Cancer Etiology: A Metabolic Disease Originating from Life's Major Evolutionary Transition?

A clear understanding of the origins of cancer is the basis of successful strategies for effective cancer prevention and management. The origin of cancer at the molecular and cellular levels is not well understood. Is the primary cause of the origin of cancer the genomic instability or impaired energy metabolism? An attempt was made to present cancer etiology originating from life's major evolutionary transition. The first evolutionary transition went from simple to complex cells when eukaryotic cells with glycolytic energy production merged with the oxidative mitochondrion (The Endosymbiosis Theory first proposed by Lynn Margulis in the 1960s). The second transition went from single-celled to multicellular organisms once the cells obtained mitochondria, which enabled them to obtain a higher amount of energy. Evidence will be presented that these two transitions, as well as the decline of NAD+ and ATP levels, are the root of cancer diseases. Restoring redox homeostasis and reactivation of mitochondrial oxidative metabolism are important factors in cancer prevention.

What can morphology tell us about ecology of four invasive goby species?

This study presents a detailed comparative analysis of external morphology of four of the most invasive goby species in Europe (round goby Neogobius melanostomus, bighead goby Ponticola kessleri, monkey goby Neogobius fluviatilis and racer goby Ponticola gymnotrachelus) and interprets some ecological requirements of these species based on their morphological attributes. The results are evaluated within an ontogenetic context, and the morphological differences between the species are discussed in terms of the question: can special external shape adaptations help to assess the invasive potential of each species? The morphometric analyses demonstrate important differences between the four invasive gobies. Neogobius melanostomus appears to have the least specialized external morphology that may favour its invasive success: little specialization to habitat or diet means reduced restraints on overall ecological requirements. The other three species were found to possess some morphological specializations (P. kessleri to large prey, N. fluviatilis to sandy habitats and P. gymnotrachelus to macrophytes), but none of these gobies have managed to colonize such large areas or to reach such overall abundances as N. melanostomus.

Morphological variability of black bullhead Ameiurus melas in four non-native European populations.

External morphology in black bullhead Ameiurus melas, a fish species considered to have high invasive potential, was studied in its four non-native European populations (British, French, Italian and Slovak). The aim of this study was to examine this species' variability in external morphology, including ontogenetic context, and to evaluate its invasive potential. Specimens from all non-native populations reached smaller body size compared to individuals from native populations. Juvenile A. melas were found to have a relatively uniform body shape regardless of the population's origin, whereas adults developed different phenotypes depending upon location. Specimens from the U.K., Slovak and French populations appeared to be rather similar to each other, whereas the Italian population showed the most distant phenotype. This probably results from the different thermal regime in the Italian habitat. Ameiurus melas from non-native European populations examined in this study showed some potential to alter the body shape both within and between populations. The phenotypic plasticity of A. melas, however, was not found to be as significant as in other invasive fish species. The results suggest that morphological variability itself is not necessarily essential for invasive success. The invasiveness of A. melas is therefore probably favoured by variations in its life-history traits and reproduction variables, together with some behavioural traits (e.g. voracious feeding and parental care) rather than by phenotypic plasticity expressed in external morphology.

The influence of platinum pathway polymorphisms on the outcome in patients with malignant mesothelioma.

BACKGROUND: Platinum-based therapy is widely used in the treatment of malignant mesothelioma (MM); however, the efficacy and toxicity of platinum agents vary greatly between patients. The aim of our study was to evaluate the influence of platinum pathway polymorphisms on treatment outcome in patients with MM. PATIENTS AND METHODS: In total, 133 patients with MM treated with (n = 97) or without (n = 36) platinum-based therapy were genotyped for common XPD, ERCC1, and GSTP1 polymorphisms, as well as for GSTM1 and GSTT1 gene deletion. Haplotype analysis was carried out to assess the combined effect of nucleotide excision repair (NER) polymorphisms. RESULTS: GST polymorphisms were not associated with treatment outcome in patients with MM. In the group of platinum-treated patients with MM, ERCC1 8092C/C wild-type genotype significantly influenced progression-free survival (PFS) in multivariable analysis accounting for clinical variables (P = 0.034). XPD 312Asp/Asp and ERCC1 8092C/C wild-type genotypes also increased the odds of treatment-related toxic effects in univariable as well as multivariable analysis. The association of wild-type NER genotypes with better PFS and higher susceptibility to treatment-related toxic effects was confirmed in haplotype analysis. CONCLUSIONS: Our results suggest that polymorphisms in NER pathway influence platinum-treatment efficacy and toxicity; therefore, these should be further evaluated as potential markers for the prediction of clinical outcome in patients with MM.

