The impact of intensity-modulated radiotherapy in conjunction with chemotherapy on proximal pT3N0 rectal cancer patients after total mesorectum excision.

BACKGROUND: This study aimed to ascertain if the incorporation of intensity-modulated radiotherapy (IMRT) with chemotherapy (CTx) offered any advantages for patients diagnosed with stage pT3N0 rectal cancer located in the proximal (upper) region following a complete total mesorectum excision (TME). METHODS: We retrospectively examined medical records of stage II/III rectal cancer patients who had undergone CTx or concurrent chemoradiation (CCRT) with IMRT after a successful TME. We juxtaposed a variety of survival outcomes across two patient cohorts. Each outcome was further classified according to Gunderson's risk stratification between proximal and distal (middle and low) rectal cancer patients, and we evaluated the factors associated with each outcome. RESULTS: The median follow-up duration was 4.9 years. Our research comprised 236 rectal adenocarcinoma patients treated at our institution between 2007 and 2019. They received either the CTx (n = 135) or the CCRT (n = 101) with 10-year locoregional recurrence-free survival (LRRFS) of 90.1% and 96.1%, respectively (p = 0.163). However, after performing multivariate adjustments, a pattern emerged hinting at a better LRRFS for the CCRT group (p = 0.052). Perforation had a strong correlation with locoregional recurrence. No significant differences were observed in other survival between the two treatment arms and their respective subgroups. The CCRT group witnessed significantly higher immediate and chronic complications with p = 0.007 and 0.009, respectively. The CCRT group had two secondary cancer-related fatalities (2%, one attributed to IMRT), and another reported by the CTx group (1%). The sole classified locoregional recurrence within the cohort of 37 individuals treated with CTx for proximal pT3N0 rectal cancer was, in fact, the development of sigmoid colon cancer. CONCLUSION: The results suggest that for patients with proximal pT3N0 rectal cancer post-TME, IMRT is better when not combined with CTx, except in highly perilous scenarios or those involving perforation.

Hippocampal-sparing whole-brain radiotherapy under coplanar or noncoplanar VMAT.

Whole-brain radiotherapy (WBRT) can alleviate symptoms in patients with brain metastases. However, WBRT may damage the hippocampus. Volumetric modulated arc therapy (VMAT) can achieve a suitable coverage of the target region and a more conforming dose distribution whereas decreasing the dose to organs-at-risk (OARs). Herein, we aimed to compare the differences between treatment plans utilizing coplanar VMAT and noncoplanar VMAT in hippocampal-sparing WBRT (HS-WBRT). Ten patients were included in this study. For each patient, the Eclipse A10 treatment planning system was used to generate 1 coplanar VMAT (C-VMAT) and 2 noncoplanar VMAT treatment plans with various beam angles (noncoplanar VMAT A [NC-A] and noncoplanar VMAT B [NC-B]) for HS-WBRT. The prescribed dose was 30 Gy in 12 fractions. Treatment plans were established based on the OAR dose constraints of the Radiation Therapy Oncology Group 0933 (RTOG 0933). Parameters such as the global maximum dose, dose conformity, dose homogeneity of plans, and OAR doses were evaluated. The maximum biologically equivalent doses in 2-Gy fractions (EQD2) of OARs in C-VMAT were 9.17 ± 0.61, 42.79 ± 2.00, and 42.84 ± 3.52 Gy in the hippocampus, brain stem, and optic chiasm, respectively, which were the lowest among the 3 treatment plans. There was no significant difference in dose conformity among the 3 treatment plans. However, NC-A had a slightly better conformity than C-VMAT and NC-B. NC-A had the best homogeneity, and NC-B had the worst homogeneity (p = 0.042). NC-A and NC-B had the lowest and highest global dose maximum, respectively. Therefore, NC-A, which had an intermediate performance in terms of OAR doses, had the best quality parameters. We used the quality score table based on the p-value to evaluate the significant difference between each treatment technique from the multiparameter results. In terms of treatment plan parameters, only NC-A received a score of 2; for OAR doses, C-VMAT, NC-A, and NC-B received a score of 6, 3, and 5, respectively. For the overall evaluation, C-VMAT, NC-A, and NC-B received a total score of 6, 5, and 5, respectively. Rather than noncoplanar VMAT, 3 full-arc C-VMATs should be utilized in HS-WBRT. C-VMAT can simultaneously maintain treatment plan quality and decrease patient alignment time and total treatment time.

