Tumor Potential Doubling Time Research Articles

Personalized radiation therapy and biomarker-driven treatment strategies: a systematic review

Radiosensitivity varies to a great extent across tumor types and also between patients bearing the same type of tumor. Radiation oncology pioneered the field of biomarkers with attempts to correlate tumor response to clonogenic survival, tumor potential doubling time (Tpot), and PaO₂. Biomarkers predicting the clinical outcome after radiotherapy are already available, but their levels of evidence are heterogeneous. In light of these molecular factors, the issue of personalized radiation therapy in combination or as a standalone modality is addressed. Known molecular prognostic and predictive biomarkers and their present or potential respective therapeutic implications are described for six tumor types where radiotherapy is considered to be part of the mainstay: chemoradiation (e.g., gliomas, head and neck, cervical cancer), radiotherapy with or without androgen deprivation (e.g., prostate), neo-adjuvant chemoradiation (e.g., rectum), or adjuvant radiotherapy (e.g., breast).

SU-E-T-256: Radiation Dose Responses for Chemoradiation Therapy of Pancreatic Cancer: An Analysis of Compiled Clinical Data Using Biophysical Models.

We have analyzed recent clinical data obtained from chemoradiation of unresectable, locally advanced pancreatic cancer in order to examine possible benefits from radiotherapy (RT) dose escalation as well as to propose possible dose escalated fractionation schemes. A modified linear quadratic (LQ) model was used to fit clinical tumor response data from chemoradiation treatments using different fractionations. Biophysical radiosensitivy parameters, a and α/β, tumor potential doubling time, Td, and delay time for tumor doubling during treatment, Tk, were extracted from the fits and were used to calculate feasible fractionation schemes for dose escalations. Examination of published data from 20 institutions showed no clear indication of improved survival with raised radiation dose. However, an enhancement in tumor response was observed for higher irradiation doses, an important and promising clinical Result with respect to palliation and quality of life. The radiobiological parameter estimates obtained from the analysis are: α/β = 10 ± 3 Gy, a = 0.010 ± 0.003 Gŷ-1, Td = 56 ± 5 days and Tk = 7 ± 2 days. Possible dose escalation schemes are proposed based on the calculation of the biologically equivalent dose (BED) required for a 50% tumor response rate. From the point of view of tumor response, escalation of the administered radiation dose leads to a potential clinical benefit, which when combined with normal tissue complication analyses may Result in improved treatments for certain patients with advanced pancreatic cancer. Based on this analysis, a dose escalation trial with 2.25 Gy/fraction up to 69.75 Gy is being initiated for unresectable pancreatic cancer at our institution. Partially supported by MCW Cancer Center Meinerz Foundation.

The impact of prostate edema on cell survival and tumor control after permanent interstitial brachytherapy for early stage prostate cancers

Previous studies have shown that procedure-induced prostate edema during permanent interstitial brachytherapy (PIB) can cause significant variations in the dose delivered to the prostate gland. Because the clinical impact of edema-induced dose variations strongly depends on the magnitude of the edema, the temporal pattern of its resolution and its interplay with the decay of radioactivity and the underlying biological processes of tumor cells (such as tumor potential doubling time), we investigated the impact of edema-induced dose variations on the tumor cell survival and tumor control probability after PIB with the 131Cs, 125I and 103Pd sources used in current clinical practice. The exponential edema resolution model reported by Waterman et al (1998 Int. J. Radiat. Oncol. Biol. Phys. 41 1069–77) was used to characterize the edema evolutions previously observed during clinical PIB for prostate cancer. The concept of biologically effective dose, taking into account tumor cell proliferation and sublethal damage repair during dose delivery, was used to characterize the effects of prostate edema on cell survival and tumor control probability. Our calculation indicated that prostate edema, if not appropriately taken into account, can increase the cell survival and decrease the probability of local control of PIB. The magnitude of an edema-induced increase in cell survival increased with increasing edema severity, decreasing half-life of radioactive decay and decreasing photon energy emitted by the source. At the doses currently prescribed for PIB and for prostate cancer cells characterized by nominal radiobiology parameters recommended by AAPM TG-137, PIB using 125I sources was less affected by edema than PIB using 131Cs or 103Pd sources due to the long radioactive decay half-life of 125I. The effect of edema on PIB using 131Cs or 103Pd was similar. The effect of edema on 103Pd PIB was slightly greater, even though the decay half-life of 103Pd (17 days) is longer than that of 131Cs (9.7 days), because the advantage of the longer 103Pd decay half-life was negated by the lower effective energy of the photons it emits (∼21 keV compared to ∼30.4 keV for 131Cs). In addition, the impact of edema could be reduced or enhanced by differences in the tumor characteristics (e.g. potential tumor doubling time or the α/β ratio), and the effect of these factors varied for the different radioactive sources. There is a clear need to consider the effects of prostate edema during the planning and evaluation of permanent interstitial brachytherapy treatments for prostate cancer.

