Clonogenic growth in vitro: an independent biologic prognostic factor in ovarian carcinoma.

A retrospective analysis was performed to investigate the prognostic value of growth in a human tumor clonogenic assay system for 84 ovarian cancer patients. A significant difference in survival probability (determined by the method of Kaplan-Meier) was found by univariate analysis between patients with ovarian carcinoma whose tumors manifested clonogenic growth (defined as growth of greater than or equal to five colonies per plate) and patients whose tumors did not grow. Clonogenic growth in vitro was associated with worse prognosis (P = .007, log-rank test). A number of generally accepted prognostic factors, International Federation of Gynecology and Obstetrics (FIGO) stage (P = .003), residual tumor mass (P less than .001), and grade (P = .011), were also of prognostic importance in our patient population. Multivariate analysis, based on the Cox regression model, identified clonogenic growth as a significant independent prognostic parameter in ovarian carcinoma (P = .031), in addition to the conventional risk factors. Estimation of survival of individual patients was best accomplished by combining the factors of residual tumor mass (P less than .05), age (P less than .01), and clonogenic growth (P less than .05) (in sequence of decreasing potential of risk).

Reactivity of urinary bladder smooth muscle in guinea pigs to acetylcholine and carbachol--participation of acetylcholinesterase.

The authors examined the influence of acetylcholinesterase inhibitor (neostigmine) on the in vitro reactivity of urinary bladder smooth muscle (UBSM) in guinea pigs. The aim of the present study was to determine the participation of pharmacokinetic properties of acetylcholine and carbachol in different UBSM reactivity to these mediators. In vitro method of organ baths was used and reactivity of UBSM strips to cumulative doses of acetylcholine and carbachol was tested before and after the incubation with neostigmine (10(-4) mol.l(-1)). Neostigmine caused a significant increase of UBSM reactivity to acetylcholine. The UBSM reactivity to acetylcholine was significantly higher at concentrations of 10(-5) and 10(-4) mol.l(-1) compared to carbachol at the same concentrations. These findings indicate that in addition to different mediator affinity to muscarinic receptors and to their different intrinsic activity, the pharmacokinetic properties of acetylcholine and carbachol also participate in UBSM reactivity.

Polymer-based or polymer-free stents in patients at high bleeding risk

BACKGROUND Polymer-free drug-coated stents provide superior clinical outcomes to bare-metal stents in patients at high bleeding risk who undergo percutaneous coronary intervention (PCI) and are treated with 1 month of dual antiplatelet therapy. Data on the use of polymer-based drug-eluting stents, as compared with polymer-free drug-coated stents, in such patients are limited. METHODS In an international, randomized, single-blind trial, we compared polymer-based zotarolimus-eluting stents with polymer-free umirolimus­coated stents in patients at high bleeding risk. After PCI, patients were treated with 1 month of dual antiplatelet therapy, followed by single antiplatelet therapy. The primary outcome was a safety composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year. The principal secondary outcome was target-lesion failure, an effectiveness composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-lesion revascularization. Both outcomes were powered for noninferiority. RESULTS A total of 1996 patients at high bleeding risk were randomly assigned in a 1:1 ratio to receive zotarolimus-eluting stents (1003 patients) or polymer-free drugcoated stents (993 patients). At 1 year, the primary outcome was observed in 169 of 988 patients (17.1%) in the zotarolimus-eluting stent group and in 164 of 969 (16.9%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% confidence interval [CI], 3.5; noninferiority margin, 4.1; P=0.01 for noninferiority). The principal secondary outcome was observed in 174 patients (17.6%) in the zotarolimus-eluting stent group and in 169 (17.4%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI, 3.5; noninferiority margin, 4.4; P=0.007 for noninferiority). CONCLUSIONS Among patients at high bleeding risk who received 1 month of dual antiplatelet therapy after PCI, use of polymer-based zotarolimus-eluting stents was noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes. (Funded by Medtronic; ONYX ONE ClinicalTrials.gov number, NCT03344653.). (AU)

Analysis of factors influencing clonogenic growth in vitro of cells from ovarian carcinoma patients.

