Tumor Volume Doubling Time Research Articles

A Simulation Model Investigating the Impact of Tumor Volume Doubling Time and Mammographic Tumor Detectability on Screening Outcomes in Women Aged 40–49 Years

Compared with women aged 50-69 years, the lower sensitivity of mammographic screening in women aged 40-49 years is largely attributed to the lower mammographic tumor detectability and faster tumor growth in the younger women. We used a Monte Carlo simulation model of breast cancer screening by age to estimate the median tumor size detectable on a mammogram and the mean tumor volume doubling time. The estimates were calculated by calibrating the predicted breast cancer incidence rates to the actual rates from the Surveillance, Epidemiology, and End Results (SEER) database and the predicted distributions of screen-detected tumor sizes to the actual distributions obtained from the Breast Cancer Surveillance Consortium (BCSC). The calibrated parameters were used to estimate the relative impact of lower mammographic tumor detectability vs faster tumor volume doubling time on the poorer screening outcomes in younger women compared with older women. Mammography screening outcomes included sensitivity, mean tumor size at detection, lifetime gained, and breast cancer mortality. In addition, the relationship between screening sensitivity and breast cancer mortality was investigated as a function of tumor volume doubling time, mammographic tumor detectability, and screening interval. Lowered mammographic tumor detectability accounted for 79% and faster tumor volume doubling time accounted for 21% of the poorer sensitivity of mammography screening in younger women compared with older women. The relative contributions were similar when the impact of screening was evaluated in terms of mean tumor size at detection, lifetime gained, and breast cancer mortality. Screening sensitivity and breast cancer mortality reduction attributable to screening were almost linearly related when comparing annual or biennial screening with no screening. However, when comparing annual with biennial screening, the greatest reduction in breast cancer mortality attributable to screening did not correspond to the greatest gain in screening sensitivity and was more strongly affected by the mammographic tumor detectability than tumor volume doubling time. The age-specific differences in mammographic tumor detection contribute more than age-specific differences in tumor growth rates to the lowered performance of mammography screening in younger women.

Pulmonary Nodules: Preliminary Experience with Semiautomated Volumetric Evaluation by CT Stratum

To evaluate the performance of custom-made software designed to quantify volume and weight of focal portions of lung tumors in regions of interest (ROI) and volume of interest on thin-section computed tomography (CT) images by stratum of CT values. Volume and weight of lung portions were measured three-dimensionally and semiautomatically by CT stratum and compared with standard manual measurements. One each of a partly solid tumor (including initial and follow-up high-resolution CT scans), partly solid tumor with most parts showing solid density, and nonsolid tumors in the mid-zone of the lung were analyzed. The doubling time (DT) of tumor volume and mass were calculated by stratum of CT values. The software-measured tumor weight in lung periphery was reproducible, with and without trimming of intervening lung structures between borders of ROIs and tumor. For the lesion in the midlung zone, the fairly thick nearby pulmonary vessels degraded the measurements, with a higher measurement error, indicating the need to trim these structures off the ROI. Software measurements allowed quantification of tumor progress based on increase in tumor mass, without significant increase in tumor volume. The DTs for both tumor volume and mass were different among the four strata of CT values in the partly solid nodule. Our semiautomated volumetric method involving measurement by CT stratum is promising for evaluation of lung tumor progress and aggressiveness.

S1281 Evaluation of the Effects of Molecular Target Agents by Tumor Marker Doubling Time

BACKGROUND/AIMS For the evaluation of response to cytostatic agents, determination of changes in tumor growth speed seems to be essential. RECIST, which lacks the dimension of time, may not be particularly suitable for these agents. The aim of this study is to elucidate the usefulness of tumor marker doubling time (DT) in the evaluation of response to a molecular target agent. PATIENTS AND METHODS A total of 25 patients with advanced HCC participated in the phase I/II clinical trial of TSU-68, a novel tyrosine kinase inhibitor of VEGF. We enrolled 15 patients whose alpha-fetoprotein (AFP) or des-gamma-carboxyprothrombin (DCP) showed exponential increase during wash-out phase before TSU administration. We analyzed the relationship between tumor marker DT and tumor volume DT measured on two CT examinations before the commencement of TSU-68 administration. Next, tumormarker DT in the first 8 weeks of TSU-68 administration was similarly calculated, and compared with DT before TSU-68 administration. DT should be elongated, or turn negative, if TSU-68 was effective. The evaluation based on tumor marker DT was compared with RECIST. Lastly, tumor marker DT after the cessation of TSU-68 was calculated and compared with DT in 4 weeks immediately before the cessation. RESULTS DT of tumor marker level and that of tumor volume before TSU-68 administration were almost identical (R2=0.94, P<0.001). The evaluation based on tumor marker DT comparison between before and during TSU-68 administration and that based on RECIST were compatible in most cases (12/15); discordance was observed in 3 cases judged as disease progression by RECIST due to substantial tumor necrosis without volume shrinkage or appearance of new lesions in spite of apparent effects on target lesions. In these cases DT elongation was observed, which suggested cytostatic effect of TSU-68. Tumor marker DT after the cessation of TSU86 administration was evaluated in 4 cases, where DT was shortened after the cessation. CONCLUSION Serum tumor marker levels can be used to evaluate viable tumor burden irrespective of the presence of tumor necrosis, which may compromise radiographic evaluation. This may be applicable to the evaluation of response to chemotherapy with cytostatic agents in particular.