TH-E-M100E-07: The Impact of Procedure-Induced Edema On Cell Survival and Tumor Control Probability in Permanent Prostate Brachytherapy Using 131Cs Radioactive Source

Purpose: Procedure‐induced prostate edema can cause significant changes to the dose delivered by a permanent prostate brachytherapy. The aim of this work was to examine systematically the impact of procedure‐induced edema on the effectiveness of cell kill in permanent prostate brachytherapy using 131 Cs radioactive sources.Method and Materials: The concept of biologically effective dose (BED) was used to quantify the impact of prostate edema on the radiation‐induced cell kill in 131 Cs permanent prostate brachytherapy. The repopulation of surviving cells and the repair of sub‐lethally damaged cells during the protracted dose delivery was modeled by the cell potential doubling time and a repair half‐time, respectively. The procedure‐induced prostate edema and its resolution dynamics was described by a quantitative model reported by Waterman et. el. (Int. J. Radiat. Oncol. Biol. Phys. 41, 1069–1077, 1998). The surviving fraction of cancer cells and the potential tumor control probability was examined over a range of edema magnitudes and resolution half‐lives observed in real patients. Results: When edema was neglected in pre‐implant treatment planning, the BED of an actual implant was found to depend strongly on the edema magnitude, its resolution half‐life, and tumor potential doubling time. For a typical edema with magnitude of 50% and half‐life of 10 days, the edema‐induced reduction in BED was greater than 15% resulting in an increase of cell‐survival by more than one order of magnitude. For larger edemas with magnitude of 90% and half‐life of 20 days, the edema‐induced increase in cell survival was more than two orders of magnitude. Conclusions: Procedure‐induced edema can cause significant reduction in BED and increase in cell survival in 131 Cs permanent prostate brachytherapy. Depending on the initial tumor burden, the increase in cell survival could lead to significant reduction in tumor control probability for patients having moderate and large edemas.

Growth Fraction of Human Tumors: Assays and Complications.

T he fraction of cells actively proliferating in human tumors is expected to be useful in predicting tumor response to therapy. 1,2 There are several excellent reviews 3-5 and a comprehensive monograph 6 describing both static and flow cytometry assays developed to measure growth fraction. This article introduces a new method, and in describing our results using clinical samples, provides a basis for understanding why this information is useful or necessary and identifies factors that may limit our ability to define growth fraction accurately for different tumor types. The doubling time of a tumor has long been known to be a valuable prognostic indicator. As an obvious generalization, patient survival is shorter when the tumor grows more rapidly, although tumor size and doubling time can vary independently] The recent application of accelerated radiotherapy to overcome rapid tumor cell repopulation a is in large part responsible for the current interest in categorizing tumors into slowly and rapidly proliferating. 9 There are three major kinetic factors contributing to tumor doubling time: growth fraction (GF), cell cycle time, and cell loss rate. l~ Although no method is able to accurately determine cell loss rate in human tumors, the two remaining factors are used to describe potential tumor doubling time (Tpot), which is proportional to the S phase duration (T~) divided by the labeling index (LI), or alternatively, the cell cycle duration divided by the GF. II It has been argued that Tpo t is more informative than GF alone in predicting tumor response to accelerated radiotherapy because Tpo~ includes a measure of rate of cell proliferation (Ts) as well as state of proliferation (LI). However, when analyzing the components that determine Tpo, it is common for tumors of the same tissue of origin

Outcome and human epidermal growth factor receptor (HER) 1-4 status in invasive breast carcinomas with proliferation indices evaluated by bromodeoxyuridine labelling.

