Definitive S-1/mitomycin-C chemoradiotherapy for stage II/III anal canal squamous cell carcinoma: a phase I/II dose-finding and single-arm confirmatory study (JCOG0903).

BACKGROUND: Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA. METHODS: Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m2 on days 1 and 29) and S-1 (60 mg/m2/day at level 0 and 80 mg/m2/day at level 1 on days 1-14 and 29-42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively. RESULTS: Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m2/day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1-73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred. CONCLUSIONS: Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA. CLINICAL TRIAL INFORMATION: jRCTs031180002.

Preoperative T staging of colon cancer using CT colonography with multiplanar reconstruction: new diagnostic criteria based on "bordering vessels".

PURPOSE: Preoperative T staging of colon cancer, in particular, for distinguishing T3 from T2 and T4, has been a challenge. The aim of this study was to evaluate newly developed criteria for preoperative T staging of colorectal cancer using computed tomography colonography (CTC) with multiplanar reconstruction (MPR), based on the spatial relationship of tumors and "bordering vessels," that is, marginal vessels that are detectable by multi-detector row CT with MPR. METHODS: A total of 172 patients with colon and upper rectal cancer who underwent preoperative CTC and surgery between August 2011 and September 2013 were included. Preoperative T staging using the new criteria was performed prospectively and compared with pathologic results. RESULTS: Sensitivity, specificity, and accuracy of T staging by CTC using the new criteria were 63%, 80%, and 77% for T2 (n = 30); 72%, 94%, and 81% for T3 (n = 95); and 79%, 99%, and 97% for T4a (n = 14), respectively. Positive predictive value for T3 was 93%, indicating that a T3 diagnosis by CTC is precise. In addition, negative predictive value for pathological T4a was 98%, indicating that a "not T4a" diagnosis by CTC is also precise. CONCLUSIONS: Our newly developed criteria are useful for preoperative T staging, particularly for distinguishing T3 from T2 and T4.

Computed tomographic colonography with a reduced dose of laxative using a novel barium sulfate contrast agent in Japan.

PURPOSE: To test the tagging efficacy, patient acceptability, and accuracy of computed tomographic colonography (CTC) with a reduced dose of laxative using a novel barium sulfate (BaSO4) contrast agent. MATERIALS AND METHODS: CTC followed by optical colonoscopy (OC) was performed on 73 patients with positive results in fecal occult blood tests. They were administrated a BaSO4 suspension and a magnesium citrate solution for bowel preparation. Patients completed a questionnaire about the acceptability of bowel preparation. Tagging efficacy was estimated using a novel categorization system, which classified all segments into 8 categories. The accuracy of detecting protruded lesions ≥ 6 mm was calculated from the comparison of CTC and OC results, using the latter as a reference standard. RESULTS: Tagging efficacy was good in 77.3% of colonic segments where residue was observed. The acceptability of bowel preparation for CTC was significantly higher than that for OC. The sensitivity, specificity, and positive and negative predictive values were 0.778, 0.945, 0.824, and 0.929, respectively. All lesions ≥ 7 mm were successfully detected by CTC. CONCLUSION: CTC with a reduced dose of laxative using a novel BaSO4 contrast agent has a favorable tagging efficacy, patient acceptability, and accuracy.

Preoperative T staging using CT colonography with multiplanar reconstruction for very low rectal cancer.

BACKGROUND: Preoperative T staging of lower rectal cancer is an important criterion for selecting intersphincteric resection (ISR) or abdominoperineal resection (APR) as well as selecting neoadjuvant therapy. The aim of this study was to evaluate the accuracy of preoperative T staging using CT colonography (CTC) with multiplanar reconstruction (MPR), in which with the newest workstation the images can be analyzed with a slice thickness of 0.5 mm. METHODS: Between 2011 and 2013, 45 consecutive patients with very low rectal adenocarcinoma underwent CTC with MPR. The accuracy of preoperative T staging using CTC with MPR was evaluated. The accuracy of preoperative T staging using MRI in the same patient population (34 of 45 patients) was also examined. RESULTS: Overall accuracy of T staging was 89% (41/45) for CTC with MPR and 71% (24/34) for MRI. CTC with MPR was particularly sensitive for pT2 tumors (82%; 14/17), whereas MRI tended to overstage pT2 tumors and its sensitivity for pT2 was 53% (8/15). CONCLUSIONS: CTC with MPR, with an arbitrary selection, could be aligned to the tumor axis and better demonstrated tumor margins consecutively including the deepest section of the tumor. The accuracy of T2 and T3 staging using CTC with MPR seemed to surpass that of MRI, suggesting a potential role of CTC with MPR in preoperative T staging for very low rectal cancer.

Cost-Effectiveness Analysis of CT Colonography for Colorectal Cancer Screening Program to Working Age in Japan.