S1282 Rate of Stage Transition From Early to Advanced Hepatocellular Carcinoma

BACKGROUND/AIMS For the evaluation of response to cytostatic agents, determination of changes in tumor growth speed seems to be essential. RECIST, which lacks the dimension of time, may not be particularly suitable for these agents. The aim of this study is to elucidate the usefulness of tumor marker doubling time (DT) in the evaluation of response to a molecular target agent. PATIENTS AND METHODS A total of 25 patients with advanced HCC participated in the phase I/II clinical trial of TSU-68, a novel tyrosine kinase inhibitor of VEGF. We enrolled 15 patients whose alpha-fetoprotein (AFP) or des-gamma-carboxyprothrombin (DCP) showed exponential increase during wash-out phase before TSU administration. We analyzed the relationship between tumor marker DT and tumor volume DT measured on two CT examinations before the commencement of TSU-68 administration. Next, tumormarker DT in the first 8 weeks of TSU-68 administration was similarly calculated, and compared with DT before TSU-68 administration. DT should be elongated, or turn negative, if TSU-68 was effective. The evaluation based on tumor marker DT was compared with RECIST. Lastly, tumor marker DT after the cessation of TSU-68 was calculated and compared with DT in 4 weeks immediately before the cessation. RESULTS DT of tumor marker level and that of tumor volume before TSU-68 administration were almost identical (R2=0.94, P<0.001). The evaluation based on tumor marker DT comparison between before and during TSU-68 administration and that based on RECIST were compatible in most cases (12/15); discordance was observed in 3 cases judged as disease progression by RECIST due to substantial tumor necrosis without volume shrinkage or appearance of new lesions in spite of apparent effects on target lesions. In these cases DT elongation was observed, which suggested cytostatic effect of TSU-68. Tumor marker DT after the cessation of TSU86 administration was evaluated in 4 cases, where DT was shortened after the cessation. CONCLUSION Serum tumor marker levels can be used to evaluate viable tumor burden irrespective of the presence of tumor necrosis, which may compromise radiographic evaluation. This may be applicable to the evaluation of response to chemotherapy with cytostatic agents in particular.

Abstract 1554: Corticorelin acetate, a synthetic corticotropin releasing factor, demonstrates antiangiogenic and antitumor activity alone and enhances bevacizumab activity in human tumor models