BackgroundWe have shown previously that whereas overexpression of human epidermal growth factor receptor (HER)1, HER2 and HER3 is associated with poor prognosis in breast cancer, HER4 is associated with a good prognosis. Cell proliferation is a key component of aggressive cancers and is driven by growth factors. In this study, bromodeoxyuridine (BrdU)-derived proliferation indices are correlated with clinical outcome and HER1–4 status for further clarification of the differing roles for the HER family at a biological level.MethodsSeventy-eight invasive breast cancers had BrdU labelling in vivo to determine the BrdU labelling index (BLI) and the potential tumour doubling time (Tpot). Long-term clinical follow-up was available for these patients. We used immunohistochemistry to establish the HER1–4 status in 55 patients from the BrdU cohort.ResultsWe demonstrate a significant correlation between high BLI values and breast cancer-specific death (P = 0.0174). Low Tpot times were also significantly correlated with breast cancer-specific death (P = 0.0258). However, BLI did not independently predict survival in Cox's multiple regression analysis when combined with other prognostic factors such as size, grade and nodal status. Tumours found to be positive for HER1, HER2 or HER3 had significantly (P = 0.041) higher labelling indices, with HER1 also showing significantly higher indices when considered independently (P = 0.024). Conversely, HER4 positivity was significantly correlated (P = 0.013) with low BLI values, in line with previous data associating this receptor with good prognosis tumours.ConclusionsThese results support the hypothesis that HER1–3 are associated with driving tumour proliferation, whereas HER4 is involved in a non-proliferative or even protective role.

790 Poster Correlation between tumor potential doubling time (Tpot), ploidy and p53 status: prognostic factors in head and neck tumors

790 Poster Correlation between tumor potential doubling time (Tpot), ploidy and p53 status: prognostic factors in head and neck tumors

Biologically effective dose for permanent prostate brachytherapy taking into account postimplant edema

Purpose: To study the influence of radiobiologic and physical parameters and parameters related to edema on the biologically effective dose (BED) for permanent prostate implants and to determine the optimal timing of seed reconstruction for BED calculation.Methods and Materials: On the basis of the linear-quadratic model, an expression for the BED was derived, including the edema parameters. A set of parameter values was defined, and these parameter values were varied one at a time to examine the effect on the BED and the theoretically effective treatment time (teff). A ratio ϵ was defined to investigate the optimal timing of seed reconstruction.Results: The maximal BED decreases when the extent of lethal damage is smaller, the potential tumor doubling time is smaller, the half-life time of the seeds is shorter, and the magnitude of prostate volume increase is larger. For 125I, the optimal timing of seed reconstruction is 25 days after implantation. Seed reconstruction 1 day after the implantation results in an underestimation of the BED of at most 43%, depending on the magnitude and half-life of edema. An overestimation of the BED of at most 22% is calculated when seed reconstruction took place at the effective treatment time.Conclusion: The maximal BED depends strongly on the value of α, the potential tumor doubling time, and the choice of isotope. If prostate volume increase due to edema is not taken into account, the BED will be underestimated shortly after the implantation and overestimated if the calculations are based on images taken several months after implantation. The optimal timing of BED evaluation for 125I seed implants and typical prostate edema values is 25 days after implantation.

Proliferation kinetics and prognosis in gastric cancer after resection

The influence of proliferation and proliferation kinetics on prognosis in gastric cancer after complete resection are controversial. In a prospective study we investigated the tumour specimens of 111 patients after resection of gastric cancer, who received 200 mg intravenous (i.v.) bromodeoxyuridine (BrdU) pre-operatively. The following biological parameters were analysed in the tumour tissue using flow-cytometry: DNA ploidy, proportion of S-phase cells, BrdU labelling index (LI), DNA synthesis time (Ts), potential tumour doubling time (Tpot), proliferating cell nuclear antigen (PCNA) and Ki-67 LI. The median follow-up time was 40 months (range 19–62 months). Besides the established pathohistological prognostic factors, univariate analysis revealed a prognostic influence on survival for BrdU LI, Tpot and the proportion of S-phase cells. By multivariate Cox analysis of the completely resected cases, only tumour stage and Tpot had a significant, independent influence on survival. By classification and regression trees (CART) analysis, resection status, tumour stage and Tpot defined risk groups with significantly different outcomes. A short Tpot was a predictor of better survival in stage I, II and IIIA tumours. Ploidy and the other investigated proliferation-related parameters failed to demonstrate any influence on prognosis after resection of gastric cancer.