Liver-directed stereotactic body radiotherapy can be reliably delivered to selected patients without internal fiducial markers-A case series.

Tumor motion and the lack of tissue-tumor contrast have been challenging parts of liver-directed stereotactic body radiotherapy (SBRT). In this study, we investigated the possibility of liver-directed SBRT without internal fiducials using breath hold technique and diaphragm matching technique. One hundred thirty-four volumetric images of 13 consecutive patients with either primary or metastatic liver tumors who underwent expiratory breath hold SBRT were compared and analyzed. Reproducibility of diaphragm position between fractions relative to bone was evaluated on image registration software. At median follow-up time of 13 months, 1-year and 2-year local control rates of index lesions were 90% and 72%, respectively. In comparison to diaphragm matching, a greater margin is required for bone matching technique for that 19 of 67 (28%) of all interfractional SI offsets were more than 6 mm, whereas 6 of 67 (9%) intrafractional SI exceeded 6 mm. Despite the small study size, our study showed that breath hold SBRT without internal hepatic fiducial is a valid approach for selected patients.

Using NIPAM gel dosimeter and concentric swing machine to simulate the dose distribu- tion during breathing: A feasibility study.

BACKGROUND: Radiotherapy plays an important role in cancer treatment today. Successful radiotherapy includes precise positioning and accurate dosimetry. OBJECTIVE: To use NIPAM gel dosimeter and concentric swing machine to simulate and evaluate the feasibility of lung or upper abdominal tumor dose distribution during breathing. METHODS: We used a concentric swing machine to simulate actual radiotherapy for lung or upper abdomen tumors. A 4 × 4 cm2 irradiation field area was set and MRI was performed. Next, readout analysis was performed using MATLAB and the 3 mm, 3% gamma passing rate > 95% was used as a basis for evaluation. RESULTS: The concentric dynamic dose curve for a simulated respiratory rate of 3 seconds/breath and 4 × 4 cm2 field was compared with 4 × 4, 3 × 3, and 2 × 2 cm2 treatment planning systems (TPS), and the 3 mm, 3% gamma passing rate was 42.87%, 54.96%, and 49.92%, respectively. Pre-simulation showed that the high-dose region dose curve was similar to the 2 × 2 cm2 TPS result. After appropriate selection and comparison, we found that the 3 mm, 3% gamma passing rate was 97.92% on comparing the > 60% dose curve with the 2 × 2 cm2 TPS. CONCLUSIONS: NIPAM gel dosimeter and concentric swing machine use is feasible to simulate dose distribution during breathing and results conforming to clinical evaluation standards.

Applying the N-isopropylacrylamide gel dosimeter to quantify dynamic dose effects: A feasibility study.

BACKGROUND: The gel dosimeter is a chemical as well as a relative dosimeter. OBJECTIVE: To evaluate the feasibility of using N-isopropylacrylamide (NIPAM) gel dosimeter to observe the dynamic dose effects and quantification of the respiration, and to help determine the safety margins. METHODS: The NIPAM gel dosimeter combined with the dynamic phantom was used to simulate radiotherapy of lung or upper abdominal tumor. The field set to 4 × 5 cm2, simulate respiratory rate of 4 sec/cycle, and motion range 2 cm. MRI was used for reading, and MATLAB was used for analysis. The 3%/3 mm gamma passing rate > 95% was used as a clinical basis for evaluation. RESULTS: The dynamic dose curve was compared with 4 × 5, 4 × 4, 4 × 3 cm2 TPS, and gamma passing rates were 74.32%, 54.83%, 30.18%. Gamma mapping demonstrated that the highest dose region was similar to the result of the 4 × 4 cm2 TPS. After appropriate selection and comparing that the ⩾ 60% part of the dose curve with TPS, the gamma passing rate was 96.49%. CONCLUSIONS: Using the NIPAM gel dosimeter with dynamic phantom to simulate organ motion during respiration for dynamic dose measurement and quantified the dynamic dose effect is feasible. The results are consistent with clinical evaluation standards.