OBJECTIVES: To assess the cost-effectiveness of computed tomography colonography (CTC) for a colorectal cancer screening program in a working population (aged 40-60 years) from a health care payer's perspective in Japan. METHODS: A Markov model for colorectal cancer was constructed to estimate the long-term (10-year, 20-year, and 30-year) effect of introducing CTC for three different strategies in the cohort aged 40 years on April 1, 2011. Strategy 1 (the current strategy in Japan): fecal occult blood test (FOBT) followed by optical colonoscopy (OC). In this case, 41.8% of those who were FOBT-positive did not undergo OC (uptake 58.2%). Strategy 2: All FOBT-positive cases would be offered CTC (uptake 79.1%) followed by OC. Strategy 3: Only those FOBT-positive cases who were reluctant to undergo OC (41.8%) would be offered CTC (assumed uptake 50.0%) followed by OC. Epidemiological data were obtained mainly from statistics published by the Japanese National Cancer Center. We set quality-adjusted life-year (QALY) as the primary outcome and colorectal cancer death and expected life-years as secondary ones. The discount rate for both costs and outcomes was set at 3%. RESULTS: In the base-case (20-year) analysis, total cost was increased from Japanese yen (JPY) 65,614 million (strategy 1) to JPY 69,405 million (strategy 2) but was decreased to JPY 63,878 million (strategy 3). The total QALY increased from 28,156,046 QALYs (strategy 1) to 28,158,349 (strategy 2) and 28,159,058 QALYs (strategy 3). Therefore, the incremental cost-effectiveness ratio was JPY 1,646,000 per QALY gained for strategy 2 and strategy 3 was dominant against strategy 1, both of which were well below the Japanese threshold (JPY 5-6 million per QALY gained). CONCLUSION: Adding CTC into the current colorectal cancer screening program for the working population seems to be a cost-effective option.

Colorectal laterally spreading tumors by computed tomographic colonography.

To date, few reports focused primarily on detecting colorectal laterally spreading tumors (LSTs) have been published. The aim of this study was to determine the visibility of LSTs on computed tomographic colonography (CTC) compared with that on colonoscopy as a standard. We retrospectively reviewed and matched data on endoscopic and CTC reports in 157 patients (161 LSTs) who received a multidetector CT scan using contrast media immediately after total colonoscopy at the National Cancer Center Hospital in Tokyo, Japan, between December 2005 and August 2010. The results of the total colonoscopy were known at the time of the CTC procedure and reading. Of the 161 LSTs detected on colonoscopy, 138 were observed and matched by CTC (86%). Of the 91 granular type LSTs (LST-Gs), 88 (97%) were observed and matched, while of the 70 non-granular type LSTs (LST-NGs), 50 (71%) were observed and matched by CTC (p<0.0001). CTC enabled observation of 73% (22/30) of 20-29 mm, 83% (35/42) of 30-39 mm, 88% (49/56) of 40-59 mm, and 97% (32/33) of ≥60 mm tumors. The rate of observed LSTs by CTC was 86% (97% of LST-G, 71% of LST-NG) of the LSTs found during total colonoscopy.

Comparative performance of a primary-reader and second-reader paradigm of computer-aided detection for CT colonography in a low-prevalence screening population.

OBJECTIVE: To compare the efficacy of computer-aided detection (CAD) for computed tomographic colonography (CTC) when employed as either primary-reader or second-reader paradigms in a low-prevalence screening population. METHODS: Ninety screening patients underwent same-day CTC and colonoscopy. Four readers prospectively interpreted all CTC data sets using a second-reader paradigm (unassisted interpretation followed immediately by CAD assistance). Three months later, randomized anonymous data sets were re-interpreted by all readers using a primary-reader paradigm (only CAD prompts evaluated). RESULTS: Compared with the average per-patient sensitivity for unassisted interpretation (0.57), both CAD paradigms significantly increased sensitivity: 0.78 (p < 0.001) for the second-reader paradigm and 0.83 (p < 0.001) for the primary-reader paradigm. There was no significant difference between CAD paradigms (p = 0.25). The average per-patient specificity for polyps ≥6 mm was significantly higher using the primary-reader paradigm than the second-reader paradigm (0.90 vs. 0.83, respectively, p = 0.006), with ROC AUCs of 0.83 and 0.68, respectively. Reading time using CAD as a primary-reader paradigm (median 1.4 min) was significantly shorter than both unassisted (median 4.0 min, p < 0.001) and second-reader paradigms (median 5.5 min, p < 0.001). CONCLUSION: CAD improves radiologist sensitivity in screening patients when used as either a second- or primary-reader paradigm, although the latter may improve specificity and efficiency more.

