystander effect.

Decreased numbers of gastric, colorectal, lung, and breast cancer surgeries performed in 17 cancer-designated hospitals in Gunma Prefecture of Japan during the COVID-19 pandemic.

PURPOSE: This study aims to clarify the influence of the COVID-19 pandemic on cancer surgery in Gunma Prefecture. METHODS: A total of 9839 cases (1406 gastric cancer, 3569 colorectal cancer, 1614 lung cancer, and 3250 breast cancer) from 17 hospitals in Gunma Prefecture were investigated. We compared the number of surgical cases, proportion of cases found by screening, and cStage at the time of the first visit by month in 2020 and 2021 with those in 2019. RESULTS: The rate of decline in cancer surgery was 8.9% in 2020 compared with 2019 (p = 0.0052). Compared with the same month of 2019, in some months of 2020 and 2021, significant decreases were observed in the number of surgeries for gastric and colorectal cancer, the percentage of surgical cases detected by screening in all four cancers, and the proportion of cancers with a relatively early cStage in gastric and breast cancer. CONCLUSIONS: The number of surgical cases of the four cancer types detected by cancer screening decreased in Gunma Prefecture owing to the influence of the COVID-19 pandemic. Furthermore, for some cancer types, the number of operations performed in patients with early-stage cancer is also decreased.

A novel one-step lens cleaning device using air and water flow for endoscopic surgery.

In a surgical operation requiring endoscopy, it is essential to obtain a clear endoscopic view. However, it is often disturbed by the contamination on the lens during the surgery. No device can clean the lens surface simply and completely. Many surgeons are hampered by the impaired view and the distraction by the repeated cleaning of the lens. Therefore, we developed a novel endoscope cleaning device to address this problem. The device was made of 3D-printed rubber-like plastic. It contains a syringe filled with saline and an aspiration system. It would be used intraoperatively to wash the lens surface in a few seconds with rapid flow of water and air. The cleaning ability of the device was evaluated using mayonnaise with adenosine triphosphate (ATP) as a model contaminant. The gauze-wiping maneuver was selected as control. After each maneuver, the clarity of the endoscopic view was evaluated, and residual contaminants were assessed quantitatively with ATP assay. The cleaning device obtained a crisp and clear view and eliminated the contaminant on the lens every time after a single cleaning maneuver. The gauze-wiping maneuver required for the lens to be wiped at least three times to obtain a clear view, and even then, some contaminants remained. Repeated contamination and cleaning using gauze led to accumulation of contaminants on the lens, which resulted in difficulty in cleaning the lens as the operation proceeded. The cleaning device did not show such accumulation. Our novel cleaning device with air and water flow has been shown to wash out the lens contaminants completely and immediately in a simple manner. It is expected to improve the safety and cost-effectiveness of endoscopic surgery.

18F-fluorodeoxyglucose uptake as predictor for invasion in preoperatively diagnosed breast ductal carcinoma in situ: Significance in cases without mass formation.

A diagnosis of ductal carcinoma in situ (DCIS) at needle biopsy often changes to that of invasive ductal carcinoma as the definitive pathological diagnosis following the surgical procedure. The present study sought to identify the factors associated with invasive disease in cases diagnosed as DCIS on needle biopsy by analyzing 18F-fluorodeoxyglucose-proton emission tomography (FDG-PET) findings. The present study retrospectively investigated the cases of 24 consecutive patients with primary breast cancer who were preoperatively diagnosed with DCIS by needle biopsy. The cases were divided into two groups based on the presence of invasion in the primary tumor. Among the 24 patients, 13 (54.7%) patients had invasive carcinoma and 11 (45.8%) had DCIS. The analysis revealed that the presence of FDG uptake in the tumor was the only independent predictor of presence of the invasive disease. No cases without FDG uptake exhibited invasion and all of these were ultimately diagnosed as DCIS. In the present study, all cases, including DCIS, with a nodular growth pattern demonstrated FDG uptake in the tumors, and all cases without FDG uptake were interpreted as having a diffuse growth pattern. The present findings suggested that the presence of FDG uptake in the tumor can be considered a predictor for invasion in cases with DCIS by needle biopsy, particularly in cases with a diffuse growth pattern. Patients preoperatively diagnosed as DCIS without mass formation and without FDG uptake in the tumor may avoid sentinel lymph node biopsy.

Implication of atypical supraclavicular F18-fluorodeoxyglucose uptake in patients with breast cancer: Association between brown adipose tissue and breast cancer.