Integrated Molecular Characterization to Reveal the Association between Kynurenine 3-Monooxygenase Expression and Tumorigenesis in Human Breast Cancers.

Kynurenine 3-monooxygenase (KMO) is overexpressed in several tumors and participates in the progression of breast cancer tumorigenesis, including cancer types such as triple-negative breast cancer (TNBC). This malignant gene is an enzyme in the kynurenine pathway, which is involved in the carcinogenesis of cancer through immune function manipulation. However, it remains unclear whether the role of the KMO contributes to tumorigenesis and immune functions in human breast cancer. In this study, we found that KMO was highly expressed in different types of tumors, especially in invasive ductal breast carcinoma. In addition, KMO expression was positively correlated with the malignant clinical features of patients with breast cancer, such as TNBC and a nodal-positive status, along with patients with a higher Nottingham prognostic index (NPI). Furthermore, the top ten KMO-correlated genes were the chemokines and pro-inflammatory cytokines known to be involved in the progression of various cancers, therefore, KMO may facilitate breast cancers via synergistically regulating inflammatory responses in tumors with these hub genes. Taken together, these findings highlight the tumor-promotion role of KMO in breast cancers and suggest that KMO can serve as a biomarker for prognosis prediction in breast cancer patients.

Relationship between Energy Dosage and Apoptotic Cell Death by Modulated Electro-Hyperthermia.

Modulated electro-hyperthermia (mEHT) is a form of mild hyperthermia (HT) used for cancer treatment. The principle utility of HT is the ability not only to increase cell temperature, but also to increase blood flow and associated pO2 to the microenvironment. While investigational evidence has shown the unique ability of mEHT to elicit apoptosis in cancer cells, in vivo and in vitro, the same trait has not been observed with conventional HT. There is dissension as to what allows mEHT to elicit apoptosis despite heating to only mild temperatures, with the predominant opinion in favor of increased temperature at a cellular level as the driving force. For this study, we hypothesized that in addition to temperature, the amount of electrical energy delivered is a major factor in induction of apoptosis by mEHT. To evaluate the impact of electrical energy on apoptosis, we divided generally practiced mEHT treatment into 3 phases: Phase I (treatment start to 10 min. mark): escalation from 25 °C to 37 °C Phase II (10 min. mark to 15 min. mark): escalation from 37 °C to 42 °C Phase III (15 min. mark to 45 min. mark): maintenance at 42 °C Combinations of mEHT at 18 W power, mEHT at 7.5 W power, water bath, and incubator were applied to each of the three phases. Power output was recorded per second and calculated as average power per second. Total number of corresponding Joules emitted per each experiment was also recorded. The biological effect of apoptotic cell death was assayed by annexin-V assay. In group where mEHT was applied for all three phases, apoptosis rate was measured at 31.18 ± 1.47%. In group where mEHT was only applied in Phases II and III, apoptosis rate dropped to 20.2 ± 2.1%. Where mEHT was only applied in Phase III, apoptosis was 6.4 ± 1.7%. Interestingly, when mEHT was applied in Phases I and II, whether Phase III was conducted in either water bath at 42 °C or incubator at 37 °C, resulted in nearly identical apoptosis rates, 26 ± 4.4% and 25.9 ± 3.1%, respectively. These results showed that accumulation of mEHT at high-powered setting (18 W/sec) during temperature escalation (Phase I and Phase II), significantly increased apoptosis of tested cancer cells. The data also showed that whereas apoptosis rate was significantly increased during temperature escalation by higher power (18 W/sec), apoptosis was limited during temperature maintenance with lower power (7.5 W/sec). This presents that neither maintenance of 42 °C nor accumulation of Joules by mEHT has immediate correlating effect on apoptosis rate. These findings may offer a basis for direction of clinical application of mEHT treatment.