Semi-automated virtual unfolded view generation method of stomach from CT volumes.

CT image-based diagnosis of the stomach is developed as a new way of diagnostic method. A virtual unfolded (VU) view is suitable for displaying its wall. In this paper, we propose a semi-automated method for generating VU views of the stomach. Our method requires minimum manual operations. The determination of the unfolding forces and the termination of the unfolding process are automated. The unfolded shape of the stomach is estimated based on its radius. The unfolding forces are determined so that the stomach wall is deformed to the expected shape. The iterative deformation process is terminated if the difference of the shapes between the deformed shape and expected shape is small. Our experiments using 67 CT volumes showed that our proposed method can generate good VU views for 76.1% cases.

Imaging study of pancreatic ductal adenocarcinomas in Syrian hamsters using X-ray micro-computed tomography (CT).

X-ray computed tomography (CT) has been used for diagnoses of human pancreatic cancer. Although micro-CT is a useful approach to evaluate macromorphology of organs/tissue also in animal models, reports on pancreatic tumors are limited. In this study, the utility of micro-CT was assessed in characterizing chemically induced pancreatic tumors in Syrian hamsters. Hamsters treated with or without N-nitrosobis(2-oxopropyl)amine (BOP) were injected with the antispasmodic agent, scopolamine butylbromide, and contrast agents, 5 or 10 mL/kg body weight of iopamidol or Fenestra VC at 18-38 weeks, then examined by micro-CT scanning with a respiratory gating system. Both peristaltic and respiratory movements were substantially suppressed by the combination of scopolamine butylbromide treatment and the respiratory gating system, resulting in improvements of image qualities. Iopamidol clearly visualized the pancreatic parenchyma and contrasted the margins among the pancreas and other abdominal organs/tissue. Meanwhile Fenestra VC predominantly contrasted abdominal vascular systems, but the margins among pancreas and other organs/tissue remained obscure. Six pancreatic tumors of 4-13 mm in diameter were detected in four of 15 animals, but not the five tumors of 1-4 mm in diameter. The inner tumor images were heterogeneously or uniformly visualized by iopamidol and Fenestra VC. Overall, iopamidol could clearly contrast between pancreatic parenchyma and the tumors as compared with Fenestra VC. All tumors confirmed were histopathologically diagnosed as pancreatic ductal adenocarcinomas. Thus, micro-CT could be useful to evaluate the carcinogenic processes and preventive methods of pancreatic cancer in hamsters and to assess the novel contrast agents for detection of small pancreatic cancer in humans.

Cancer prevention by bovine lactoferrin: from animal studies to human trial.

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers and, despite improved colonoscopic screening, CRC is a leading cause of death from cancer. Administration of bovine lactoferrin (bLF) suppresses carcinogenesis in the colon and other organs of test animals, and recently it was shown that ingestion of bLF inhibits the growth of adenomatous polyps in human patients. Here we review work which established bLF as an anti-carcinogenic agent in laboratory animals and the results of a clinical trial which demonstrated that bLF can reduce the risk of colon carcinogenesis in humans.

Effect of orally administered bovine lactoferrin on the growth of adenomatous colorectal polyps in a randomized, placebo-controlled clinical trial.

Lactoferrin (LF), a secreted, iron binding glycoprotein originally discovered as a component of milk, is found in a variety of exocrine secretions and in the secondary granules of polymorphonuclear leukocytes. Animal experiments have shown that oral administration of bovine lactoferrin (bLF) exerts anticarcinogenesis effects in the colon and other organs of the rat. The aim of this study was to determine whether oral bLF could inhibit the growth of adenomatous colorectal polyps in human patients. A randomized, double-blind, controlled trial was conducted in 104 participants, ages 40 to 75 years, with polyps

Accuracy of high-resolution magnetic resonance imaging in preoperative staging of rectal cancer.

BACKGROUND: To achieve better prognosis and quality of life for patients with rectal cancer, extent of surgery and neoadjuvant chemoradiotherapy should accurately reflect disease extent. The aim of this study was to evaluate accuracy of high-resolution magnetic resonance imaging (HRMRI) for preoperative staging of rectal cancer. METHODS: Between 2001 and 2003, 104 patients with primary rectal cancer were examined with HRMRI and underwent radical surgery. Transmural invasion depth and lymph node metastasis were assessed prospectively and classified according to the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) system by both HRMRI and histopathology, and results were compared. Criteria for mesorectal and lateral pelvic lymph node involvement were short-axis diameters of > or =5 mm and > or =4 mm, respectively. RESULTS: There were 15 pT1, 25 pT2, 50 pT3, and 14 pT4 tumors. Overall accuracy rate for transmural invasion depth was 84%. The mesorectal fascia could be visualized in 98% of patients. Twenty-three patients had mesorectal fascia involvement and the overall accuracy rate was 96% (sensitivity, 96%; specificity, 96%). Fifty-three patients had mesorectal lymph node metastasis and the overall accuracy rate was 74% (sensitivity, 83%; specificity, 64%). Lateral pelvic lymph node metastasis was observed in 15 patients and the overall accuracy rate was 87% (sensitivity, 87%; specificity, 87%). CONCLUSIONS: HRMRI was moderately accurate for prediction of mesorectal lymph node metastasis and highly accurate regarding transmural invasion depth, and mesorectal fascia and lateral pelvic node involvement. Therefore, HRMRI appears useful for preoperative decision-making in rectal cancer treatment.