Abstract Corticorelin acetate (CrA) is a synthetic form of corticotropin-releasing factor undergoing clinical trials in the treatment of peritumoral brain edema (PBE). A corneal micropocket angiogenesis assay (CMA) was performed to assess the activity of CrA relative to bevacizumab (BEV). We also investigated the in vivo anti-tumor efficacy of CrA as a single agent and in combination with BEV, in two preclinical human tumor models, the MX-1 breast and Colo-205 colon carcinomas. These models were selected based on their sensitivity to BEV. In the CMA, six groups of female mice were implanted with pellets containing VEGF or no VEGF, and treated for 7 days. The vehicle control group received phosphate buffered saline, sc, bid. The positive reference group received BEV, ip, qd, at 5 mg/kg/inj. The two remaining groups received CrA sc, bid, at 0.1 mg/kg/inj or 0.2 mg/kg/inj. Treatment outcome was determined from semi-quantitative characterization of neovascularization. CrA produced a substantial (&amp;gt;70%) inhibition of neovascularization (p&amp;lt;0.01) in the CMA. In the xenograft studies, mice were implanted sc in the flank with approximately 1 mm3 tumor fragments obtained from donor passage mice (MX-1), or with 1 × 106 tissue culture-derived Colo-205 cells implanted in 50% matrigel. When tumors were generally between 80-240 mg (mm3), mice were distributed to control and treatment sets. CrA was administered at two dose levels, 0.1 and 0.2 mg/kg/injection, sc, twice daily (bid). BEV was administered at a dose of 5 mg/kg/inj, ip, twice weekly. All treatments were continued until each group achieved its tumor target size, 1 gm in the Colo-205 experiment, and 1.5 gm in the MX-1 experiment. A log cell kill (LCK) of ≥1.0, equivalent to a delay in tumor growth of ≥ 3.32 x tumor volume doubling time, accompanied by statistical significance (p&amp;lt;0.05) was considered indicative of activity. CrA was active as a single agent in the MX-1 breast carcinoma (1.0 LCK; p&amp;lt;0.02), but inactive in the Colo-205 colon carcinoma. BEV was active (1.1 LCK; p&amp;lt;0.002) or near active (0.9 LCK; p&amp;lt;0.001) in both the MX-1 and Colo-205 models, respectively. When BEV was administered concomitantly with CrA, therapeutic outcomes were observed that were significantly better (3.3 LCK in MX-1, p&amp;lt;0.03; 1.9 LCK in Colo-205, p&amp;lt;0.01) than those obtained using either monotherapy. These therapeutic potentiations using CrA plus BEV were obtained in the absence of any observable increase in toxicities. Conclusion: CrA has demonstrated anti-angiogenic activity in vivo, which may be one possible mechanism to explain its observed preclinical antitumor activity. Importantly it enhances the antitumour activity of BEV in both MX-1 and Colo-205 models. Given the good safety profile of CrA and its lack of hypertensive side effects in clinical trials, CrA should be evaluated clinically in combination with BEV. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1554.

Abstract 5524: Radiosensitization of nanoparticle-based thermal delivery in mice bearing human prostate cancer

Abstract Heat is a potent sensitizer for radiation therapy. Technical hurdles associated with the selective and tumor-specific delivery of cytotoxic heat have precluded the widespread clinical adoption of heat as a therapeutic agent. Iron oxide magnetic nanoparticles have recently emerged as a promising alternative. Male nude mice bearing PC3 tumors, a human prostate cancer cell line, were used for the study. A total of fifteen cohorts of mice, with ten mice per group, were used. Five groups received nanoparticle thermal therapy (no radiation) at varying thermal doses; four groups received the combination of heat with 5 Gy radiation within five minutes post thermal therapy; three groups received radiation only (5, 8, and 10 Gy); and, three groups served as controls (no treat, magnetic field only, and particles with 5 Gy but no magnetic field). Magnetic nanoparticles suspensions were injected directly into the tumors at doses 5, 2.5, and 1 mg Fe/g tumor. Two to four hours post-injection, the mice were anesthetized and placed in a helical solenoid alternating magnetic field coil. Particle heating was initiated by an AC field with frequency of 160 kHz and varying amplitudes of 600, 500, and 400 Oersteds for twenty minutes. The particle heat output varies with field amplitude. Cohorts of mice receiving combined radiation and heat therapy were given 5 Gy radiation within five minutes of thermal therapy. Tumor growth was monitored and growth delay and survival was measured. Intratumor and rectal temperatures were monitored in five mice of each heat therapy cohort with optical fiber-based temperature probes. Complete tumor regression was observed for the 600 Oe and 5 mg Fe/g tumor combination, with local morbidity. Radiosensitization was achieved with lower thermal doses (400 Oe and 500 Oe with 5 mg Fe/g tumor) and no morbidity. For these cohorts, the heat alone was not effective. Tumor volume doubling time for 400 Oe and 5 mg Fe was 7 days (5 days for no treat control), and 10 days for 500 Oe and 5 mg Fe. However, the combination of 5 Gy (doubling time 22 days) with heat, even with the low thermal dose, produced significant tumor responses. For the combination of 400 Oe and 5 mg Fe with 5 Gy, tumor doubling time was increased to 32 days, and for the combination of 500 Oe with 5 mg Fe and 5 Gy, tumor volume failed to achieve doubling 45 days post therapy. Further study and analysis is ongoing and the results of their conclusions will be presented. Magnetic nanoparticle-based heat delivery has the potential to sensitize tumors to radiation even with low thermal doses. This offers the potential to improve therapeutic response while simultaneously minimizing therapy-related morbidity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5524.