Morphological variability of the Asiatic cyprinid, topmouth gudgeon Pseudorasbora parva, in its introduced European range.

To assess the spatial variability in external morphology of non-native populations of topmouth gudgeon Pseudorasbora parva within an ontogenetic context, triple regression analysis (distance-based measurements) was applied to data from eight European populations (two Slovak, four Romanian, one English and one French). The data from Slovakia were also subjected to geometrical analysis (co-ordinates-based measurements) to obtain a more complex picture of the species' overall morphology. Great phenotypic variability was observed, being expressed not only in the formation of different definite phenotypes but also in the manner by which the phenotypes are achieved. Thus, both the definite phenotype and the patterns of development in invasive P. parva may be highly influenced by environmental conditions. Such great morphological (phenotypic) variability is likely to be one of the attributes that make this species such a successful invader.

Predicting the intention to quit smoking and quitting behaviour: extending the theory of planned behaviour.

OBJECTIVES: The present study examined the ability of the TPB to predict the intention to quit smoking and quitting behaviour. In addition, the predictive power of future orientation, number of cigarettes smoked, planning, past behaviour and the interactions between intention and other predictors was examined. MATERIAL AND METHODS: The data were derived from a longitudinal survey among 103 daily smoking students at the University of Oslo (mean age 24.6 years, mean number of years of smoking = 8 years). These data were collected by means of self-administered questionnaires at T1 (October 2003) and at T2 (February 2004) in terms of recording actual quitting. RESULTS: The TPB components accounted for 30% of the variance in quitting intentions, and affective attitude and descriptive norm emerged as the strongest predictors of quitting intention. Ordinal regression analysis showed that intention was a borderline significant predictor of subsequent quitting behaviour, while the impact of PBC was non-significant (model 1). The inclusion of the additional variables improved the fit of the model, with number of cigarettes and planning appearing as significant predictors of behaviour (model 2). As predicted, there was a significant interaction between perceived control and intentions on quitting (model 3). Nagelkerke R(2) increased from .07 in model 1 to .54 in model 2, and finally to .58 in model 3. CONCLUSIONS: The results indicate that affective attitude and descriptive norm play a more crucial role than the other TPB predictors in motivating smokers to quit. The results also indicate that self-regulatory strategies are important in relation to addictive behaviours.

Phase I-II trial of low-dose gemcitabine in prolonged infusion and cisplatin for advanced non-small cell lung cancer.

After monotherapy with gemcitabine in low dose in long infusion, promising results in a variety of advanced chemoresistant tumors have been reported. In a previous phase I trial on heavily pre-treated patients, maximum tolerated dose (MTD) of gemcitabine in a 6 h infusion was 250 mg/m. The objective of our phase I-II trial was to test the combination of gemcitabine in a 6-h infusion and cisplatin in the treatment of advanced non-small cell lung cancer (NSCLC). Eligible patients were chemonaive, had locally advanced or metastatic NSCLC, Eastern Oncology Cooperative Oncology Group performance status 0-2 and normal organ function. Treatment consisted of gemcitabine in a 6-h infusion on days 1 and 8, and cisplatin at 75 mg/m on day 2 of a 3-week cycle. During phase I of the trial, the dose of gemcitabine was escalated from 130 to 170, 210 and 250 mg/m. After establishing dose-limiting toxicity (DLT) and MTD of the combination, the trial continued as phase II. Altogether, 61 patients were enrolled, of whom 54 had stage IV disease. In phase I of the trial, groups of six, seven, eight and eight patients were treated at the four dose levels of gemcitabine. In phase II, the remaining 32 patients all received gemcitabine at 250 mg/m. Serious toxicity included a patient with grade 5 ventricular arrhythmia and another with grade 4 cerebrovascular ischemia; four patients had grade 3 anemia. Reversible thrombocytosis with platelets over 500 was recorded in 32 patients; 42 patients had grade 2 alopecia. In general, tolerance to this treatment was good. One patient had complete response and 27 had partial responses, for a 28 of 61 (46%) response rate. Median progression-free survival, median survival and 1-year survival were 6 months, 9.5 months and 40%, respectively. We conclude that this treatment has an acceptable, yet distinct, toxicity profile; routine thromboprophylaxis is recommended. In our population of chemonaive patients, no DLT has been encountered. Due to the remarkable response rate, further research is warranted.