Interaction between potential doubling time and TP53 mutation: predicting radiotherapy outcome in squamous cell carcinoma of the head and neck

Purpose: To investigate the correlation between tumor potential doubling time, Tpot, and mutations in the p53 gene, TP53, and the potential of these parameters to predict outcome of head and neck cancer patients treated with radiotherapy. Methods and Materials: Data from two independent studies on Tpot and TP53 mutations were combined, including 58 patients with squamous cell carcinoma of the head and neck. Tpot was estimated on biopsies obtained 6–9 h after infusion of iododeoxyuridine by combined flow cytometry and immunohistology. TP53 mutations were detected using DGGE and sequenced. All patients received primary radiotherapy alone. Results: The predictive value of Tpot alone was of borderline significance. However, in TP53 wild-type tumors, Tpot was a strong predictor of outcome, whereas Tpot in TP53 mutant tumors failed to provide any information. Tpot and TP53 were not associated with nodal control; however, there was a strong relationship with control in the T-position, disease-specific survival, and overall survival. Conclusion: Tpot can to be a relevant parameter for predicting outcome of radiotherapy in head and neck cancer but only in the subset of patients without mutations in the p53 gene.

Effect of radiation therapy on the potential doubling time of tumours in colorectal cancers.

The aim of the present study was to investigate the effects of standard fractionated radiation therapy on the kinetic parameters of colorectal adenocarcinomas. The study of tumour kinetics involved in vivo injection of bromodeoxyuridine. Endoscopic biopsies were obtained from the tumour and analysed with flow cytometry. This procedure provides a rapid calculation of qualitative parameters such as ploidy and quantitative parameters such as the in vivo S-phase fraction labelling index which indicates the percentage of cells that have entered into the cycle, the duration of S-phase (Ts) and the potential tumour doubling time (Tpot). Thirty-eight colorectal carcinomas were studied without prior chemotherapy or radiation therapy (group 1) and ten rectal carcinomas were studied following radiation therapy (group 2). In diploid tumours, the labelling index was significantly lower in the post-radiotherapy group than in the pre-radiotherapy group (2.7 +/- 1.1% versus 6.4 +/- 4.2%, respectively; P= 0.01), and the Tpot was significantly longer after radiotherapy (group 2) (22.0 +/- 7.0 days versus 8.6 +/- 6.0 days, P = 0.002). Standard fractionated radiation therapy also appears to result in a longer Tpot in diploid adenocarcinomas of the colon and rectum. This effect was not observed in aneuploid tumours. The effectiveness of hyperfractionated schedules of radiation therapy for aneuploid rectal tumours with short Tpot warrants further investigation in a larger patient population.

The predictive role of flow cytometry-derived tumor potential doubling time (Tpot) in radiotherapy: open questions and future perspectives.

Measurement of tumor-cell kinetic parameters, following in vivo administration of thymidine analogues and bivariate flow cytometry, allows quantitative cell kinetic determinations in a clinically relevant time-scale, potentially useful for selection of individual radiotherapy schedules. Among the dynamic cell kinetic parameters that can be measured using the in vivo method, the tumor potential doubling time (Tpot), defined as the time to double the number of proliferating tumor cells in the absence of cell loss, has been postulated to be a predictor of a tumor's proliferative capability, thus representing a potential predictive factor of local control after irradiation. So far, published data have shown the safety and feasibility of the technique, even in multicenter studies, and demonstrated a wide range of parameter values in many tumor sites. With only a few exceptions the hypothesis that Tpot is an independent prognostic indicator cannot be considered proven yet. We review the major controversial issues and open questions, mainly in the area of data production and analysis, that must be resolved before the predictive role of Tpot is unequivocally defined. The future of radiotherapy predictive assays lies in the development of multiparametric studies, accounting for multiple factors of radiation response, which may prove of greater prognostic significance than any single parameter approach based only on cell kinetics.

Potential tumour doubling time: determination of Tpot for various canine and feline tumours.