MIB-1 labeling index correlated with magnetic resonance imaging detected tumor volume doubling time in pituitary adenoma

The purpose of this study was to evaluate whether MIB-1 labeling index (LI) could be used to predict growth velocity of residual pituitary adenomas after surgery. One hundred and sixty pituitary adenomas which had not received other treatment modality except for surgery were collected. Each of them had at least two post-operative magnetic resonance imaging (MRI) studies with an interval of at least 1 month apart. Tumor volume doubling time (TVDT) was calculated for those in which volume increased. Post-operative tumor progression was noted in 54 (33.8%) cases, of which 39 (72.2%) cases were non-functioning adenomas. The MIB-1 LIs of the functioning and non-functioning adenomas were not significantly different. The median TVDT of these 54 cases was 34.6 months. The mean and median MIB-1 LI were 2.7 and 1.1 respectively (range 0.4-20.6). The MIB-1 LI was significantly correlated with log(2)(TVDT) (r=-0.363, P=0.007); when LI was <0.8, the TVDT of 90.5% cases was >or= 2 years. Only one-third of the pituitary adenomas progressed after surgery, and their MIB-1 LIs were generally low. The MIB-1 LI was significantly correlated with the MRI detected TVDT of post-operative residual pituitary adenomas.

Natural history study of postoperative residual non-functioning pituitary adenomas

To observe the postoperative residual non-functioning pituitary adenomas (PR-NFPAs) without postoperative radiotherapy and to analyze the natural history of PR-NFPAs' growth in order to provide a basis for selecting appropriate strategies of clinical treatment. We evaluated the natural history of 20 patients with PR-NFPAs who did not receive postoperative radiotherapy and drug therapy. Through MRI images, the residual tumor volumes of those patients were serially measured. We further calculated the monthly growth rate and the tumor volume doubling time (TVDT) and analyzed the correlations between the patient age, gender, volume of residual tumor, cavernous sinus (CS) invasion and TVDT. All patients received observation alone. Among which, 17 adenomas increased in volume and 3 remained unchanged during a follow-up period of 7 months to 17 years (mean 3.90 yr). The mean patient age was 41.8 years. As to 17 patients with tumor regrowth, the tumor volume at the beginning of MRI observation period was 4.73 cm(3) and tumor volume at the last MRI observation was 16.98 cm(3). During the mean 4-year follow-up period, the average monthly growth rate of PR-NFPAs was 7.87% and the mean TVDT was 724 days. Such factors as patient age, gender, volume of residual tumor and CS invasion did not affect the TVDT of PR-NFPAs. The tumor growth rate of PR-NFPAs is not significantly correlated with the patient gender, age, volume of residual tumor and CS invasion. In conjunctions with the volume of PR-NFPAs and the distance between residual adenoma and optic chiasm, we should take the TVDT into consideration and determine the appropriate and safe follow-up period.

Structure-activity relationships of mono-substituted trisulfonated porphyrazines for the photodynamic therapy (PDT) of cancer

The impact of lipophilicity on biological parameters critical to photodynamic efficacy was analyzed for a new generation of trisulfobenzo(mononaphtho)porphyrazines. The porphyrazines were substituted on the naphtho ring with linear alkynyl side chains of various lengths. When compared to the analogous phthalocyanine structures, the added benzo ring in the porphyrazine structures increased the lipophilicity for analogs with short alkynyl chains, while this effect disappeared for analogs with longer side chains. In aqueous media, the analogous phthalocyanine series showed aggregation tendencies. In contrast, no correlation between aggregate formation and the length of the alkynyl side chain was evident in the porphyrazine series. At low concentrations, the length of the side chain did not affect cell uptake, while phototoxicity towards EMT-6 mouse tumour cells showed a parabolic relationship, where the hexynyl derivative showed the highest activity. The trisulfonated porphyrazines localized at intracellular organelles, plasma and perinuclear membranes, but could not be found in the nucleus. Total cell uptake of dye did not correlate with phototoxicity, suggesting that localization in certain intracellular organelles, and distribution into critical intracellular sites are important determinants of their photodynamic activity. The hexynyl trisulfonated zinc porphyrazine derivative (ZnNPcS(3)C(6)) showed the strongest in vitro photodynamic activity and therefore was further studied in an EMT-6 mouse tumour model. An i.v. dose of 1 micromol of ZnNPS(3)C(6) per kg, followed 24 h later by activation with light, induced 100% tumour necrosis within 24 h post-PDT. This treatment delayed tumour volume doubling time from 5 days to >2 weeks, and gave 41% tumour cure >3 weeks post-PDT. Applying the same light dose fractionated (5 min on, 2 min off), further improved tumour response, leading to a doubling time of 26 days and a 73% tumour cure. At the administered 1 micromol kg(-1) dye dose, no skin phototoxicity was observed and >90% blood clearance was observed within 5 h post-injection. Compared to the analogous trisulfo monohexynyl zinc phthalocyanine, the new trisulfobenzo(mononaphthohexynyl)porphyrazine provided a broader range of excitation wavelengths, and improved photodynamic potency, while apparently being free of unwanted systemic side effects.