Computer-aided detection in computed tomography colonography: current status and problems with detection of early colorectal cancer.

PURPOSE: The aim of this study was to evaluate the usefulness of computer-aided detection (CAD) in diagnosing early colorectal cancer using computed tomography colonography (CTC). MATERIALS AND METHODS: A total of 30 CTC data sets for 30 early colorectal cancers in 30 patients were retrospectively reviewed by three radiologists. After primary evaluation, a second reading was performed using CAD findings. The readers evaluated each colorectal segment for the presence or absence of colorectal cancer using five confidence rating levels. To compare the assessment results, the sensitivity and specificity with and without CAD were calculated on the basis of the confidence rating, and differences in these variables were analyzed by receiver operating characteristic (ROC) analysis. RESULTS: The average sensitivities for the detection without and with CAD for the three readers were 81.6% and 75.6%, respectively. Among the three readers, only one reader improved sensitivity with CAD compared to that without. CAD decreased specificity in all three readers. CAD detected 100% of protruding lesions but only 69.2% of flat lesions. On ROC analysis, the diagnostic performance of all three readers was decreased by use of CAD. CONCLUSION: Currently available CAD with CTC does not improve diagnostic performance for detecting early colorectal cancer. An improved CAD algorithm is required for detecting flat lesions and reducing the false-positive rate.

CT colonography: computer-aided detection of morphologically flat T1 colonic carcinoma.

The purpose was to evaluate the ability of computer-aided detection (CAD) software to detect morphologically flat early colonic carcinoma using CT colonography (CTC). Twenty-four stage T1 colonic carcinomas endoscopically classified as flat (width over twice height) were accrued from patients undergoing staging CTC. Tumor location was annotated by three experienced radiologists in consensus aided by the endosocpic report. CAD software was then applied at three settings of sphericity (0, 0.75, and 1). Computer prompts were categorized as either true positive (overlapping tumour boundary) or false positive. True positives were subclassified as focal or non focal. The 24 cancers were endoscopically classified as type IIa (n=11) and type IIa+IIc (n=13). Mean size (range) was 27 mm (7-70 mm). CAD detected 20 (83.3%), 17 (70.8%), and 13 (54.1%) of the 24 cancers at filter settings of 0, 0.75, and 1, respectively with 3, 4, and 8 missed cancers of type IIa, respectively. The mean total number of false-positive CAD marks per patient at each filter setting was 36.5, 21.1, and 9.5, respectively, excluding polyps. At all settings, >96.1% of CAD true positives were classified as focal. CAD may be effective for the detection of morphologically flat cancer, although minimally raised laterally spreading tumors remain problematic.

CT colonography - towards applications for colorectal cancer screening.

Three-dimensional (3D) imaging of the large intestine is globally called computed tomography colonography (CTC). CTC has been intensively investigated for application in colorectal cancer screening in Western countries and with the advent of multi-slice CT (MSCT), which provides effective high resolution in 3D CT images, the diagnostic use of CT for colorectal lesions has become a concept widely accepted throughout the world. Computer-aided detection (CAD) for colorectal polyps using digital CT image data and digital pre-processing are also advancing in the West. Compared with colonoscopy, which depends largely on the skill of the performer, CTC produces objective and reproducible diagnostic images and presents a high probability of standardizing examination protocols. Development of effective systems for screening colorectal lesions is expected, leveraging the excellent processing capability of MSCT to enhance 3D visualization and allow efficient detection.

Technical aspects of X-ray micro-computed tomography: initial experience of 27-microm resolution using Feldkamp cone-beam reconstruction.

The objective of this study was to introduce the technical utility of micro-computed tomography (CT) with 27-mum resolution by cone-beam CT algorithm. Whole-body micro-CT scans were performed to honeybee. Two- and three-dimensional image analyses were performed by originally developed and available open-source software for acquired images. The original contribution of this work is to describe the technical characteristics of the X-ray micro-CT system, keeping a small experimental insect in a unique condition. Micro-CT may be used as a rapid prototyping tool to research and understand the high-resolution system with Feldkamp cone-beam reconstruction.