Meta-analyses of clinical trials in patients with non-small cell lung cancer. Minireview.

Currently lung cancer is the most common worldwide cause of major cancer incidence and mortality. The treatment outcome is poor and there are still many questions which remain unanswered such as the interest of the best treatment schedule. To approach the answer what is the best treatment for patients with non-small cell lung cancer (NSCLC) we made a review of the published meta-analyses. Meta-analysis is a systematic approach to identification and abstraction of critical information from different randomized, controlled trials. The review of meta-analyses of clinical trials we had made showed that --in radically operated patients the postoperative radiotherapy should be detrimental if standard fields are used; postoperative chemotherapy with regimens based on cisplatin has an absolute benefit of 5% at 5 years survival; we can improve the survival of patients with locally advanced NSCLC using chemoradiation comparing to radiotherapy alone; chemotherapy with cisplatin can prolong the survival and improve the quality of life in patients with advanced NSCLC; platinum-based doublets remain the standard regimen in patients with advanced NSCLC; there is a slight but significant improvement in efficacy of gemcitabine plus platinum agent when compared with other platinum based comparators in regard to the survival and time to disease progression. In our dealing with NSCLC patients there are still many controversial opinions, and the meta-analyses are seldom the only way to find more effective treatment regimen, while the improvement in lung cancer treatment is a story of small steps.

Surgical treatment of extension contractures caused by war injuries to the knee.

Immobilization with external fixation bridging the knee joint in extension is frequently used after sustaining a war injury to the region of the knee joint with femoral and tibial bone fractures. Immobilization of the knee with plaster splints is performed in the same position. This usually prolonged treatment results in extension contractures of the knee joint. From June 1991 until March 1994, 54 patients with extension contractures of the knee caused by war wounds were treated at the Department of Orthopedics, Zagreb University Hospital Center, in Zagreb, Croatia. Results of surgical treatment of 44 patients are presented. The operative procedure consisted of extensive intra- and extra-articular adhesiolysis of the knee. The control group included 30 patients with knee contractures caused by injuries sustained in car crashes or secondary to previous operative procedures. The mean duration of immobilization was 5 months and 6 days. The mean preoperative knee motion amplitude ranged from 5 degrees in extension to 38 degrees in flexion. The mean postoperative knee motion was 98 degrees (range, 2 to 110 degrees). Treatment results did not depend on either duration of preoperative immobilization of the knee or previous infection in the region of injury. Previous knee joint bridging with an external fixator had no impact on the results of extension contracture treatment. Adequate intra- and extra-articular adhesiolysis with appropriate long-term postoperative rehabilitation is essential for the success of the operative treatment for knee joint contracture.

Scoliosis curve correction, thoracic volume changes, and thoracic diameters in scoliotic patients after anterior and after posterior instrumentation.

Thoracic volume was calculated in 50 adolescent patients operated on for severe idiopathic thoracic scoliosis. In 25, anterior instrumentation was used (group 1), and posterior instrumentation in the other 25 patients (group 2). Calculation of thoracic volume was made from measurements of pre-operative and post-operative radiographs. The mean spinal curvature in group 1 was 73+/-12.4 degrees before the operation, and 19+/-15 degrees after the operation, and in group 2 the curvature was 75+/-13 degrees before the operation and 37+/-10 degrees after the operation. The calculated thoracic volume in the group with anterior instrumentation increased from 5234 ml pre-operatively to 6043 ml post-operatively, while with posterior instrumentation it increased from 5155 ml to 5489 ml. The correlation between the change in the Cobb angle and the thoracic volume change was poor for both groups. To determine the role in the thoracic volume increase of the frontal, sagittal and vertical thoracic diameters, further correlation tests were made between these and the thoracic volume increase in each diameter. The best correlation was found between the frontal and vertical increase of diameters in group 1, whereas in group 2 the best correlation was found between the volume increase and the sagittal parameters.

[Multisegmental posterior wedge osteotomies of the lumbar vertebrae for correction of kyphosis in ankylosing spondylitis. A report on 5 cases]. / Visesegmentne straznje klinaste osteotomije lumbalne kraljeznice u korekciji kifoze kod ankilozantnog spondilitisa. Prikaz 5 bolesnika.