Clonogenic growth (defined as the formation of greater than or equal to 5 colonies per 5 x 10(5) viable nucleated cells per plate) of ovarian cancer specimens assessed in our clonogenic assay system was significantly associated with the proportion of tumor cells in the suspensions plated (N = 87; P = 0.0006), although there was no quantitative relationship with the corresponding plating efficiencies. An inverse correlation was observed between monocytes/macrophages/mesothelial cells (M) proportion and clonogenic growth (P = 0.013). These associations were most evident when only effusions were considered. Univariate analyses identified tumor cell content, M proportion and, to a lesser degree, granulocyte content as the only factors out of 12 examined to be correlated with colony formation. Multivariate analysis using a logistic regression model identified the proportion of tumor cells as the only significant factor predicting clonogenic growth in vitro (P = 0.0006). The overall accuracy of prediction for growth or non-growth was 63.2%.

Octreotide combined with goserelin in the therapy of advanced pancreatic cancer--results of a pilot study and review of the literature.

The two hormone analogues octreotide and goserelin have been shown to decelerate growth of human pancreatic cancer in vitro and in vivo. The objective of this pilot study was to investigate the efficacy and toxicity of the combination of these two agents in patients with advanced pancreatic cancer. Octreotide was injected subcutaneously in dosages increasing weekly, starting with 50 micrograms twice daily, until the level of maintenance therapy of 500 micrograms three times a day was reached. In addition, 3.8 mg goserelin acetate was administered subcutaneously at monthly intervals. A median of 7 cycles (range 1-27 cycles) were applied; 13 out of 14 patients entered into the study were evaluable for response and all 14 were evaluated for toxicity. In one patient with initially non-resectable pancreatic cancer, systemic therapy yielded a partial remission lasting 9 months. The degree of tumour regression then allowed a consecutive macroscopic radical tumour resection followed by an additional 6 months of no evidence of disease while the same drug combination was continued. In an additional 9 patients, no change of disease was observed, in some cases for a remarkably long time (up to 27 months). Nevertheless, the objective response rate of 7% (95% confidence interval 0 +/- 21%) was low. In 5 patients a clear improvement in their performance status was seen soon after the start of therapy; 3 patients showed progression of the disease at first evaluation or earlier and 1 patient was not evaluable at the time of study assessment. According to the product-limit method of Kaplan and Meier, the time to progression was 3.0 +/- 1.8 months [median +/- asymptotic standard error (ASE)] and overall survival was 6.0 +/- 1.5 months (median +/- ASE). Toxicity was rare and only of mild to moderate degree. Overall, the regimen under investigation did not meet the criteria for sufficient antitumoural effectiveness. Nevertheless, this study reinforces the concept that pancreatic cancer is principally responsive to endocrine therapy and therefore the further investigation of hormonal manipulation seems worth while in the future.

Early prediction of deep sternal wound infection after heart operations by alpha-1 acid glycoprotein and C-reactive protein measurements.

Serum C-reactive protein (CRP) and alpha 1-acid glycoprotein (AAG) levels were studied in 188 patients undergoing heart operations with cardiopulmonary bypass. Mediastinitis or osteomyelitis of the sternum or both developed in 10 patients on postoperative day 4 to 13 (median, day 9). The mean CRP levels on day 2 were lower in patients with later deep sternal wound infection (9.1 +/- 1.5 mg/dl [mean +/- standard error]) compared with patients without major infections (14.0 +/- 0.8 mg/dl; p = 0.103 [univariate logistic regression]). AAG levels on day 2 reacted in a similar manner, yielding 78.2 +/- 5.5 mg/dl and 100.9 +/- 2.7 mg/dl, respectively (p = 0.0004). No correlation was found between CRP or AAG and duration of cardiopulmonary bypass, number of blood transfusions, or total protein levels on day 2. The white blood cell count (WBC) on day 2 was 13.1 +/- 1.7 X 10(3)/microliter for patients with infection and 9.7 +/- 0.3 for those without infection. Multivariate logistic regression analysis revealed that AAG, WBC, and CRP on day 2 were significant risk factors sufficiently predicting the probability of a deep sternal infection. After adjustment for these three variables, other variables (age, sex, total protein on day 2, diabetes mellitus, type of operation, duration of cardiopulmonary bypass, length of operation, repeat thoracotomy for bleeding, number of blood transfusions on the day of operation, intraaortic balloon pumping, reoperation, emergency operation, and surgeon's professional status) were not of additional significance. The goodness of fit of the statistical model was confirmed by a high correspondence between predicted and observed cases of deep sternal infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors for severe bacterial infections after valve replacement and aortocoronary bypass operations: analysis of 246 cases by logistic regression.