Spontaneous tumours in dogs and cats are an excellent model for clinical human research, such as in developing proton conformation radiotherapy for humans. The kinetics of tumour cells can be used effectively to predict prognosis and response to therapy in patients with tumours. Knowledge of the kinetic parameters in these tumours is therefore important. In the present study the kinetic parameters evaluated included the labelling index (LI), relative movement (RM), mitotic index (MI), and potential doubling time (Tpot). These parameters were determined using in vivo labelling with bromodeoxyuridine, flow cytometry and histological preparation. Samples were obtained and evaluated from 72 dogs and 20 cats, presenting as patients in our clinic. Within the groups of epithelial and mesenchymal tumours from dogs and cats, the kinetic parameters LI, RM and MI were compared with Tpot. Significant correlations were observed for the comparison Tpot and LI. No correlation was found between Tpot and RM.

The Effect of Paclitaxel on the Cell Cycle Kinetics of a Murine Mammary Adenocarcinoma In Vivo

Abstract: This article reports data that describe perturbations in cell-cycle dynamic kinetic parameters following in vivo treatment of a syngeneic murine mammary tumor (MCa-4) with paclitaxel. The kinetic parameters include the duration of the S (Ts) and G2M (TG2M) phases of the cell cycle, the tumor potential doubling time (Tpot), the bromodeoxyuridine (BrdUrd) labeling index (Ll), and the fraction of proliferating cells that successfully completed mitosis following paclitaxel treatment. When tumors transplanted into the right thigh of 4-month-old male C3Hf/kam mice grew to 8 mm mean diameter, the mice were injected intravenously with 40 mg/kg paclitaxel. At one of a range of times thereafter (1–72 hours) animals were pulse labeled with 60 mg/kg BrdUrd. Mice were sacrificed and tumors excised either immediately or at 3 or 6 hours after BrdUrd labeling. Single-nuclei suspensions were prepared, and the kinetic parameters evaluated using bivariate DNA versus BrdUrd flow-cytometric methods. For at least 72 hours after paclitaxel treatment, the major cell kinetic perturbation was a consistent prolongation of the duration of G2M from approximately 2 hours to 5 hours. Tpot increased from about 30 hours to 40 hours. The rate of cell progression through S-phase remained unchanged. The fraction of BrdUrd-labeled cells that completed mitosis was markedly reduced by paclitaxel (to 10% of control values when measured 7 hours after treatment) but never reached zero. Apoptotic nuclei were discernible as BrdUrd-labeled particles with sub-G1 DNA contents. These data show that in this model tumor system, paclitaxel treatment leads to profound cell-cycle perturbations, largely a buildup of cells in G2M. This phenomenon is expected to contribute to the radiosensitization of this tumor by paclitaxel, in addition to reoxygenation that we reported earlier (1).

Flow Cytometric Evaluation of Proliferating Cell Nuclear Antigen Expression in Human Hematopoietic Malignancies

Cell proliferation is a strong prognostic factor in various malignancies including non-Hodgkin's lymphoma's (NHL). Several methods to evaluate tumour proliferation are available based on immunohistochemical and flow cytometric techniques, but none has been widely accepted for multicenter studies. In the present study 51 samples from patients with haematological disorders were analysed for the expression of proliferating cell nuclear antigen (PCNA) by a previously described flow cytometric approach. S-phase specific PCNA (PCNA-S) as well as growth fraction-associated PCNA (PCNA-tot) expression were evaluated. The mean value for PCNA-S was 9.0% and for PCNA-tot 17,4%. PCNA-S and PCNA-tot correlated strongly to each other (r s = 0.969, p < 0.001) and to the S-phase fraction determined by DNA histogram analysis (rs = 0.927 and 0.934 respectively, p < 0.001). In 23 cases with NHL in vivo iododeoxyuridine (IdUrd) labelling was performed to assess the labelling index (IdUrd-LI, i.e. S-phase fraction), S-phase duration time (Ts) and potential tumour doubling time (Tpot). IdUrd-Li correlated significantly to both PCNA-S and PCNA-tot (rs = 0.704 and 0.622 respectively, p < 0.001 and 0.02). In conclusion, especially the PCNA-S seemed to be a candidate for future larger studies of proliferation related aspects of haematological malignancies.