Operative treatment of Ankylosing spondilitis is usually performed in treatment of extraspinal pathology, i.e. in treatment of hip contractures. Operative treatment of fixed spinal kyphosis in AS is rarely indicated, and patients make their decision for the operation when deformation becomes extreme. Instead of several hundred of operated patients in foreign literature, authors describe only 5 operations from 1989 to 2000. Results suggest that multiple spinal osteotomy in AS is a time consuming operation with a significant intraoperative and postoperative blood loss. Mild, transient radicular irritations are noticed. However, reconstruction of lumbar lordosis significantly improve quality of life in operated patients. It is concluded that indication for the operation in AS should be indicated earlier. Better results with less risk would be achieved.

Breast metastases from cutaneous melanoma: a report of three cases.

In this report we describe three female patients with breast metastases from cutaneous melanoma (CM) who were treated in Slovenia in the period from 1988 to 1991. We found that in 476 Slovenian patents with this disease diagnosed in the given period CM disseminated to the breast less frequently than in other series. In one pregnant and one perimenopausal patient breast involvement by CM was confirmed at the time of widespread dissemination of the disease. Treatment was not effective and the survival of these patients was four months and two weeks and six months, respectively. A slightly better outcome was observed in a normally menstruating patient referred from another country with an isolated solitary breast metastasis from CM. In this patient quadrantectomy seemed to have been sufficient to achieve a disease-free interval of more than eight months. Special attention should therefore be given to a small subset of patients with isolated solitary breast metastases from CM, since their prognosis may be less dismal than in patients with massively infiltrated breasts and disseminated disease.

Molecular mechanisms involved in the antiproliferative action of protein tyrosine phosphatase inhibitor potassium bisperoxo(1,10-phenanthroline)oxovanadate.

Potassium bisperoxo(1,10-phenanthroline)oxovanadate, bpV(phen), a powerful protein phosphotyrosine phosphatase inhibitor and a potent insulinomimetic, influenced three fundamental cellular processes in HL-60 human leukemic cells: 1) inhibition of proliferation, 2) induction of differentiation and 3) apoptotic cell death. In the presence of micromolar concentrations of bpV(phen) cell number and DNA synthesis decreased progressively with time of incubation. A single treatment with bpV(phen) (3 microM) activated a differentiation program; after 6 days of incubation 82% of cells were differentiated, but differentiation started already within the first 24 h. Concentrations of 5-10 microM bpV(phen) caused the characteristic DNA ladder pattern, starting after 4.5 h. Differentiation in HL-60 cells appear to be associated with activation of extracellular signal-regulated kinase while apoptosis is connected with phosphorylation and activation of both extracellular signal-regulated kinase and c-Jun N-terminal kinase in a concentration and time-dependent manner. The antiproliferative and apoptotic action of bpV(phen) could be exploited in combination chemotherapy in leukemia.

Moiré topography in measurement of the sagittal curvatures of the spine.

The purpose of the investigation was to establish the accuracy of moiré topography in the analysis of the kyphotic spine. Using simplified instrumentation, moiré topogram was performed in the 50 outpatients at the Department of Orthopaedic Surgery, School of Medicine, University of Zagreb. Lateral x-ray and meticulous clinical measurements of the spine were included as well. A correlation between the obtained results was established. A high correlation (r = 0.847) was found between the results obtained by means of X-rays and those obtained by means of moiré topography. The authors concluded that the method is ideal for the determination of a morphotypology of the kyphotic spine and can significantly contribute to the differentiation between normal and pathological sagittal curvatures of the spine without the need for x-ray of the spine. The authors conclude that the application of moiré topography in the biomechanical laboratories can contribute to the new cognition on kinematics of the spine. The investigation demonstrated that simple and nonexpensive apparatus can be used for the moiré topography in the follow-up of the sagittal curvatures of the spine.

[The thrombocytopenia syndrome caused by heparin]. / Sindrom trombocitopenije izazvane heparinom.

Heparin represents the basis for drug treatment and prevention of thrombosis. However, heparin itself may produce side effects, among others two types of heparin-induced thrombocytopenia (HIT). The more frequent type 1 occurs in about 10% of patients within the first days of the treatment and disappears spontaneously without sequelae. HIT type 2 represents a far more serious complication occurring in 0.1-1% of patients somewhat later, between days 4 and 10 of heparin therapy, and may provoke severe arterial and venous thrombosis. Apart from the differences in clinical picture, data regarding platelet count and platelet aggregation test are significant for the diagnosis. Heparin should be discontinued immediately and another anticoagulant therapy introduced. We are presenting the case of a patient with thrombosis of the left external iliac artery following surgery for ovarian cancer as a complication of HIT type 2, which was recanalized successfully and the leg was saved.