Risk factors for severe bacterial infections, that is, deep sternal wound infection, pneumonia, septicemia, and prosthetic valve endocarditis, were evaluated in 246 consecutive patients undergoing valve replacement (N = 84) or aortocoronary bypass operation (N = 162). Multiple logistic regression analysis was applied to determine the ability of putative risk factors to predict infection. The risk factors considered were age, sex, diabetes mellitus, duration of cardiopulmonary bypass (CPB), duration of operation, amount of blood restored on the day of operation, repeat thoracotomy for bleeding, intraaortic balloon pumping, reoperation, emergency operation, and the professional status of the surgeon. Severe infections occurred in similar frequency after valve replacement (8/84; 9.5%) and aortocoronary bypass (11/162; 6.8%). For patients who had a bypass procedure, repeat thoracotomy was the only factor significantly associated with infection (p = 0.0004). However, the classification analysis revealed that this variable alone is too unspecific for a reliable prediction. Univariate analysis indicated that restoration of more than 2,500 ml of blood (p = 0.0001), reoperation (p = 0.0821), duration of operation (p = 0.0061), duration of CPB (p = 0.0318), and intraaortic balloon pumping (p = 0.0281) were associated with infection following valve replacement. A model with three variables emerged from the multiple logistic regression: after correction for blood restoration, reoperation, and duration of CPB, no other variable was of additional predictive value. For patients who underwent valve replacement, the model performed well in predicting complications. The classification analysis revealed a high correspondence between observed and predicted instances of infection: it correctly predicted 75% of the patients with infection and 96% of those without infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption of the impact energy in the palmar soft tissues.

In 30 anatomical specimens of the forearm the dynamic fracture of radius has been performed with a special hammer. In these specimens the pure kinetic energy of the fracture of the radius and the absorption of the impact energy in the palmar soft tissues has been determined.

Biostatistical aspects of adjuvant therapy assay.

The specific problems of biostatistical evaluation of adjuvant therapy are discussed. These problems arise from the fact that the effect of adjuvant therapy is usually rather small; in particular, for many kinds of cancer it is smaller than the variability in prognosis among patients due to different prognostic factors. Knowledge about prognostic factors for a particular type of cancer is therefore an essential precondition for the correct planning of controlled clinical trials. The importance of prognostic factor studies is stressed and it is shown how results of such studies can be utilized for the design of efficient trials for adjuvant therapy assay. The results of the retrospective DOSAK study on carcinomas of the oral cavity are reported. Based on a sample of 1021 patients in this study, numerous prognostic factors were analysed by both univariate and multivariate statistical techniques. On the basis of these analyses, a prognostic index was developed which should be a valuable aid for the design of clinical trials.

Computer-aided individual prognoses of squamous cell carcinomas of the lips, oral cavity and oropharynx.

Computer-aided individual prognoses (CIP) is a software-package developed on the basis of an empirical study and can be installed on any IBM-compatible personal computer. The project which went into the making of CIP was called "Prospective DOSAK-study on squamous cell carcinomas of the lips, oral cavity and oropharynx". In the course of the study 1485 patients were treated between 1977 and 1982, and followed up through 1985. CIP facilitates individual prognoses and comparisons of independent patient groups with parallel groups from the data of the above-mentioned study. In practical clinical work individual prognoses allow exact and reliable judgements on individual patients. In clinical cancer research it provides the information about prognostic factors required for controlled clinical studies. The comparison of independent patient populations allows for an ongoing qualitative control of the patients in each clinical institution. In clinical cancer research such a comparison means that certain characteristics of the patient, the tumor and of the disease can be given higher prognostic value. The same is true of the clinical testing of therapeutic measures which is typically carried out during phase-II-studies. Due to its menu-based organization CIP does not presuppose any specialist knowledge on the part of its users and can be regarded as particularly user-friendly.

Botryoid odontogenic cyst. Report of a case with histologic evidence of multicentric origin.

Histologic examination of an excisionally biopsied botryoid odontogenic cyst (BOC) documented that it was composed of at least 2 separate cysts, the location of which suggested that both originated within the alveolar bone rather than from within the periodontal ligament. These observations provide evidence for a multicentric origin of this example of BOC, and are consistent with a previous suggestion that lateral periodontal cysts of non-inflammatory origin arise from remnants of the dental lamina.

Chemoradiotherapy with 5-fluorouracil/leucovorin, surgery and adjuvant chemotherapy for locally advanced rectal cancer.