Accelerated radiation therapy for locally advanced squamous cell carcinomas of the oral cavity and oropharynx selected according to tumor cell kinetics—A phase II multicenter study

Purpose: A Phase II multicenter trial testing an accelerated regimen of radiotherapy in locally advanced and inoperable cancers of the head and neck, in patients selected on the basis of 5-bromo-2-deoxyuridine/DNA flow cytometry-derived tumor potential doubling time (Tpot).Methods and Materials: From September 1992 to September 1993, 23 patients consecutively diagnosed to have locally advanced, inoperable carcinomas of the oral cavity and the oropharynx, with Tpot of ≤ 5 days, received an accelerated radiotherapy regimen (AF) based on a modification of the concomitant boost technique: 2 Gy/fraction once a day, delivered 5 days a week up to 26 Gy, followed by 2 Gy/fraction twice a day, with a 6-h interval, one of the two fractions being delivered as a concomitant boost to reduced fields, up to 66 Gy total dose (off-cord reduction at 46 Gy), shortening the overall treatment time to 4.5 weeks. A contemporary control group of 46 patients with Tpot of >5 days or unknown was treated with conventional fractionation (CF):2 Gy/fraction once a fay, 5 days a week, up to 66 Gy in 6.5 weeks, with fields skrinkage after 46 Gy.Results: All patients completed the accelerated regimen according to protocol and in the prescribed overall treatment time. Immediate tolerance was fairly good: 65% of the patients inthe AF group experienced Grade 3 mucositis vs. 45% in thee CF group (p = n.s.). Symptoms related to mucosal reactions seemed to persist longer in AF than in CF patients. The crude proportion of mild (Grades 1 and 2) late effects on skin (p < 0.01) and salivary glands (p < 0.05) was higher in AF than in CF patients, although these reactions dis not exceed the limits of tolerance. Three patients in the AF and 1 in the CF arm experienced a late Grade 4 bone complication. Actuarial estimates of severe (Grade 3 and 4) late complications showed a 2-year hazard of 33.3% in the AF arm and 49.7% in CF (p = NS). The actuarial 2-year local control rate of the AF patients was 49.4%, while actuarial 2-year overall survival for the same patients was 43.5%.Conclusions:The results suggested that this accelerated regimen is worth testing in a controlled randomized trial to compare different accelerated schedules. Our findings also confirmed the 5-bromo-2-deoxyuridine/DNA flow cytometry technique as a suitable method of evaluating tumor cell kinetics in multicenter clinical studies, on conditions thal all measurements are carried out by one most experienced laboratory.

Cell kinetics and tumor regression during radiotherapy in head and neck squamous-cell carcinomas.

Head and neck squamous-cell carcinoma (HN-SCC) patient management is mainly based on TNM classification and needs be improved by considering other potentially useful prognostic factors. We examined the pre-radiotherapy tumor potential doubling time (Tpot) evaluated after in vivo infusion of bromodeoxyuridine and flow-cytometric analysis and the early clinical tumor regression after 40 Gy (40 Gy-TR). Tpot values and clinical 40 Gy-TR classes (minor and major) were available for 82 HN-SCC patients. Radiation therapy completion was done either with 1 dose per day (conventional regimen) or 2 doses per day (accelerated regimen). Local control was also available for follow-up times above 4 years. We found that major 40 Gy-TR was strongly correlated with fast tumor growth, characterized by Tpot values below 5 days, and that patients with major 40 Gy-TR showed better local control than those with minor 40 Gy-TR, independently from the radiotherapy regimen type. We also found that treatment completion with accelerated radiotherapy gave better local control for patients with major 40 Gy-TR and fast tumor growth than conventional radiotherapy. Multivariate analysis, performed on all patients, assigned an independent prognostic value to Tpot, tumor classification and 40 Gy-TR.

Potential doubling time and tumour doubling time in meningiomas and neurinomas.