It has been reported that F18-fluorodeoxyglucose (FDG) uptake in the neck and supraclavicular lesions represents activated brown adipose tissue (BAT). In the present study, the association between BAT activity, detected by FDG-positron emission tomography (PET), and the clinicopathological features of patients with breast cancer was investigated. The cases of 156 consecutive patients with breast cancer who underwent FDG-PET preoperatively were analyzed. The distribution and intensity of atypical FDG uptake in the neck and/or supraclavicular region was reviewed. The intensity was graded as follows: 1, weak; 2, moderate; and 3, intense. Among the 156 patients, 70 (44.9%) exhibited grade 1 intensity, 65 (41.7%) exhibited grade 2 intensity and 21 (13.5%) exhibited grade 3 intensity. The intensity of FDG was significantly associated with human epidermal growth factor receptor 2 (HER2) expression and progesterone expression. Among the 156 patients, 6 (3.8%) had recurrent disease. Multivariate analysis revealed that showing a low grade of atypical FDG uptake was the only independent risk factor of short-term recurrence, and none of the patients with recurrent disease had atypical FDG uptake that may reflect the activation of BAT. These results indicated that the presence of BAT is associated with HER2 expression and the absence of BAT may be a prognostic factor for breast cancer.

Implication of 18F-fluorodeoxyglucose uptake by affected lymph nodes in cases with differentiated thyroid cancer.

In this study, we evaluated the usefulness of positron emission tomography using 18F-fluorodeoxyglucose (FDG-PET) to detect metastatic lymph nodes in differentiated thyroid cancer. We also investigated whether certain factors, including the size of the metastasis to the lymph nodes, are associated with FDG avidity. A total of 22 consecutive patients with differentiated thyroid cancer who underwent FDG-PET preoperatively were enrolled in this study. Lymph node metastasis was diagnosed in the final pathology in 10 of the 22 patients (45.5%). The mean maximum standardized uptake value of the metastatic lymph nodes was 4.53 (range, 0-23.5). The 22 cases with differentiated thyroid cancer were divided into two groups based on lymph node metastasis. Clinicopathological variables other than FDG uptake of metastatic lymph nodes were not predictors of lymph node metastasis of thyroid cancer. The sensitivity, specificity, overall accuracy and false-negative rates of preoperative FDG-PET in the prediction of lymph node status were 40.0, 100, 72.7 and 60.0%, respectively. The false-positive rate of FDG-PET evaluation was 0%. The mean largest dimension of metastasis was 23.0 mm for FDG-positive cases and 10.9 mm for FDG-negative cases. There was a marked difference in the size of metastases between FDG-positive and -negative cases; however, even in patients with node metastasis >10 mm, the false-negative rate was 50.0%. Therefore, FDG-PET imaging was not found to be sufficient for the evaluation of lymph node status, particularly in cases with small metastases. Our findings indicate that preoperative FDG-PET evaluation of the lymph nodes cannot be considered predictive of the final pathology.

Control of primary lesions using resection or radiotherapy can improve the prognosis of metastatic colorectal cancer patients.

BACKGROUND: Control of the primary lesions in metastatic colorectal cancer (mCRC) is still controversial. For rectal cancer patients, not only resection but also irradiation is expected to provide palliative effects. We investigated the effects of resection and irradiation of primary lesions (local control) on the prognosis of mCRC patients. PATIENTS: Forty-seven patients with mCRC at our institute were examined, with 34 in the local controlled group and 13 in the uncontrolled group. RESULTS: The median survival time (MST) of the local controlled and uncontrolled groups were 2.90 and 1.39 years (P = 0.028). Cox proportional hazard regression analysis showed that local control was an independent prognostic factor (P < 0.05). The patients who underwent primary lesion resection had significantly longer MST (2.90 vs. 1.39 years, P = 0.032) than those in the uncontrolled group. In rectal cancer patients, the patients who underwent irradiation to control the primary lesions had a significantly longer MST than the uncontrolled patient group (1.97 vs. 1.39 years, P = 0.019). CONCLUSIONS: Local control of primary lesions may improve the prognosis in mCRC patients. In rectal cancer patients with metastasis, not only resection but also irradiation of the primary lesions may be a useful therapeutic strategy. J. Surg. Oncol. 2016;114:75-79. © 2016 Wiley Periodicals, Inc.

Prediction of Extracapsular Invasion at Metastatic Sentinel Nodes and Non-sentinel Lymph Nodal Metastases by FDG-PET in Cases with Breast Cancer.