The aim of this study was to demonstrate a pathologic complete response (pCR) rate of at least 10% with an acceptable toxicity achieved by preoperative chemoradiotherapy with 5-fluorouracil (5-FU)/leucovorin in patients with locally advanced rectal cancer. Patients were treated by radiotherapy targeting 50 Gy and 5-FU/leucovorin intravenously during the 1st, 4th and 7th week after start of radiotherapy followed by surgery and adjuvant chemotherapy. In 71 evaluable patients, the pCR rate was 14.1% (95% CI, 6.0-22.2); the local relapse rate, 6.1%; the 5-year disease-free survival, 54% and the overall 5-year survival, 68%. The most severe adverse events were neutropenia (17%), diarrhoea (17%), infection (8%) and fatal cardiovascular function (1%). This therapy yielded a high rate of pCR, a low rate of local relapse and a long disease-free and overall survival. To increase its feasibility, radiation dose reduction to 45 Gy and administration of only two preoperative cycles of chemotherapy is recommended.

Ifosfamide/mesna as salvage therapy in platinum pretreated ovarian cancer patients--long-term results of a phase II study.

PURPOSE: Salvage chemotherapy in advanced ovarian cancer is not yet standardized. PATIENTS: Twenty-one consecutive patients progressing on or relapsing after previous platinum-containing treatment were eligible for treatment with ifosfamide 5 g/m(2) infused over a 24-hour period every 3 weeks in a Phase II trial. After an initial bolus of 1 g/m(2) of mesna, mesna was applied at a dosage of 5 g/m(2) concomitantly with ifosfamide followed by additional dosages of 200 mg 3 times at 4-hour intervals after termination of the ifosfamide infusion. RESULTS: The rate of objective responses was 19 percent, with a 95%CI [5.45-41.91 percent]. One patient achieved a pathologic complete remission (pCR) and 3 patients a clinical partial remission (PR). Median time-to-progression was 3 months. One patient was a long-term survivor. Main toxicities according to NCI-CTC included Grade 4 neurotoxicity in one patient, Grade 3 gastrointestinal toxicity in 5 patients, Grade 3 infection in one patient, and Grade 3 and 4 leucopenia in 6 and 2 patients, respectively. CONCLUSIONS: Monotherapy with ifosfamide represents an active regimen for salvage chemotherapy in advanced ovarian cancer patients progressing on or relapsing after previous platinum-pretreatment, even yielding a long-term surivor.

Phase I/II study of oral etoposide plus GM-CSF as second-line chemotherapy in platinum-pretreated patients with advanced ovarian cancer.

The aim of this phase I/II study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities of chronic oral etoposide given on days 1-10 followed by rescue with subcutaneous (s.c.) granulocyte-macrophage colony-stimulating factor (GM-CSF) on days 12-19 as second-line chemotherapy in platinum-pretreated patients (pts) with advanced ovarian carcinoma. Cohorts of three to six pts were treated with doses of oral etoposide from 750 mg m(-2) cycle(-1) escalated to 1250 mg m(-2) cycle(-1) over 10 days, every 3 weeks. Subcutaneous GM-CSF, 400 mug once daily, days 12-19, was added if dose-limiting granulocytopenia was encountered. In total, 18 pts with a median Karnofsky index of 80% (range, 70-100%) and a median time elapsed since the last platinum dose of 10 months (range, 1-24 months), 30% of whom showed visceral metastases, were treated at four dose levels (DLs) of oral etoposide on days 1-10 of each cycle as follows: DL 1, 750 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 2, 1000 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 3, 1000 mg m(-2) cycle(-1), with GM-CSF, six pts; and DL 4, 1250 mg m(-2) cycle(-1), with GM-CSF, six pts. All pts were assessable for toxicity and 16 pts for response. Dose-limiting toxicity (DLT) was reached at DL 4 by three of six pts, showing World Health Organization (WHO) toxicity grade 4. One patient died from gram-negative sepsis associated with granulocytopenia grade 4. Two more pts developed uncomplicated granulocytopenia grade 4. Thus, we recommend that DL 3 can be used for further phase II evaluation (i.e. oral etoposide 1000 mg m(-2) cycle(-1), days 1-10, followed by s.c. GM-CSF 400 mug, days 12-19). The clinical complete or partial responses in each patient cohort were: DL 1, one of three pts; DL 2, one of three pts; DL 3, three of five pts; and DL 4, two of five pts. In conclusion, in this phase I/II study, we defined the MTD and the dose recommended for the therapy with oral etoposide given over 10 days followed by s.c. GM-CSF in platinum-pretreated patients with advanced ovarian cancer. Our data demonstrate encouraging activity of this regimen and strongly support its further investigation in a phase II study.