Cell kinetic study plays an important role in treatment planning of brain tumour patients. MIB-1 antibody has recently become available, which detects Ki-67 antigen even in the formalin-fixed paraffin-embedded specimens. We performed MIB-1 immunostaining in 50 meningiomas and 50 neurinomas, and estimated the cell cycle time (tc) and potential doubling time (Tpot) from MIB-1 staining index (MIB-1 SI) and mitotic index (MI). MIB-1 SI logarithmically correlated with MI in both meningiomas and neurinomas. The tc and the Tpot were expressed as a function of the mitosis time (tm), while the tm is known to be around one hour and not exceeding two hours. When the tm was assumed to be one hour, the average tcs of meningiomas and neurinomas were 6.53 +/- 3.56 days and 7.67 +/- 3.27 days, respectively. The Tpots were 447 X (MIB-1 SI)-1.29 X tm in meningiomas, and 490 X (MIB-1 SI)-0.98 X tm in neurinomas. The tumour doubling times (Tds) were calculated from serial imaging studies in 22 neurinomas and 15 meningiomas. The Tds were formulated as 794 X (MIB-1 SI)-0.83 in meningiomas and 1380 X (MIB-1 SI)-0.97 in neurinomas. Most of the Tds correlated well with the Tpots in meningiomas and neurinomas, and exceeded values of the Tpot when the tm is assumed to be one hour, although a few tumours showed unexpectedly longer Tds. The Tpot and the to estimated from MIB-1 SI and MI are clinically useful parameters for predicting the growth potential of meningiomas and neurinomas where no other simple methods are available.

Proliferative characteristics of head and neck tumors. In vivo evaluation by bromodeoxyuridine incorporation and flow cytometry.

Cell proliferation of head and neck cancers was studied in 52 patients using in vivo bromodeoxyuridine (BUDR) incorporation. Patients received 250 mg BUDR intravenously several hours prior to biopsy of the tumor tissue. Bivariate flow cytometry was used and enabled us to rapidly obtain DNA ploidy, labelling index (LI), DNA synthesis time (TS) and tumor potential doubling time (Tpot). This method was found to be suitable to obtain complete cytokinetic data in 46/52 (88.5%) patients. The mean BUDR LI was 7.9% (range 2-18%); mean TS was 11.6 h (range 6-28.5 h); mean Tpot was 5.7 days (range 2-30 days). BUDR LI and TS were significantly correlated with histological differentiation grading: G3 tumors showed higher LI values and shorter TS values than G1/G2 tumors. A similar correlation was found between LI or TS and tumor dimensions. Tpot was also significantly lower in larger tumors, such as in those with a higher grading. No significant correlation was found between LI or TS and DNA ploidy (50% of the tumors in our series were DNA aneuploid), while Tpot was found to be 10 days in diploid tumors, compared to only 6.3 days for the aneuploid tumors (p < 0.05). All cases with documented lymph node involvement (N+) showed significantly higher LI, and shorter TS and Tpot values if related to nodal free ones (Tpot = 10 days in N+ patients and 6.3 days in N- patients; p < 0.05). The results of this study suggest that the method employed is clinically feasible and could be a useful aid in defining the prognosis of head and neck cancer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell kinetic analysis of non-Hodgkin's lymphomas using in vivo iododeoxyuridine incorporation and flow cytometry.

The aim of this study was to analyse dynamic cell proliferation parameters in non-Hodgkin's lymphomas. Sixty-one patients with newly diagnosed or with recurrent disease were given iododeoxyuridine (IdUrd) intravenously near 4 h prior to tumour biopsy. After staining with an IdUrd reactive antibody and propidium iodide, S-phase fraction (SPF), labelling index (LI), S-phase duration time (Ts) and potential tumour doubling time (Tpot) were determined by flow cytometry. Thirty-eight samples, 15 low grade (LGM) and 23 high grade (HGM) malignant lymphomas, were possible to evaluate. Twenty-three cases were excluded due to aneuploidy, insufficient amount of material or technical problems. Tpot values varied between 0.8-32.9 days (mean 7.0 days). HGM lymphomas had shorter mean Tpot times than LGM lymphomas (4.8 versus 10.4 days, p = 0.05). For Ts the range was 4.2-20.1 h (mean 9.1 h), and a difference between the two histological groups was demonstrated with a longer mean Ts for HGM compared with LGM cases (10.0 versus 7.8 h, p = 0.04). Tpot showed a negative correlation with SPF (P = 0.003), and Ts demonstrated a positive correlation to SPF (p = 0.02). The clinical significance of the dynamic cell proliferation parameters studied remains to be clarified, but the interrelationships between Ts/SPF and Ts/morphologic subtype might be factors of interest for future prognostic studies in malignant lymphomas.