Structure-Activity Relationships of Ligand Binding to Oxysterol-Binding Protein (OSBP) and OSBP-Related Protein 4.

Oxysterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4) have emerged as potentially druggable targets in antiviral and precision cancer drug development. Multiple structurally diverse small molecules function through targeting the OSBP/ORP family of proteins, including the antiviral steroidal compounds OSW-1 and T-00127-HEV2. Here, the structure-activity relationships of oxysterols and related compound binding to human OSBP and ORP4 are characterized. Oxysterols with hydroxylation at various side chain positions (i.e., C-20, C-24, C-25, and C-27)─but not C-22─confer high affinity interactions with OSBP and ORP4. A library of 20(S)-hydroxycholesterol analogues with varying sterol side chains reveal that side chain length modifications are not well tolerated for OSBP and ORP4 interactions. This side chain requirement is contradicted by the high affinity binding of T-00127-HEV2, a steroidal compound lacking the side chain. The binding results, in combination with docking studies using homology models of OSBP and ORP4, suggest multiple modes of steroidal ligand binding to OSBP and ORP4.

Detection of epidermal growth factor receptor mRNA in peripheral blood: a new marker of circulating neoplastic cells in bladder cancer patients.

Despite the large number of studies performed in solid tumors, few attempts at molecular detection of urothelial cells in blood have been made. Specifically, only uroplakin II (UP-II) and cytokeratin 20 (CK-20) have been suggested as tumor markers in the blood of bladder cancer patients. Epidermal growth factor receptor (EGFR) mRNA expression was found in the blood of patients with some types of carcinoma; nevertheless, its expression has been never investigated in the blood of patients with urothelial tumors. We used a EGFR-based reverse transcription-PCR assay for the detection of tumoral cells in the blood of 27 patients with bladder cancer, in 30 healthy donors, and in 9 patients with cystitis. EGFR expression was compared with that of known markers of circulating epithelial cells, CK-19 and CK-20, and to a urothelial-specific marker, UP-II. Analysis by reverse transcription-PCR and Southern blot hybridization showed no evidence of EGFR and UP-II mRNA expression in any of the samples used as controls. Analysis of healthy donors showed mRNA expression for CK-19 and CK-20 in 6 of 30 and in 4 of 30 samples, respectively. All patients with cystitis resulted negative for EGFR expression, whereas 3 of 9, 2 of 9, and 3 of 9 were found expressing CK-19, CK-20, and UP-II, respectively. Among blood samples from tumoral patients, 74% had EGFR mRNA and 41% had positive signals for CK-19, whereas positivity for CK-20 and UP-II was found in 15% and 37% of patients, respectively. These results seem to indicate that EGFR mRNA in the blood may be a useful tumor marker in bladder cancer patients, as well as in other patients with epithelial tumors.

The use of colony stimulating factors in elderly patients with cancer.

Hematological toxicity is the most common and the most frequent fatal complication of chemotherapy. It is observed with increased frequency with age, it is a significant independent predictor of the development of febrile neutropenia, and may contribute to a reluctance to administer chemotherapy in the elderly patient population. The authors analyze published data on effectiveness and results of the use of colony stimulating factors for preventing and treating elderly patients affected by tumors during chemotherapy.

The unexpected contribution of immunosenescence to the leveling off of cancer incidence and mortality in the oldest old.

In this paper the hypothesis that some features of immunosenescence might impact on the levelling off of cancer incidence and mortality in the oldest old will be considered. In fact, the term immunosenescence suggests that a progressive loss of immune system (IS) function occurs with aging. However, the age-related modifications of the IS can be more properly acknowledged as a 'remodeling' characterized by profound structural changes, which modify the functional properties of IS. We suggest that the expansion with age of natural killer cells (NK) and of T cells which progressively acquire phenotypes intermediate between T lymphocytes and NK cells, together with the age-related changes in the production of inflammatory/anti-inflammatory cytokines, such as INFgamma and IL-4, might create an environment unfavorable for neoplastic growth in the oldest old. In this perspective, studies on immunosenescence likely provide insights on mechanisms responsible for the individual capacity to escape from the life-threatening consequences of cancer outgrowth.

Geriatric oncology: a clinical approach to the older patient with cancer.