Fitting regression models to censored survival data.

A short review of regression models for the analysis of censored survival data is given. These include multiplicative hazard rate models, log-linear models (accelerated failure time models), linear models and polynomial models. An application of some of these models to the analysis of a large retrospective study on carcinomas of the oral cavity is described. The results obtained by parametric and semiparametric analyses are compared.

Retrospective DOSAK Study on carcinomas of the oral cavity: results and consequences.

In a multicentre, retrospective observational study on carcinomas of the oral cavity, including the lips and oropharynx, data material of 1021 patients has been analysed. The specific goals of this study were: Review of existing proposals for classification. Analysis of prognostically relevant factors of the tumour disease. Construction of a prognostic index for the determination of individual and collective prognoses. The following results were achieved: ad 1: All existing TNM-Classifications of oral cavity carcinomas so far fail to meet the requirements of the necessary criteria. ad 2: The multivariate analyses of prognostically relevant factors were performed with and without taking therapeutic factors into account. The results show unequivocally that reliable prognoses are only possible if various treatment modalities are considered. ad 3: This led to the construction of the treatment-dependent prognostic index TPI, which will be eligible for use in clinical-therapeutic cancer research and in clinical practice.

[Critical evaluation of the treatment-dependent prognosis index TPI based on the "prospective DOSAK study on squamous cell carcinomas of the lips, oral cavity and oropharynx"]. / Kritische Validierung des Therapieabhängigen Prognoseindex TPI anhand der "Prospektiven DOSAK-Studie über Plattenepithelkarzinome der Lippen, der Mundhöhle und des Oropharynx".

The "Treatment Dependent Prognostic Index" (TPI), which has been published by the authors in 1982 as a result of a retrospective observational study of the DOSAK (German-Austrian-Swiss Association for Head and Neck Tumors), is submitted to a critical review. For this purpose a sample of 1485 patients representing the "Prospective DOSAK-Study on Squamous Cell Carcinomas of the Lips, the Oral Cavity and the Oropharynx" were classified according to TPI. 13 TPI groups exhibited greater than or equal to 20 patients and were suitable for calculation of observed survival and comparison to their TPI prognoses. In 10 of 13 TPI groups observed and predicted survival are almost identical. 3 TPI groups show a considerable lack of correspondence between observation and prognosis. In general, the analyses revealed a high prognostic validity of TPI in its substantial parts. A further improvement of TPI by taking several tumor sites into consideration seems possible and will be a subject of future investigations.

[Retrospective DOSAK study of oral cavity carcinomas. Results and consequences]. / Retrospektive DOSAK-Studie über Karzinome der Mundhöhle. Ergebnisse und Konsequenzen.

In a multicentric, retrospective observational study on carcinomas of the oral cavity including the lips and the oropharynx a data material of 1021 patients has been analyzed. The specific goals of this study were: Review of existing proposals for classification; Analysis of prognostically relevant factors of the tumor disease; Construction of a prognostic index for the determination of individual and collective prognoses. The following results were gained: None of the TNM-classifications of oral cavity carcinomas does the necessary criteria justice not even approximately. The multivariate analyses of prognostically relevant factors were performed with and without taking therapeutical factors into account. The results unequivocally show that reliable prognoses are only possible under consideration of various treatment modalities. This led to the construction of the treatment-dependent prognostic index TPI, which will be eligible for the use within the clinical-therapeutical cancer research and within the clinical practice.

[Criteria for evaluating calcium carbonate from the point of view of chlortetracycline biosynthesis]. / Kriterii otsenki uglekislogo kal'tsiia s tochki zreniia biosinteza khlortetratsiklina

Calcium carbonate is added to fermentation media in biosynthesis of tetracyclines for providing definite pH values and binding tetracycline into insoluble complexes. Seven different samples were studied with respect to their physical properties, such as the microscopic size of the particles, their form, capacity for agglomeration, specific volume, rate of the particle precipitation and chemical properties, such as purity, buffer capacity, effect on the medium pH before and after sterilization. The above properties were studied in comparison with activity chlortetracycline biosynthesis. Microfine calcium carbonate proved to be the best from the point of view of productivity of Str. aureofaciens. With its use the activity of the culture fluid increased by 20 per cent as compared to the other samples. The titration curve of the sample had the lowest bend.