We have previously reported that the presence of an extracapsular invasion (ECI) at sentinel lymph nodes (SLNs) is a strong predictor of non-SLN metastasis in breast cancer. We hypothesized that(18)F-fluorodeoxyglucose (FDG) uptake by metastatic SLNs reflects invasive disease, or ECI. In this study, we evaluated the association of FDG uptake with ECI on SLNs and the possibility of FDG-positron-emission tomography (PET) assessment of axillary non-SLN metastases. We retrospectively investigated the cases of 156 consecutive patients with primary breast cancer who underwent SLN biopsy and FDG-PET preoperatively. Among 35 patients (22.4%) in whom the presence of SLN metastases was diagnosed, 10 cases (28.6%) had FDG uptake in the axillary lesion. The sensitivity, specificity, overall accuracy, and false-negative rates in the diagnosis of SLN status by FDG-PET were 28.6%, 99.2%, 83.3%, and 71.4%, respectively. The false-positive rate of FDG-PET evaluation was 0.8%. The 35 cases with lymph node metastases were divided into two groups based on the presence of FDG uptake in the axillary lesions. None of the clinicopathological features of the primary tumor were significantly associated with FDG uptake in the axillary lesion. The present analysis revealed that only tumor size of the metastatic lymph node was significantly associated with FDG uptake in the axillary lesion. The two groups were not significantly different in terms of presence of ECI and non-SLN metastasis. Among the 35 cases with SLN metastases, 13 cases (37.1%) had non-SLN metastasis. Only ECI was a predictor of non-SLN involvement. FDG uptake in the axilla was not associated with non-SLN metastasis in this study. In conclusion, FDG-PET evaluation of lymph nodes is not a sufficient indicator of ECI at SLN metastasis or non-SLN metastasis, suggesting that axillary lymph node dissection cannot be avoided. However, since the positive predictive value for SLN metastasis is high, positive FDG uptake in the axillary lesions may be useful for avoiding SLN biopsy.

Implication of ¹8F-Fluorodeoxyglucose Uptake of Affected Axillary Lymph Nodes in Cases with Breast Cancer.

In order to evaluate affected axillary lymph nodes in breast cancer by positron-emission tomography using (18)F-fluorodeoxyglucose (FDG-PET), an understanding of FDG avidity is important. In the present study, we examined whether certain factors, including lymphatic spread and size of metastatic lymph nodes, were associated with FDG avidity in order to evaluate the benefits of a FDG-PET assessment of axillary node metastases. We retrospectively investigated the cases of 179 consecutive patients with primary breast cancer who underwent FDG-PET preoperatively. Among the 179 patients, 48 (26.8%) had axillary lymph node metastases. The sensitivity, specificity, overall accuracy, and false-negative rates in the diagnosis of axillary lymph node status by FDG-PET were 47.9%, 98.5%, 84.9%, and 52.1%, respectively. The 48 cases with lymph node metastases were divided into two groups based on the presence or not of FDG uptake in the axillary lesions. Clinicopathological features of the primary tumor, including tumor size, standardized uptake value (SUVmax and biomarkers, were not statistically significant factors; only the clinicopathological features of metastatic lymph nodes, including the size of node metastasis, were significantly associated with FDG uptake in the axillary lymph nodes. Among the eight cases of micrometastasis, seven were not detected by FDG-PET. The number of cases with only one affected node was significantly higher in the group without FDG uptake in the axillary lesion. Although the number of lymph node metastases was relatively higher in the FDG-PET-positive patients, the difference was not statistically significant. FDG-PET may help identify patients with high axillary lymph node burden. Our findings imply that preoperative FDG-PET evaluation of lymph nodes is not sufficient to predict lymphatic spread or micrometastasis because FDG avidity is mainly influenced by the size of the tumor.

Anticancer effect of rapamycin on MCF-7 via downregulation of VEGF expression.

The importance of mTOR signaling in tumor biology is widely accepted and a number of agents that selectively target mTOR are being developed in cancer therapy. On the other hand, it has been demonstrated that mTOR can act as an angiogenic agent. Thus, we hypothesized that the mTOR inhibitor-induced anticancer effect is affected by expression of a key angiogenic factor, vascular endothelial growth factor (VEGF) and investigated the anticancer effect underlying mTOR using an in vitro assay. The mTOR inhibitor rapamycin dose-dependently reduced the cell viability of the breast cancer cell line, MCF-7, but did not reduce the cell viability of the colon cancer cell line, HT-29. Rapamycin reduced the VEGF expression in the culture medium of MCF-7, while rapamycin did not contribute VEGF expression in the culture medium of HT-29. VEGF stimulated cell viability and VEGF inhibition reduced cell viability of MCF-7, and rapamycin dose-dependently restored the cell viability of MCF-7 reduced by rapamycin. These findings suggest that mTOR acts as a direct anticancer agent and that the mTOR-inhibitor-induced anticancer effect involved the reduced expression of VEGF in MCF-7. Our results imply that mTOR regulates the expression of VEGF and is involved in breast cancer progression.

Establishment of a novel method to evaluate peritoneal microdissemination and therapeutic effect using luciferase assay.