Modulated electro-hyperthermia-enhanced liposomal drug uptake by cancer cells.

PURPOSE: Modulated electro-hyperthermia (mEHT) stands to be a significant technological advancement in the hyperthermia field, utilizing autofocusing electromagnetic power on the cell membrane to create massive apoptosis. Since mEHT possesses the unique ability to excite cell membranes, we hypothesized that mEHT could enhance the uptake of liposomal drugs by enhancing phagocytic activity. MATERIALS AND METHODS: Water bath control and mEHT were used to compare the enhancement of liposome-encapsulated doxorubicin (Lipodox®) uptake by cancer cells. Cancer cells were made visible by doxorubicin fluorescence to investigate drug uptake. Viable cell yield was determined via the Trypan Blue exclusion method. Various substrates were used to investigate the mechanism of drug-uptake enhancement. The murine colon carcinoma model, CT26, was used to confirm the tissue infiltration of Lipodox® and its therapeutic effect. RESULTS: mEHT treatment showed a significant enhancement of Lipodox® uptake of doxorubicin fluorescence compared with 37°C or 42°C water bath treatment. Tumor tissue sections also confirmed that mEHT treatment achieved the highest doxorubicin concentration in vivo (1.44±0.32 µg/g in mEHT group and 0.79±0.32 µg/g in 42°C water bath). Wortmannin was used to inhibit the macropinocytosis effect and 70 kDa dextran-FITC served as uptake substance. The uptake of dextran-FITC by cancer cells significantly increased after mEHT treatment whereas such enhancement was significantly inhibited by wortmannin. CONCLUSION: The result showed mEHT-induced particle-uptake through macropinocytosis. mEHT-enhanced uptake of Lipodox® may amplify the therapeutic effect of liposomal drugs. This novel finding warrants further clinical investigation.

Intensity modulated radiotherapy delivers competitive local control rate with limited acute toxicity in the adjuvant treatment of rectal cancer.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) has yet to show its capability in the adjuvant treatment of locally advanced rectal cancer. The purpose of this study is to evaluate the clinical efficacy and safety profile of IMRT in the adjuvant treatment of rectal cancer. METHOD: Consecutive patients with resected locally advanced rectal cancer who had IMRT as part of adjuvant treatment between 2008 and 2014 were identified. The medical records and dosimetric parameters of 72 patients were retrospectively examined. RESULTS: The median follow-up time was 4.36 years (range 0.16-8.49 years). Overall survival rate and disease-free survival rate at 3 year was 79% (95% CI: 66.4-7.3%) and 70% (95% CI: 56.6-79.6%), respectively. Local control rate was 95%. The median bowel bag V45 was 282 ml (249-458 ml) and bone marrow V40 was 29%. Most acute toxicities were self-limited. Concurrent use of chemotherapy was associated with greater odds of ≥Grade 2 acute neutropenia (OR 25.44, P = 0.022). CONCLUSION: Integration of IMRT in the adjuvant treatment of rectal cancer is promising with competitive local control rate. Acute toxicities are mostly self-limited.

Improving immunological tumor microenvironment using electro-hyperthermia followed by dendritic cell immunotherapy.