HRCT Features of Small Peripheral Lung Carcinomas Detected in a Low-dose CT Screening Program

To define high-resolution computed tomography (HRCT) features of lung cancers detected by computed tomography (CT) screening according to histopathology and prognosis. Tumor size, CT value, morphology, and tumor volume doubling time (TVDT) were determined for 10 atypical adenomatous hyperplasias (AAH) and 50 lung cancers followed between 1996 and 1998 to 2007. For the 10 AAHs, the density less than -500 HU in all lesions (mean, -654 HU) and the size was up to 14 mm (mean, 9 mm); all patients remain alive. Focal bronchioloalveolar cell carcinomas (BAC) were denser (mean, -537 HU) than AAH and mostly less dense than -350 HU; all patients remain alive. All 22 adenocarcinomas (ADC) were denser than -450 HU (mean, -186 HU); 6 were problematic and measured >-150HU and >10 mm or had >10 mm of central denser zone (CDZ) (partly solid tumors) or tumor size (solid tumor). Two of four squamous cell carcinomas (SCC) measuring 15 and 10 mm, respectively, were problematic. Two patients with small-cell lung carcinomas (SCLC) measuring 15 and 23 mm, respectively, remain alive. AAH, BAC, ADC, and SCC lesions were in general polygonal in shape. SCLC lesions appeared as round nodules with excrescence. The mean TVDT for AAH, BAC, ADC, SCC, and SCLC was 1278, 557, 466, 212, and 103 days, respectively. The CT features reflected tumor aggressiveness. Non-SCLC lesions of >-150HU and >10 mm (or >-100HU and >10 mm for the solid portion of the tumor) are associated with unfavorable prognosis. Timely interventions should be undertaken before problematic increase in number of cases.

Ultrasound surveillance for early detection of hepatocellular carcinoma among patients with chronic hepatitis C

Ultrasonography is the most frequently used modality in surveillance for HCC among patients with chronic hepatitis C. However, the optimal surveillance interval is still controversial and the usefulness of supplementary tumor marker determination has not been confirmed. A total of 243 cases of naive HCC were detected among 1,431 patients with chronic hepatitis C under outpatient-based surveillance. The mode of HCC detection, including ultrasound surveillance interval, was retrospectively examined and the relation between the interval and detected tumor size was analyzed. Tumor volume doubling time was estimated from exponential increase in serum tumor marker levels when applicable. HCC was first detected by ultrasonography in 221 patients. Ultrasound surveillance interval, ranging between 2 and 8 months, was not correlated with the size of tumor at detection. Patients with cirrhosis were likely to be surveyed at shorter intervals. The size of tumor exceeded 30 mm only in three (1.4%) cases. They were all positive for a biomarker and the estimated tumor doubling time was short. In 14 cases, HCC was first detected by CT indicated by abnormal rise in tumor marker levels despite negative ultrasound findings. In the remaining eight cases, ultrasonography had been replaced by CT as surveillance modality because of excessive obesity or coarseness of liver parenchyma. Ultrasound surveillance at 6-month intervals was appropriate in general for the detection of HCC at a size smaller than 30 mm. However, in patient with established cirrhosis, more frequent screening would be needed to detect tumors of the same size.

Establishment of patient-derived xenotransplantation models for non-small cell lung cancer in immune deficient mice

Targeted therapies have become a valuable therapeutic option for cancer. Establishment of different animal tumor models has become necessary. This study was to establish xenotransplantation models for patient-derived non-small cell lung cancer (NSCLC) in immune deficient mice. Immune deficient mice, BALB/C-nu, NOD/scid and SCID, 16 in each strain, were used. Sixteen tumor specimens were obtained from patients with NSCLC. Each specimen was subcutaneously transplanted into one mouse from each of the three strains. The tumor formation rate, time to tumor engraftment, tumor volume doubling time were recorded and compared among the three strains of mice. Histology of xenograft tumors was examined. The total tumor formation rate was 75% (12/16). The tumor formation rate was the highest in SCID mice (56.25%). Only four tumors were engrafted in SCID mice, and two in BALB/C-nu mice. The tumor formation rate, time to tumor engraftment, and tumor volume doubling time were not significantly different among the three strains of mice. The incidence of tumor size over 1cm in the upper flanks of the mice (56.25%) was significantly higher than that in the lower flanks (25%) (P=0.037). Haematoxylin Eosin staining revealed a high degree of histological similarity between all xenograft and the parental tumors. We have established xenotransplantation models for patient-derived NSCLC with a success rate of 75% in BALB/C-nu and SCID mice. The xenograft tumors have the same histological features to those of their parental tumors.