Due to the ageing of the population and the sharp increase in life expectancy, cancer in the older person has become an increasingly common problem in the Western world. Although several authors have stressed that elderly cancer patients deserve special attention as a target group for research efforts, older aged patients are still less likely to be offered participation in clinical trials. The cellular and molecular mechanisms regulating the physiological process of ageing and senescence are far from understood, although inflammation is likely to play an important role, at least in some cancers. In addition, the relationship between ageing and cancer risk is also far from understood. One of the most intriguing aspects of ageing is how different the ageing process is from person to person; the basis for this variation is largely unknown. Population-based studies and longitudinal surveys have shown that comorbidity and physical and mental functioning are important risk factors; thus, a meaningful assessment of comorbidity and disability should be implemented in clinical practice. Modern geriatrics is targeted towards patients with multiple problems. Such patients are not simply old, but are geriatric patients because of interacting psychosocial and physical problems. As a consequence, the health status of old persons cannot be evaluated by merely describing the single disease, and/or by measuring the response, or survival after treatment. Conversely, it is necessary to conduct a more comprehensive investigation of the 'functional status' of the aged person. A geriatric consultation provides a variety of relevant information and enables the healthcare team to manage the complexity of health care in the elderly; this process is referred to as the Comprehensive Geriatric Assessment (CGA). The use of CGA is now being introduced into oncological practice. The definition of frailty is still controversial and represents a major issue of debate in clinical geriatrics. As the frail population increases, clinical trials in frail persons are needed. The usefulness of these trials requires a consensus as to the definition of frailty. Clearly, the management of older persons with cancer requires the acquisition of special skills in the evaluation of the older person and in the recognition and management of emergencies as well as experience in geriatric case management.

Epidemiological aspects of cutaneous malignant melanoma (review).

There is an increasing interest in the etiology of cutaneous malignant melanoma (CMM). Once considered a rare tumour, CMM is now the fourth commonest cancer in Australia and New Zeland, the tenth in the Usa, Canada and Scandinavia and the eighteenth in Great Britain. The growing scientific concern on the urgent need to highlight the cause/s of CMM is well documented by the large number of well-designed and well-conducted epidemiological studies reported in the last two decades. Such studies facilitated testing of many etiological hypotheses derived from earlier descriptive investigations and contributed to significant progress in understanding the etiology of such disease. The quantification of the extent to which the increases in CMM incidence and mortality rates are related to new lifestyles and to new patterns of exposure to potential carcinogenetic agents is essential in order to establish an appropriate preventive strategy. In population of mainly European origin a substantial proportion of the increased incidence of CMM is attributable to steady change from predominantly occupational to predominantly recreational exposure to solar radiation. Therefore the present review puts particular emphasis on exposure to sunlight as well as to artificial ultraviolet light, as modifiable causes of CMM. Incidence and mortality data and other potential risk factors for the development of CMM will also be briefly reviewed.

In vivo study of a technetium labelled anti-EGFr MoAB.

Epithelial Growth Factor receptors (EGFr) are normally present in all the epithelial cells, but their overexpression is closely related to presence of cancer. We have raised EGF-competitive antibody against EGFr and have labelled it with 131I and technetium. The ability of this antibody to bind to A431 cells to be internalized has been tested on A431 cells cultures. Its ability to give scintigraphic images of epithelial tumors has been tested on nu/nu balb c mice xenografted with A431 cells. The labelled antibody is well internalized by cultured cells. Xenografted tumors are clearly imaged both by 131I and 99mTc anti EGFr Mo/Ab. 99mTc labelling is very interesting. The tumor/background ratio was 0.72 +/- 0.2 for 99mTc and 0.40 +/- 0.6 for 131I labelling. Moreover very high uptake of 99mTc MoAb was obtained 2 hours after injection whereas the 131I antibody required 24 hours.

Effect of aerobic training on the cognitive performance of elderly patients with senile dementia of Alzheimer type.

The importance of physical activity to maintain a healthy psychological functions is widely known. The present study involved 15 males affected by senile dementia of Alzheimer type (SDAT) and assessed their functional capabilities by means of the following neuropsychological tests: test of attentional matrix, verbal span test, supraverbal span test, mini mental state examination. After an exercise training program of 3 months, patients were assessed again by the same psychological tests which demonstrated a significant improvement.

Influence of obesity on cardiac mass and blood pressure in the elderly.

Obesity is a physical condition, related to abnormalities of glucose and insulin metabolism; it plays a substantial role in development of cardiovascular disease. The aim of this study was to establish the correlations among cardiac mass determined by echography according to the PENN Convention criteria (Devereux Index), blood pressure measured by ambulatory blood pressure monitoring (ABPM), and anthropometric indexes such as body mass index (BMI) and local adipose tissue distribution expressed as the waist to hip ratio (WHR). Two groups of subjects were selected, matched for age (67 +/- 2.5 years): 10 obese subjects with BMI = 34.5 +/- 2.8 and WHR = 1.02 +/- 0.004; and 10 non-obese subjects with BMI = 26.8 +/- 2.1 and WHR = 0.088 +/- 0.003. Statistical analysis was carried out by the Mann-Whitney U-Test, and linear regression analysis. The statistical analysis revealed a higher mean blood pressure (MBP) in the nonobese group (138.5 +/- 16.9 / 82.2 +/- 5.09 mmHg) compared to the obese subjects (131 +/- 15.3 / 84.29 +/- 11.72 mmHg), the difference was not significant (p > 0.05). Nevertheless, a significant difference was found in the left ventricular mass (LVM) and the LVM index (LVMI) of the two groups (p < 0.005) as follows: LVM(norm) = 224.55 +/- 50.59; LVM(ob) = 295.02 +/- 43.54; LVMI(norm) = 127.56 +/- 18.58; LVMI(ob) = 172.48 +/- 15.44. These results represent an evidence showing that obesity and blood pressure are two independent risk factors in the determination of the ventricular cardiac mass.