BACKGROUND: The treatment of intratumoral dentritic cells (DCs) commonly fails because it cannot evoke immunity in a poor tumor microenvironment (TME). Modulated electro-hyperthermia (mEHT, trade-name: oncothermia) represents a significant technological advancement in the hyperthermia field, allowing the autofocusing of electromagnetic power on a cell membrane to generate massive apoptosis. This approach turns local immunogenic cancer cell death (apoptosis) into a systemic anti-tumor immune response and may be implemented by treatment with intratumoral DCs. METHODS: The CT26 murine colorectal cancer model was used in this investigation. The inhibition of growth of the tumor and the systemic anti-tumor immune response were measured. The tumor was heated to a core temperature of 42 °C for 30 min. The matured synergetic DCs were intratumorally injected 24 h following mEHT was applied. RESULTS: mEHT induced significant apoptosis and enhanced the release of heat shock protein70 (Hsp70) in CT26 tumors. Treatment with mEHT-DCs significantly inhibited CT26 tumor growth, relative to DCs alone or mEHT alone. The secondary tumor protection effect upon rechallenging was observed in mice that were treated with mEHT-DCs. Immunohistochemical staining of CD45 and F4/80 revealed that mEHT-DC treatment increased the number of leukocytes and macrophages. Most interestingly, mEHT also induced infiltrations of eosinophil, which has recently been reported to be an orchestrator of a specific T cell response. Cytotoxic T cell assay and ELISpot assay revealed a tumor-specific T cell activity. CONCLUSIONS: This study demonstrated that mEHT induces tumor cell apoptosis and enhances the release of Hsp70 from heated tumor cells, unlike conventional hyperthermia. mEHT can create a favorable tumor microenvironment for an immunological chain reaction that improves the success rate of intratumoral DC immunotherapy.

N-isopropylacrylamide gel dosimeter to evaluate clinical photon beam characteristics.

The introduction of beam intensity control concept in current radiotherapy techniques has increased treatment planning complexity. Thus, small-field dose measurement has become increasingly vital. Polymer gel dosimetry method is widely studied. It is the only dose measurement tool that provides 3D dose distribution. This study aims to use an N-isopropylacrylamide (NIPAM) gel dosimeter to conduct beam performance measurements of percentage depth dose (PDD), beam flatness, and symmetry for photon beams with field sizes of 3×3 and 4×4 cm(2). Computed tomography scans were used to readout the gel dosimeters. In the PDD measurement, the NIPAM gel dosimeter and Gafchromic™ EBT3 radiochromic film displayed high consistency in the region deeper than the build-up region. The gel dosimeter dose profile had 3% lower flatness and symmetry measurement at 5 cm depth for different fields compared with that of the Gafchromic™ EBT3 film. During gamma evaluation under 3%/3 mm dose difference/distance-to-agreement standard, the pass rates of the polymer gel dosimeter to the TPS and EBT3 film were both higher than 96%. Given that the gel is tissue equivalent, it did not exhibit the energy dependence problems of radiochromic films. Therefore, the practical use of NIPAM polymer gel dosimeters is enhanced in clinical dose verification.

Improving Detection Accuracy of Lung Cancer Serum Proteomic Profiling via Two-Stage Training Process.

BACKGROUND: Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) is a frequently used technique for cancer biomarker research. The specificity of biomarkers detected by SELDI can be influenced by concomitant inflammation. This study aimed to increase detection accuracy using a two-stage analysis process. METHODS: Sera from 118 lung cancer patients, 72 healthy individuals, and 31 patients with inflammatory disease were randomly divided into training and testing groups by 3:2 ratio. In the training group, the traditional method of using SELDI profile analysis to directly distinguish lung cancer patients from sera was used. The two-stage analysis of distinguishing the healthy people and non-healthy patients (1st-stage) and then differentiating cancer patients from inflammatory disease patients (2nd-stage) to minimize the influence of inflammation was validated in the test group. RESULTS: In the test group, the one-stage method had 87.2% sensitivity, 37.5% specificity, and 64.4% accuracy. The two-stage method had lower sensitivity (> 70.1%) but statistically higher specificity (80%) and accuracy (74.7%). The predominantly expressed protein peak at 11480 Da was the primary splitter regardless of one- or two-stage analysis. This peak was suspected to be SAA (Serum Amyloid A) due to the similar m/z countered around this area. This hypothesis was further tested using an SAA ELISA assay. CONCLUSIONS: Inflammatory disease can severely interfere with the detection accuracy of SELDI profiles for lung cancer. Using a two-stage training process will improve the specificity and accuracy of detecting lung cancer.

Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a mono-institutional experience.

BACKGROUND: Upfront tyrosine kinase inhibitor (TKI) has proved effective for selective advanced lung cancer patients in Taiwan. We hypothesized that early integration of radiotherapy during TKI treatment would decrease the chance of drug resistance and prolong progression-free survival (PFS). METHODS: This study included 25 patients with stage IIIb or IV non-squamous cell, non-small cell lung cancer (NSqCLC) who responded to upfront TKI treatment. Multi-target radiotherapy was administered during the TKI treatment course. Tomotherapy comprising a hypofractionated schedule with a dose of 40-50 Gy in 16-20 fractions was used for individual metastatic lesions. RESULTS: The patients' median follow-up duration was 30 months (range, 9-62 months). Of the 23 patients who had stage IV disease, 9 had oligometastases (≤5 gross target volumes) and 14 were in the more advanced stages of the disease. Twelve patients received more than 1 cycle of radiotherapy (median, 3; range, 2-6) with TKI being the only systemic treatment before they were salvaged with chemotherapy. The overall response rate after radiotherapy was 84.0%, and the median PFS was 16 months. The 3-year overall survival rate was 62.5% (95% confidence interval [CI], 39.1-85.8%). Toxicities were generally tolerated but it is necessary to prevent radiation-induced pneumonitis. CONCLUSION: We showed that combined first-line TKI therapy and early multi-target radiotherapy are very effective in selected patients that respond to TKI, when the status of mutations in the epidermal growth factor receptor (EGFR) are not known before the treatment. Our data may aid expansion of the effectiveness of TKI treatment through radiotherapy in Asian patients with stage IV NSqCLC.

Angiogenic blockade and radiotherapy in hepatocellular carcinoma.

PURPOSE: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC. METHODS AND MATERIALS: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial alpha-fetoprotein (AFP) kinetics, and survival. RESULTS: Of 23 evaluable patients, 60% had >or=2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenance sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had >or=50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had >or=Grade 2 elevation of liver enzymes, and 15 had >or=Grade 2 thrombocytopenia. CONCLUSIONS: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.

Synergistic anti-tumor effect of combination radio- and immunotherapy by electro-gene therapy plus intra-tumor injection of dendritic cells.

Interleukin-2 (IL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF) facilitate the maturation and functioning of injected DC. We developed a method of in situ electroporation using IL-2 and GM-CSF genes (EGT/cytokines), followed by intra-tumoral (i.t.) immature DC to determine the immune response at the tumor site using prostate-specific antigen-transfected CT26 cells. Three cycles of EGT/cytokines and i.t. DC inhibited tumor growth most effectively, but not superior to EGT/cytokines alone. However, the role of i.t. DC became significant when radiation was given after immunotherapy, which may have clinical implications on achieving better local control and prevention of systemic relapse.

Cutaneous metastases from squamous cell carcinoma of the ureter.

OBJECTIVE: To present an extremely rare case of squamous cell carcinoma of the ureter with cutaneous metastases. CLINICAL PRESENTATION AND INTERVENTION: A case is presented involving a 67-year-old woman presenting with a clinical history of squamous cell carcinoma of the ureter and who had undergone a nephro-ureterectomy with a bladder cuff excision in May 2004. The pathologic report showed squamous differentiation, as well as keratin pearl formation. A large regional cutaneous lesion on the chest wall was found in January 2006, and a biopsy showed metastatic malignant urothelial tumors consisting of squamous cell carcinomas. CONCLUSION: This report describes a case of cutaneous metastasis from a squamous cell carcinoma of the ureter that is extremely rare with a generally dismal prognosis.