Ki Jung Ahn

Tetra-arsenic oxide (Tetras) enhances radiation sensitivity of solid tumors by anti-vascular effect

Tetras (tetra-arsenic oxide, As(4)O(6)) is a derivative of arsenic used in Korean traditional medicine for the treatment of cancer, but its mechanism remains largely undefined. Recently, a similar arsenic derivative, diarsenic trioxide (As(2)O(3), ATO), has been shown to mediate anti-tumor activity, therefore reigniting interest in the therapeutic effect of arsenic compounds. Here we report that Tetras can effectively mediate an anti-vascular effect on tumors, leading to delay in tumor growth and increased survival. Our study demonstrates for the first time the potential use of Tetras as a radiation therapy enhancement agent for solid tumors. These findings reveal an unappreciated role of Tetras in cancer therapy and its potential application to radiotherapy in achieving local tumor control.

Enhancement of radiation effect using beta-lapachone and underlying mechanism

Beta-lapachone (β-Lap; 3,4-dihydro-2, 2-dimethyl-2H-naphthol[1, 2-b]pyran-5,6-dione) is a novel anti-cancer drug under phase I/II clinical trials. β-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human cancer cells in vitro and in vivo. The mechanisms underlying the β-Lap toxicity against cancer cells has been controversial. The most recent view is that β-Lap, which is a quinone compound, undergoes two-electron reduction to hydroquinone form utilizing NAD(P)H or NADH as electron source. This two-electron reduction of β-Lap is mediated by NAD(P)H:quinone oxidoreductase (NQO1), which is known to mediate the reduction of many quinone compounds. The hydroquinone forms of β-Lap then spontaneously oxidizes back to the original oxidized β-Lap, creating futile cycling between the oxidized and reduced forms of β-Lap. It is proposed that the futile recycling between oxidized and reduced forms of β-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced β-Lap is converted first to one-electron reduced β-Lap, i.e., semiquinone β-Lap (SQ)·- causing production of reactive oxygen species (ROS), which then causes apoptotic cell death. The second mechanism is that severe depletion of NAD(P)H and NADH as a result of futile cycling between the quinone and hydroquinone forms of β-Lap causes severe disturbance in cellular metabolism leading to apoptosis and necrosis. The relative importance of the aforementioned two mechanisms, i.e., generation of ROS or depletion of NAD(P)H/NADH, may vary depending on cell type and environment. Importantly, the NQO1 level in cancer cells has been found to be higher than that in normal cells indicating that β-Lap may be preferentially toxic to cancer cells relative to non-cancer cells. The cellular level of NQO1 has been found to be significantly increased by divergent physical and chemical stresses including ionizing radiation. Recent reports clearly demonstrated that β-Lap and ionizing radiation kill cancer cells in a synergistic manner. Indications are that irradiation of cancer cells causes long-lasting elevation of NQO1, thereby sensitizing the cells to β-Lap. In addition, β-Lap has been shown to inhibit the repair of sublethal radiation damage. Treating experimental tumors growing in the legs of mice with irradiation and intraperitoneal injection of β-Lap suppressed the growth of the tumors in a manner more than additive. Collectively, β-Lap is a potentially useful anti-cancer drug, particularly in combination with radiotherapy.

Adverse effect of excess body weight on survival in cervical cancer patients after surgery and radiotherapy.

Purpose This study aimed to assess the effects of body mass index (BMI) on survival in cervical cancer patients who had undergone surgery and radiotherapy (RT). Materials and Methods We retrospectively reviewed the medical records of 70 cervical cancer patients who underwent surgery and RT from 2007 to 2012. Among them, 40 patients (57.1%) had pelvic lymph node metastases at the time of diagnosis. Sixty-seven patients (95.7%) had received chemotherapy. All patients had undergone surgery and postoperative RT. Median BMI of patients was 22.8 kg/m2 (range, 17.7 to 35.9 kg/m2). Results The median duration of follow-up was 52.3 months (range, 16 to 107 months). Twenty-four patients (34.3%) showed recurrence. Local failure, regional lymph nodal failure, and distant failure occurred in 4 (5.7%), 6 (8.6%), and 17 (24.3%) patients, respectively. The 5-year actuarial pelvic control rate was 83.4%. The 5-year cancer-specific survival (CSS) and disease-free survival (DFS) rates were 85.1% and 65.0%, respectively. The presence of pelvic lymph node metastases (n = 30) and being overweight or obese (n = 34, BMI ≥ 23 kg/m2) were poor prognostic factors for CSS (p = 0.003 and p = 0.045, respectively). Of these, pelvic lymph node metastasis was an independent prognostic factor (p = 0.030) for CSS. Conclusion Overweight or obese cervical cancer patients showed poorer survival outcomes than normal weight or underweight patients. Weight control seems to be important in cervical cancer patients to improve clinical outcomes.

Association between obesity and local control of advanced rectal cancer after combined surgery and radiotherapy.