Peritoneal dissemination is a major cause of recurrence in patients with malignant tumors in the peritoneal cavity. Effective anticancer agents and treatment protocols are necessary to improve outcomes in these patients. However, previous studies using mouse models of peritoneal dissemination have not detected any drug effect against peritoneal micrometastasis. Here we used the luciferase assay to evaluate peritoneal micrometastasis in living animals and established an accurate mouse model of early peritoneal microdissemination to evaluate tumorigenesis and drug efficacy. There was a positive correlation between luminescence intensity in in vivo luciferase assay and the extent of tumor dissemination evaluated by ex vivo luciferase assay and mesenteric weight. This model has advantages over previous models because optimal luciferin concentration without cell damage was validated and peritoneal microdissemination could be quantitatively evaluated. Therefore, it is a useful model to validate peritoneal micrometastasis formation and to evaluate drug efficacy without killing mice.

KPNA2 over-expression is a potential marker of prognosis and therapeutic sensitivity in colorectal cancer patients.

BACKGROUND: Karyopherin α 2 (KPNA2) is a member of the Karyopherin α family and has recently been reported to play an important role in tumor progression. The aim of the current study was to elucidate the clinicopathological significance of KPNA2 over-expression in colorectal cancer (CRC). PATIENTS AND METHODS: KPNA2 expression was evaluated by immunohistochemistry in 122 surgically resected CRC and 13 biopsy specimens obtained at colonoscopy during screening for preoperative hyperthermochemoradiation therapy (HCRT). The association between KPNA2 expression and clinicopathological features and preoperative HCRT efficacy were examined. RESULTS: The high and low KNPA2 expression groups were comprised of 91 (74.6%) and 31 CRC patients, respectively. A significant association was observed between high expression and lymphatic invasion (P = 0.0245). KPNA2 high expression group had decreased overall survival (P = 0.00374). Multivariate analysis demonstrated high KPNA2 expression was independently associated with poor prognosis. Histological examinations revealed 11 (84.6%) and 2 (15.4%) of cases were KPNA2 positive and negative, respectively. Pathological complete response (pCR) was observed in 9.1% of KPNA2-positive cases and 100% of KPNA2-negative cases. CONCLUSION: High KPNA2 expression was found to be associated with poor prognosis and resistance to HCRT.

Implication of duration of clinical presentation on tumor progression and short-term recurrence in patients with early breast cancer.

Breast cancer growth is dependent on time and it may be of utmost importance to take into consideration the duration of clinical symptoms in order to predict which patients are at high risk for disease recurrence. The aim of this study was to determine the association between duration of clinical symptoms and disease recurrence in patients with breast cancer. A total of 139 consecutive patients with primary breast cancer who underwent a radical breast operation were retrospectively investigated and the association between recurrence and the duration of symptoms was investigated. The duration of clinical signs was defined as the time from the onset of symptoms to the date of surgery. The breast cancer cases were divided into two groups on the basis of symptom duration (≤6 and >6 months). The mean duration of symptoms was 191.0±242.6 days. Of the 139 cases, 36 (25.9%) had a duration of symptoms of >6 months. In the univariate analysis, a statistically significant association with long symptom duration was observed for disease recurrence. Of the 139 patients, 6 (4.3%) developed recurrent disease. The univariate analysis revealed that long duration of symptoms and nuclear grade were significantly associated with recurrence. In conclusion, our results indicated that breast cancer progression is dependent on time. A long duration of symptoms (>6 months) may be considered as an indicator of tumor progression and a strong prognostic factor in breast cancer patients.

Significance of lymphatic invasion combined with size of primary tumor for predicting sentinel lymph node metastasis in patients with breast cancer.

BACKGROUND/AIM: Lymphatic invasion (ly) may mainly reflect the selective affinity of breast cancer cells for lymph nodes. We conducted the present study to investigate whether the presence of lymphatic invasion is a predictor of sentinel lymph node (SLN) metastasis in clinically node-negative breast cancer. PATIENTS AND METHODS: We retrospectively evaluated the cases of 202 consecutive female patients with clinically node-negative primary breast cancer who underwent a radical breast operation with SLN biopsy. We examined the relationship between SLN metastasis and the significance of clinicopathological factors, including lymphatic invasion. RESULTS: Among the 202 patients, 49 (24.3%) had SLN metastasis. The univariate and multivariate analyses revealed that the size of the tumor and lymphatic invasion were independent risk factors for SLN metastasis. Among the 96 patients who were ly-negative and had a tumor size of less than 20 mm, only 5 (5.2%) had 1-2 metastases within the SLN. Among the 34 patients who were ly-negative and had a tumor size of less than 10 mm, there were no patients with SLN metastasis. CONCLUSION: Our results suggest that the presence of lymphatic invasion combined with the size of the primary cancer could be considered a strong risk factor for SLN metastasis in clinically node-negative breast cancer, and patients with a tumor size of less than 20 mm and clinically node-negative breast cancer may avoid axillary lymph node dissection after SLN biopsy. There is also a possibility that SLN biopsy could be unnecessary for patients with clinically node-negative breast cancer who are ly-negative and have a tumor size of less than 10 mm.