W1969 Colorectal Cancer Despite Colonoscopy: Estimated Size of the Truly Missed Lesions

Background: Colorectal cancer (CC) discovered within 3 years after a normal or clearing colonoscopy (C) is considered to be the result of a missed polyp or cancer at the time of the preceding C. Multiple studies comparing sequential images of colon lesions over time have calculated lesion volume doubling rates varying from 4 months for very large lesions (~35 mm) to more than 2 years for medium size polyps (~10 mm). Aim: To estimate the size of CC considered missed (i.e., diagnosed within 3 years of a prior C) using the tumor size at the time of CC diagnosis.Methods: A large dataset was created containing (1) patients who had undergone C at Mayo Clinic Rochester (MCR) between 1992 and 2002 (138,318 Cs in 98,960 patients), and (2) patients who had a tissue diagnosis of CC between 1992 and 2004 (N=10,136). We defined a missed CC (CCdespiteC) as a CC occurring from 90 to 1095 days after C. The estimated size of the tumor at the time of the C preceding the date of CC diagnosis was estimated using the exponential growth function y=xeβt where t is the interval between date of the preceding C and the date of CC diagnosis; y and x are the tumor size (diameter of the greatest dimension) at the time of the CC diagnosis and the preceding C respectively. Despite the fact that most lesions missed during preceding C were expected to be medium sized, we elected an aggressive tumor volume doubling rate of 6 months (i.e., β=0.0013). Results: Among the 10,136 patients with either primary or metastatic colon cancer 2692 patients had undergone a total of 4743 colonoscopies at MCR. From this cohort, we identified 187 Cs in 145 patients who developed CCdespiteC. There was a subset in which the CC was truly missed: no lesion was seen or treated in the colonic segment during the preceding C: 120 Cs in 100 patients. Of these 120 truly missed tumors, we were able to retrieve the tumor size at the time of CC diagnosis of 96 tumors using the pathology and surgical reports. Out of 96 CCdespiteC tumors, 67 lesions have an estimated maximal diameter (obtained using the exponential growth model) of more than 10 mm at the time of preceding C. Nearly all lesions (94 out of 96) have an estimated maximal diameter of more than 5 mm at the time of the preceding C. Conclusions: Almost all CC diagnosed within 3 years after a negative or clearing colonoscopy have an estimated maximal tumor diameter greater than 5 mm using an exponential growth model and a very aggressive tumor volume doubling time. Our results strongly suggest that CCdespiteC is the result of a lesion truly being missed at the time of the preceding C and not the result of a de novo rapidly growing neoplasm.

Initial Findings and Progression of Lung Adenocarcinoma on Serial Computed Tomography Scans

To study the initial findings of lung adenocarcinoma revealed by computed tomography (CT) scanning and observe tumor progression and elucidate appropriate follow-up schedule of tumor diagnosis via CT findings of suspected lung adenocarcinoma. We studied 59 patients who had undergone CT scanning twice or more at intervals of 3 months or longer before surgery. We evaluated the initial CT findings as well as all subsequent changes. The rate of tumor growth was estimated by tumor volume doubling time, using the original method of Schwartz. The histological classifications were evaluated according to the criteria of Noguchi et al (Cancer 1995;75:2844-2852). The initial appearances of lung adenocarcinoma were divided into 4 types: (1) ground-glass opacity-like lesions, (2) bubble-like appearance, (3) small nodules, and (4) scar-like lesions. Ground-glass opacity-like lesions tended to increase in size over the years, with solid parts appearing in some lesions during follow-up examinations. Bubble-like appearance displayed characteristic CT findings and tended to increase over the years from the time of initial diagnosis, and we therefore tended to consider them as old inflammatory lesions. Small nodules tended to increase in size over the months more rapidly than in other types. Scar-like lesions tended to exist mainly in the lungs already damaged by lung fibrosis and/or emphysema and therefore were difficult to detect on initial CT scans. We categorized 4 types of initial findings of lung adenocarcinomas detected by CT. We determined that each type of lesion had its own unique characteristic growth patterns and required varying follow-up periods.