Superior sulcus tumor (SST): management at the Institute of Oncology in Ljubljana, Slovenia, 1981-1994.

During the 14-year period under study, 48 patients with SST were treated at the Institute of Oncology in Ljubljana, Slovenia. There were 46 males and two females, aged 29-88 years (median, 60 years). Of 37 cytologically or histologically confirmed tumors, 12 were squamous, eight large-cell, one small-cell, eight adeno, and eight unclassified carcinomas. Performance status (Karnofsky) was assessed as > 90 in eight, 70-90 in 31 and < 70 in nine patients. The duration of symptoms before diagnosis ranged from 1 to 36 months (median, 5 months). All patients had pain, while six also had hemophthysis, 14 Horner's syndrome, and four Horner's syndrome and upper limb paresis. Before the first chest X-ray, 19 patients- were treated for shoulder pain by different specialists. Apical tumor infiltration only on the chest X-ray was found in 13, destruction of the ribs in 31, and destruction of the ribs and vertebral bodies in four patients. Treatment was as follows: radiotherapy in 39 patients (22 with radical, 17 with palliative dose), a combination of surgery and radiotherapy in seven, radiotherapy and chemotherapy in one, and symptomatic therapy alone in one patient. One- and four-year survival of all treated patients was 27% and 11%, respectively. One of the seven patients operated on survived for 44 months, and 2/39 irradiated ones survived for 37 and 56 months, respectively, while others died within 24 months from diagnosis. In 81% of patients the pain was subdued after radiotherapy. The disease-specific survival of all patients included in the follow-up correlated with performance status and M stage, while that of those treated by irradiation alone correlated with tumor dose (P < 0.05).

Postoperative radiotherapy for radically resected N2 non-small-cell lung cancer (NSCLC): randomised clinical study 1988-1992.

In the period 1988-1992, 74 consecutive radically resected patients with NSCLC were randomised to postoperative radiotherapy or surgery alone in order to evaluate the influence of postoperative radiotherapy on survival. There were 61 males and 13 females, aged 35-80 years, median 59 years. Their distribution by stage was as follows: pT1N2 = 19, pT2N2 = 54, pT3N2 = one patient; histology: 32 squamous, 32 adeno and 10 large cell carcinomas; surgery: atypical resection in six, lobectomy in 27, bilobectomy in ten, and pneumonectomy in 31 patients. In 27 patients, only one lymph node in a single mediastinal lymph node site was affected; in 31 patients more than one lymph node in one site; in 16 patients more sites were affected. In 35/74 patients radiotherapy of hilar and mediastinal sites with 3000 cGy in 2 weeks was performed. On December 31, 1994, 19 patients (26%) were still alive; 39/55 patients died of the following causes: locoregional failure-10(26%), distant metastases- 25 (64%), other tumor-unrelated causes-four patients (10%). Five-year survival rates did not show statistically significant differences between the irradiated and surgically treated patients only with respect to sex, pTNM stage, histology and frequency of locoregional failure. The number of metastatic mediastinal lymph nodes was the only significant prognostic factor (P < 0.005) in both randomised groups.

The role of cisplatin in chemotherapy of advanced breast cancer.

Cisplatin containing regimens as first-line, second-line or as a third-line chemotherapy were administered in 26 and 36 patients, respectively. The overall response rate in patients on first-line chemotherapy was 53.9%, in patients on second or third-line chemotherapy 30.6%. The differences both in overall and disease-free survival between patients on first-line and on second/third-line chemotherapy were statistically significant in favor of women treated with first-line chemotherapy (p = 0.05). Hematologic and nonhematologic toxicities were mild to moderate and were more pronounced in patients on second and third-line chemotherapy. The overall response rate, DFS and OS were significantly better and longer in the group of patients treated with "bolus" CDDP in comparison to the group of patients treated with CVI CDDP. Our results confirm the activity of cisplatin-containing regimens (mainly CAP schedules) in patients with advanced breast cancer not only as a first-line therapy but also in heavily pretreated patients by chemotherapy and/or radiation therapy and endocrine manipulation.