Dipyridamole technetium-99m Sestamibi imaging in the diagnosis of syndrome X.

In a middle-aged woman with anginal chest pain and a normal-appearing angiogram, dypiridamole technetium-99m Sestamibi scintigraphy, a noninvasive method, provided the diagnosis of syndrome X and was used in follow-up to monitor the course of disease.

Role of aging in malnutrition and in restitution of nutritional parameters by tube feeding.

Aging and malnutrition are connected by social and pathological factors; many studies show that 60-80% of hospitalized elderly patients are malnourished. The aim of this study was to establish a correlation between age and nutritional parameters in malnourished, hospitalized, elderly patients before and after restitution by tube feeding (using Clintec chemicals) for 45 days, with a mean caloric contribution of 2670 +/- 235 Kcal/day. Twenty-three patients were examined, matched for age (80.59 + 8.35 years) and sex (11 females and 12 males). Patients affected by malignant, chronic or acute diseases that could directly increase cytokine production (TNF-alpha, IL-1, etc.) were excluded. Anthropometric measurements were carried out always by the same operator using a fiberglass tape measure and a Harpenden skinfold caliper. Statistical analysis was carried out by ANOVA test and linear regression analysis. The main observations before and after tube feeding were the following: (i) Significant increases were found in serum albumin, triglyceride and cholesterol levels, whereas slightly increasing tendencies occurred, without reaching statistical significance, in serum transferrin levels, in triceps skinfold (TSF) and mid arm muscle circumference (MAMC) values. In malnourished patients close correlations were found between the age and serum albumin (r = 0.486; p = 0.022), as well as between age and MAMC (r = 0.576; p = 0.005), however, these correlations disappeared after tube feeding. These data show that age itself does not represent an important impediment for nutritional restitution; the possibilities of the latter appear to be dependent on the self-sufficiency and cognitive faculty of the patient, as measured by the activity of daily living (ADL), instrumental activity of daily living (IADL) and mini mental state evaluation (MMSE) scores (p < 0.005).

[Role of rectal exploration, suprapubic and transrectal prostatic ultrasonography, and PSA in the diagnosis and follow-up of prostatic carcinoma]. / Il ruolo dell'esplorazione rettale, dell'ecografia prostatica sovrapubica e transrettale e del PSA nella diagnosi e follow-up del carcinoma prostatico.

BACKGROUND AND AIM: The aim of this study was to evaluate the advantages and limits of the various examinations, namely rectal exploration, suprapubic and transrectal scan and PSA, used in the diagnosis and follow-up of prostatic carcinoma. METHODS: The study was carried out in 21 cases of histologically confirmed prostatic carcinoma in patients aged between 57 and 82 years old (mean age: 69.5) referred to the authors' attention between January 1990 and August 1993. RESULTS: With regard to the diagnosis, rectal exploration showed a sensitivity of 80.9%, suprapubic scan 95.2%, transrectal scan and PSA 100%. During the follow-up, patients were divided into operated (9) and non-operated (12) groups. Of the 9 patients undergoing radical prostatectomy, 5 showed residual locoregional disease; of the other 4 who had undergone a complete removal of the gland, one subsequently reported local recidivation. In those patients with residual disease, rectal exploration showed a postoperative sensitivity of 20%, nil sensitivity in the case of local recidivation and 100% specificity in successfully operated patients. Suprapubic scan showed a sensitivity of 60% in patients with residual disease, nil sensitivity in the case of local recidivation and 100% specificity in successfully operated patients. Transrectal scan and PSA revealed 100% sensitivity and specificity in all cases. These patients who were not operated owing to the presence of metastases at the time of diagnosis were divided into those who responded to hormone and chemotherapy (3 total responses, 6 partial responses) and patients who did not respond to this type of treatment (3 non-responders). In the cases of total response, all the tests used obtained 100% specificity. Serum levels of PSA were higher than the threshold value owing to the persistence of metastases. In the cases of partial response to treatment, rectal exploration revealed 50% sensitivity, suprapubic scan 83%, and transrectal scan and PSA 100%. Sensitivity to the four methods used was 100% in all non-responders. CONCLUSIONS: From the results obtained it can be affirmed that the diagnosis of prostate pathology should start with rectal exploration and in the event that this method suggests the probable benignity of the lesion, the diagnostic process should conclude with a suprapubic scan. If rectal examination or suprapubic scan reveal a suspected malignancy, it is essential to perform a transrectal scan or PSA assay which has a high level of sensitivity and specificity for values over 10 ng/ml. During follow-up the only tests which show a high level of sensitivity are transrectal scan and PSA, whereas suprapubic scan and rectal exploration are not reliable in view of the high percentage of false negatives observed. The follow-up of those patients who were not operated and responded totally or partially to treatment must be carried out exclusively using transrectal scan and PSA assay. Suprapubic scan enables the evolution of the neoplasia to be followed over time in those patients who did not respond to treatment.