Intranodular Blood Supply Correlates Well with Biological Malignancy Grade Determined by Tumor Growth Rate in Pathologically Proven Hepatocellular Carcinoma

This study was carried out to investigate whether intranodular blood supply in histologically proven well-differentiated hepatocellular carcinomas (HCCs) correlates with tumor growth rates. A total of 52 well-differentiated HCCs were enrolled in this study. Ultrasound angiography with intra-arterial CO₂ microbubble injection was performed in all 52 HCCs and computed tomography during arterial portography was performed in 21 of the 52 HCCs. Tumor volume doubling time (TVDT) was measured in all 52 nodules by B-mode ultrasonography performed at 2- to 3-month intervals for a follow-up period of at least 6 months (range: 6 months to 8 years) with respect to arterial vascularity. In the hypervascular (n = 27), isovascular (n = 9), and hypovascular nodules (n = 16), the mean values of TVDT (mean ± SD) were 79 ± 131, 98 ± 227, and 782 ± 324 days, respectively (r_s = 0.722, p < 0.0001). Concerning portal blood supply, the mean TVDT in nodules in which the portal supply was reduced (n = 5) was 178 ± 78 days compared with 592 ± 211 days in nodules in which the portal supply was preserved (n = 11), with a significant difference (p < 0.01). Five nodules in which the portal supply was preserved did not enlarge during the follow-up period of 3–5 years. There was a significant correlation among the three groups (r_s = 0.804, p < 0.05). In conclusion, intranodular blood flow dynamics in patients with well-differentiated HCC reflect the biological malignancy or cancer progression in the process of multistep hepatocarcinogenesis, suggesting the importance of this parameter in deciding on a treatment strategy. In other words, nodules in which arterial vascularity is present and those in which the portal blood flow is reduced should be treated for reasons such as a short doubling time and the risk of rapid progression to artery-dominant classical HCC.

Recurrence of Retroperitoneal Liposarcoma: Imaging Findings and Growth Rates at Follow-Up CT

The purpose of this study was to evaluate the CT features and growth rates of recurrent retroperitoneal liposarcoma on follow-up CT scans. Retroperitoneal liposarcoma frequently recurs asymptomatically within 2 years, usually within 6 months-2 years, of the initial surgical resection. The CT features of recurrent liposarcoma are similar to those of the initial manifestation; recurrent liposarcoma shows rapid growth, with a mean tumor volume doubling time of 98 days (range, 46-151 days; median, 104 days).

Tumor growth inhibition of paclitaxel-octreotide conjugates on human non small cell lung cancer: experiment with mice

To evaluate the antitumor effects of the conjugates synthesized by coupling cytotoxic paclitaxel (PTX) to somatostatin analog octreotide (OCT) on human non small cell lung cancer (NSCLC). Two cytotoxic somatostatin analog, PTX-OCT and 2PTX-OCT, were developed in which PTX was linked to octreotide. Forty-five BALB/c nu/nu nude mice were injected with human NSCLC cells of the line A549 into the right armpit. The nude mice that were xenografted were randomly divided into 8 groups. (1) control group (n = 6), (2) PTX-OCT group (n = 5), injected intravenously with PTC-OCT 150 nmol/kg on days 1, 7, and 21, (3) 2PTX-OCT group (n = 6), injected intravenously with PTC-OCT 150 nmol/kg, (4) OP group (n = 6), injected with mixture of PTX and OCT 150 nmol/kg, (5) OCT group (n = 5) injected with OCT 150 nmol/kg (6) PTX group (n = 6), injected with PTX 150 nmol/kg, (7) 2PTX group, injected with PTX 300 nmol/kg, and (8) 2(PTX-OCT) injected with PTX-OCT 300 nmol/kg, The tumor volume and body weight (BW) were observed regularly. The tumor volume doubling time was calculated. White blood cells were counted by collecting peripheral blood sample. By the end of experiment the mice were killed with the tumors taken out. The expression of mRNA of subtypes1-5 of human somatostatin receptor (SSTR1-SSTR5) were investigated using RT-PCR. Histological apoptosis was detected by DNA ladder. Immunohistochemistry was used to examine the SSTR2 and SSTR5 expression and tumor microvessel density (MVD). The tumor volumes of 2PTX-OCT and 2(2PTX-OCT) groups were significantly smaller than those of other groups (all P < 0.01). The tumor doubling times of the 2PTX-OCT and 2 (2PTX-OCT) groups were significantly longer than those of the other groups too (all P < 0.01). The MVD levels of the 2PTX-OCT and 2 (2PTX-OCT) groups were significant lower than those of the other groups (all P < 0.01). The toxicity of the PTX group was more obvious. The WBC count levels of the PTX and 2PTX groups were significantly lower than those of the other groups (all P < 0.05). mRNA expression could be found for SSTR1, 2, 4, and 5 in the A549 xenografts. Immunohistochemistry showed that SSTR2 was mainly found in the tumor cell membrane, and SSTR5 was found in the tumor cell membrane and cytoplasm. More histological apoptosis bands were shown by DNA ladder method in the 2PTX-OCT and 2 (PTX-OCT) groups. The targeting conjugate 2PTX-OCT inhibits the proliferation of tumor cells, reduces microvessel, and decreases the toxicity in comparison with the cytotoxic radical PTX.