Purpose: The association between metabolism and cancer has been recently emphasized. This study aimed to find the prognostic significance of obesity in advanced stage rectal cancer patients treated with surgery and radiotherapy (RT). Materials and Methods: We retrospectively reviewed the medical records of 111 patients who were treated with combined surgery and RT for clinical stage 2–3 (T3 or N+) rectal cancer between 2008 and 2014. The prognostic significance of obesity (body mass index [BMI] ≥25 kg/m2) in local control was evaluated. Results: The median follow-up was 31.2 months (range, 4.1 to 85.7 months). Twenty-five patients (22.5%) were classified as obese. Treatment failure occurred in 33 patients (29.7%), including local failures in 13 patients (11.7%), regional lymph node failures in 5, and distant metastases in 24. The 3-year local control, recurrence-free survival, and overall survival rates were 88.7%, 73.6%, and 87.7%, respectively. Obesity (n = 25) significantly reduced the local control rate (p = 0.045; 3-year local control, 76.2%), especially in women (n = 37, p = 0.021). Segregation of local control was best achieved by BMI of 25.6 kg/m2 as a cutoff value. Conclusion: Obese rectal cancer patients showed poor local control after combined surgery and RT. More effective local treatment strategies for obese patients are warranted.

Being Overweight or Obese Increases the Risk of Progression in Triple-Negative Breast Cancer after Surgical Resection

This study aimed to evaluate the association between body mass index (BMI) and progression in triple-negative breast cancer (TNBC). We retrospectively reviewed the medical records of 50 patients with TNBC who underwent breast-conserving surgery or mastectomy between 2007 and 2014. All patients were classified according to BMI (median 23.5 kg/m2, range 17.2–31.6 kg/m2): 31 patients (62%) were classified as being overweight or obese (BMI ≥ 23 kg/m2) and 19 patients (38%) were classified as having a normal body weight (BMI < 23 kg/m2). The median follow-up for patients was 31.1 months (range, 6.7–101.9 months). Progression occurred in 7 patients (14%), including 5 ipsilateral breast tumor recurrences, 2 regional lymph node metastases, and 5 distant metastases. Progression was significantly correlated with overweight or obese patients (P = 0.035), while none of the normal weight patients showed progression. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 85.0% and 87.7%, respectively. DFS was significantly reduced in overweight or obese patients compared to that in normal weight patients (P = 0.035). However, OS was not significantly compromised by being overweight or obese (P = 0.134). In conclusion, being overweight or obese negatively affects DFS in TNBC patients.

Lymphovascular invasion as a negative prognostic factor for triple-negative breast cancer after surgery

Purpose This study aimed to evaluate the prognostic effects of lymphovascular invasion (LVI) in triple-negative breast cancer (TNBC) patients who underwent surgical resection. Materials and Methods A total of 63 non-metastatic TNBC patients who underwent surgical resection were retrospectively investigated from 2007 to 2016 in Inje University Busan Paik Hospital. Pathological tests revealed that 12 patients (19.0%) had LVI. Approximately 61.9% (n = 39) of the patients’ samples stained positive for p53. Additional chemotherapy and radiotherapy (RT) were performed in 53 (84.1%) and 47 (74.6%) patients, respectively. Results The median follow-up period was 39.5 months (range, 5.9 to 123.0 months). The pathological T stage (p = 0.008), N stage (p = 0.014), and p53 positivity (p = 0.044) were associated with LVI. Overall, the 3-year disease-free survival (DFS) rate and overall survival (OS) rate were 85.4% and 90.2%, respectively. Ten patients (15.9%) experienced relapse. LVI (n = 12) was associated with relapses (p = 0.016). p53 positivity was correlated with poor DFS (p = 0.048). Furthermore, LVI was related to poor DFS (p = 0.011) and OS (p = 0.001) and considered as an independent prognostic factor for DFS (p = 0.039). The 3-year DFS of patients with LVI (n = 12) was only 58.3%. Adjuvant RT minimized the negative prognostic effect of LVI on DFS (p = 0.068 [with RT] vs. p = 0.011 [without RT]). Conclusion LVI was related to the detrimental effects of disease progression and survival of TNBC patients. Thus, a more effective treatment strategy is needed for TNBC patients with LVI.

Difference in Tumor Area as a Predictor of a Pathological Complete Response for Patients With Locally Advanced Rectal Cancer

Purpose This study was conducted to discover the clinical factors that can predict pathologically complete remission (pCR) after neoadjuvant chemoradiotherapy (CRT), so that those factors may help in deciding on a treatment program for patients with locally advanced rectal cancer. Methods A total of 137 patients with locally advanced rectal cancer were retrospectively enrolled in this study, and data were collected retrospectively. The patients had undergone a total mesorectal excision after neoadjuvant CRT. Histologic response was categorized as pCR vs. non-pCR. The tumor area was defined as (tumor length) × (maximum tumor depth). The difference in tumor area was defined as pre-CRT tumor area – post-CRT tumor area. Univariate and multivariate logistic regression analyses were conducted to find the factors affecting pCR. A P-value < 0.05 was considered significant. Results Twenty-three patients (16.8%) achieved pCR. On the univariate analysis, endoscopic tumor circumferential rate <50%, low pre-CRT T & N stage, low post-CRT T & N stage, small pretreatment tumor area, and large difference in tumor area before and after neoadjuvant CRT were predictive factors of pCR. A multivariate analysis found that only the difference in tumor area before and after neoadjuvant CRT was an independent predictor of pCR (P < 0.001). Conclusion The difference in tumor area, as determined using radiologic tools, before and after neoadjuvant CRT may be important predictor of pCR. This clinical factor may help surgeons to determine which patients who received neoadjuvant CRT for locally advanced rectal cancer should undergo surgery.