Preliminary evaluation of the usefulness of Tc-99m (V) DMSA in pancreatic neuroendocrine tumors.

The authors describe the possible application of Tc-99m (V) DMSA scintigraphy in pancreatic neuroendocrine tumors. In consideration of the common embryonic origin of these tumors and other neoplastic diseases (medullary thyroid carcinoma, pheocromocytoma, neuroblastoma) that have been well studied with radionuclide imaging, five cases of pancreatic neuroendocrine tumors (two insulinomas, one vipoma, and two unclassified neuroendocrine tumors) were successfully visualized with Tc-99m (V) DMSA scintigraphy, thus giving an overall "imaging confirmation" of the histologic and/or cytologic results in terms of primary and metastatic localization. The authors point out the importance of their results, obtained in a simple and repeatable manner, and suggest a real comparison in this setting between this approach and octreotide scintigraphy.

Cancer stem cells and epithelial-mesenchymal transition: revisiting minimal residual disease.

The cancer stem cell (CSC) hypothesis provides an attractive model of tumour development and progression, holding that solid tumours are hierarchically organized and sustained by a minority of the tumour cell population with stem cell properties, such as self-renewal, tumorigenicity and multilineage differentiation capacity. Therapeutic resistance, underlying tumour recurrence and the lack of curative treatments in metastatic disease, raise the question if conventional anticancer therapies target the right cells. Indeed, these treatments might miss CSCs, which represent a more chemoresistant and radioresistant subpopulation within cancer. Recently, a direct link between the epithelial-mesenchymal transition process and the gain of stem cell competence were demonstrated in cultured breast cells. In particular, it was shown that the induction of EMT program not only allow cancer cells to disseminate from the primary tumor, but also promotes their self-renewal capability. Furthermore, the expression of stemness and EMT markers in CTCs were associated with resistance to conventional anti-cancer therapies and treatment failure, highlighting the urgency of improving tools for detecting and eliminating minimal residual disease.

Circulating tumor cells in cancer therapy: are we off target?

What clinical oncologists learned about metastatic process, is that it is the main cause of cancer-related deaths. What scientists learned about metastatic disease, is that it is due to a highly selective process, which involves a minority of tumor cells that are able to survive within the bloodstream, and to initiate a new growth in distant sites. These cells "in transit" are known as circulating tumor cells (CTCs). Although their nature is not fully understood, what is widely accepted, is that they are drug resistant, and that their presence may represent the main reason for treatment failure. Despite this body of evidence, the pharmacological approach against cancer, with both chemotherapic and biological drugs, is still targeted on the primary tumor, raising the question as to whether we are missing the target. Targeting circulating tumor cells, may represent a new promising approach to indivisualize anticancer therapy.

Prevalence of pain in elderly hospitalized patients.

Several studies indicate that pain, although very common in the elderly, is under-treated, because it is considered as a concomitant effect of aging. This study aimed to evaluate the prevalence of pain among patients in eight Italian geriatric hospital departments, correlated to prescribed therapy. We enrolled 387 patients in the study, 367 of whom were evaluated. Each patient's recovery, co-morbidity, pain intensity, prescribed therapy, side effects, duration of pain, and efficacy of therapy were monitored during two 15-day periods from 15 July to end of August 2008, and from 1 October to 15 November 2008. The results of this study confirmed that hypertension, cardiopathic disease, diabetes, and chronic obstructive pulmonary disease (COPD) are common pathologies, and that pain is present in 67.3% of those recovered in geriatric departments. In general, however, pain is not treated. Indeed only 49% of those with pain had any type of treatment, which was adequate for the pain intensity. In fact 74.5% of patients considered the therapy to be of low or no efficacy. These data demonstrate the presence of pain in a high percentage of elderly patients, which is either not treated, or treated inadequately. Controlling pain is essential in elderly patients in order to allow a normal life and an active role in family and society. The main conclusion is that pain is often poorly considered in the elderly, thus leading to a dangerous under-treatment. We want to underline the crucial clinical impact of such under-treatment in elderly patients.