Growth Rate of New Hepatocellular Carcinoma After Percutaneous Radiofrequency Ablation: Evaluation with Multiphase CT

The purpose of this study was to evaluate with serial follow-up CT examinations the growth rate of new hepatocellular carcinoma (HCC) developing after percutaneous radiofrequency ablation and to determine an appropriate follow-up interval for imaging. Sixty-two new HCCs appearing after percutaneous radiofrequency ablation in 59 patients who underwent follow-up multiphase CT were retrospectively identified. The volume of the new HCCs at follow-up CT was measured on a PACS monitor with an area measuring tool and summation-of-areas technique. We calculated tumor volume doubling time and tumor diameter doubling time. The growth rate was represented by tumor volume doubling time. We also used stepwise multiple linear regression analysis to evaluate the relation between clinical variables and tumor volume doubling time. Mean baseline and follow-up tumor volumes were 580 mm(3) (range, 85-13,861 mm(3)) and 2,072 mm(3) (range, 535-35,937 mm(3)). Mean baseline and follow-up tumor diameters were 9.9 mm (range, 5.5-29.8 mm) and 15.0 mm (range, 10.1-40.9 mm). Mean tumor volume and tumor diameter doubling times were 75 days (range, 21-209 days) and 219 days (range, 57-897 days). Volume doubling times of baseline tumors with a diameter of 1 cm or less were significantly shorter than those of the larger baseline tumors (mean, 55 vs 88 days; p = 0.024). The growth rate of new HCCs after percutaneous radiofrequency ablation was higher than that reported in natural outcome studies of untreated HCCs. The results of our study suggest that a shorter follow-up interval for imaging, 2.5 months (75 days), is appropriate.

Turning Gray: The Natural History of Lung Cancer Over Time

As newer therapies for lung cancer are being explored it becomes more important to understand the natural history of lung cancer. A systematic review of the data shows that untreated lung cancer is almost uniformly rapidly fatal, even if it is stage I. Analysis of data regarding tumor volume doubling times shows that conventionally detected lung cancers have short mean doubling times, and only a small proportion with very long doubling times. Lung cancers found during the course of a CT screening program have markedly longer mean doubling times and a substantially greater proportion with very long doubling times (>400 days). Models of tumor growth, however, are not understood well enough to use the observed doubling time to predict length of survival without treatment.

Variation in Experts’ Beliefs about Lung Cancer Growth, Progression, and Prognosis

Little is known about the natural history of malignant solitary pulmonary nodules (SPN). Experts' beliefs may help fill these knowledge gaps and explain variation in clinical practices. Using a modified Delphi process, we surveyed a group of lung cancer experts about tumor growth, disease progression, and prognosis in patients with malignant SPN. After completing the first survey, experts were given the opportunity during a second survey to revise their responses in light of their peers' beliefs. The response rate was 100% (14 of 14) for both surveys. There was consensus that disease progression depends on the tumor growth rate, that survival for patients with untreated lung cancer is approximated by a declining exponential function, and that treatment is delayed by approximately 1 tumor volume doubling time (TVDT) in patients who undergo a period of "watchful waiting." Just over half of experts (8 of 14) agreed that lung cancer progresses in three steps (from local to regional to distant disease), whereas 43% (6 of 14) preferred a 2-step model (from local to systemic disease). Likewise, 64% of experts (9 of 14) believed that malignant nodules grow exponentially, whereas 36% (5 of 14) believed that growth is slower than exponential. Experts' estimates of the risk of disease progression during a period of observation lasting 1 TVDT varied from 1 to 50%. Estimates of 5-year survival for patients in whom diagnosis and treatment were delayed by 1 TVDT varied between 40% and 80%. There is substantial variability in experts' beliefs about the natural history of untreated, malignant SPN. Different beliefs may be partly responsible for variation in management practices.