Efficacy of Dose-Escalated Radiotherapy for Recurrent Colorectal Cancer.

Purpose This study aimed to evaluate the effects of radiotherapy (RT) on progression-free survival (PFS) for patients with recurrent colorectal cancer. Methods We reviewed the records of 22 patients with recurrent colorectal cancer treated with RT between 2008 and 2014. The median radiation dose for recurrent disease was 57.6 Gy (range, 45–75.6 Gy). Patients were divided into 2 groups according to the type of RT: patients underwent RT without previous history of irradiation (n = 14) and those treated with secondary RT (reirradiation: n = 8) at the time of recurrence. Results The median follow-up period was 24.9 months (range, 4.5–66.6 months). Progression was observed in 14 patients (including 8 with loco-regional failure and 9 with distant metastases). Distant metastases were related to the RT dose (<70 Gy, P = 0.031). The 2-year loco-regional control (LRC), PFS, and overall survival (OS) rates were 74.6%, 45.1%, and 82.0%, respectively. The LRC rate was not different between the patients treated with RT for the first time and those treated with reirradiation (P = 0.101, 2-year LRC 79.5% vs. 41.7%). However, reirradiation was related to poor PFS (P = 0.022) and OS (P = 0.002). An escalated RT dose (≥70 Gy) was associated with a higher PFS (P = 0.014, 2-year PFS 63.5% vs. 20.8%). Conclusion Salvage RT for locally recurrent colorectal cancer can be offered when surgery is impossible. Dose-escalated RT shows a possible benefit in reducing the risk of progression.

The Effect of Levothyroxine Discontinuation Timing on Postoperative Hypothyroidism after Hemithyroidectomy for Papillary Thyroid Microcarcinoma

Objective. No previous studies regarding the appropriate timing of thyroid hormone discontinuation after hemithyroidectomy have been published. This study aimed to identify the appropriate timing for levothyroxine discontinuation after hemithyroidectomy among patients with papillary thyroid microcarcinoma (PTMC). Methods. This study retrospectively evaluated 304 patients who underwent ≥1 attempt to discontinue levothyroxine after hemithyroidectomy for treating PTMC between January 2008 and December 2013. Fifty-three patients were excluded because of preoperative hypothyroidism or hyperthyroidism, a history of thyroid hormone or antithyroid therapy, no available serological data, or a postoperative follow-up of <24 months. We evaluated the associations of successful levothyroxine discontinuation with patient age, sex, preoperative serological data, underlying thyroid gland histopathology, anteroposterior diameter of the residual thyroid gland, number of discontinuation attempts, and initial discontinuation timing. Results. Among the 251 included patients, 125 patients (49.8%) achieved successful levothyroxine discontinuation during the follow-up period after hemithyroidectomy. There was a significant difference in the outcomes for patients who underwent an initial discontinuation attempt at ≤3 months and ≥4 months after hemithyroidectomy (p < 0.001). There were significant differences in the discontinuation outcomes according to underlying thyroid histopathology (p = 0.001), preoperative thyroid-stimulating hormone levels (p < 0.001), and number of discontinuation attempts (p < 0.001). Conclusions. Among patients with PTMC, the initial levothyroxine discontinuation attempt is recommended at ≥4 months after hemithyroidectomy.

Utility of including BRAF mutation analysis with ultrasonographic and cytological diagnoses in ultrasonography-guided fine-needle aspiration of thyroid nodules

This study investigated the role of BRAF mutation analysis in thyroid fine-needle aspiration (FNA) samples compared to ultrasonographic and cytological diagnoses. A total 316 patients underwent ultrasonography (US)-guided FNA with BRAFV600E mutation analysis to diagnose thyroid nodules. One hundred sixteen patients with insufficient US images (n = 6), follow-up loss (n = 43), or unknown final diagnosis (n = 67) were excluded from the study. Comparisons between US diagnoses, cytological diagnoses, and BRAF mutation analysis were performed. Of 200 thyroid nodules, there was US diagnosis with 1 false negative and 11 false positive cases, cytological diagnosis with 10 false negative and 2 false positive cases, and BRAFV600E mutation analysis with 19 false negative and 2 false positive cases. The sensitivity, specificity, positive and negative predictive values, and accuracy of BRAFV600E mutation analysis were 83.2%, 98.1%, 97.5%, 86.6%, and 91%, respectively. Of the 18 nodules with Bethesda category III, 9 were true positive, 6 were true negative, 3 was a false negative, and none were false positive on BRAF mutation analysis. In conclusion, we recommend that BRAFV600E mutation analysis only be performed for evaluating thyroid nodules with Bethesda category III, regardless of US diagnosis.