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.

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.

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.

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.

Duloxetine in the management of elderly patients with major depressive disorder: an analysis of published data.

BACKGROUND: Major depressive disorder (MDD) is a common condition in the elderly that is frequently associated with disability and cognitive impairment. Duloxetine is an antidepressant medication that inhibits both 5-HT and NE reuptake. OBJECTIVE: The objective of this review is to summarize the available know-how on the use of duloxetine in elderly population. METHODS: An extensive literature search was performed in Medline and Embase. Peer-reviewed articles only were included in this review. RESULTS: A total of four articles meeting search criteria were identified in the Medline and Embase databases. In the short-term controlled studies, treatment with duloxetine was associated with significantly greater improvement in cognitive function, depression and health state compared with placebo, as well as in rate of patients achieving response or remission. Overall pain and back pain also improved in patients receiving duloxetine. The long-term open-label data showed that the significant improvements of HAM-D-17 score and of both clinician-(CGI-S) and patient-(PGI-I) rated health state were rapid and sustained up to week 52. Observed case response and remission rates at end point were 89.4% and 72.3% respectively. Duloxetine was effective in patients who did not respond or tolerate previous treatment with escitalopram. Nausea and dry mouth were the most common events. The safety results in the long-term study, in which duloxetine was given at the upper dose limit, showed that most events occurred early in the study and that rates of events in patients aged >or= 65 years were not greater than those in the younger cohort. CONCLUSIONS: Duloxetine given in elderly patients with MDD provides rapid and sustained antidepressant efficacy and seems to be as safe as in younger patients.

Celecoxib upregulates multidrug resistance proteins in colon cancer: lack of synergy with standard chemotherapy.

Recent phase II randomised trials in colorectal cancer failed to demonstrate any advantage of celecoxib combined with standard chemotherapy; some authors even reported that the addition of celecoxib to irinotecan and oxaliplatin in colon cancer results in an inferior response rate. This observation leads to the hypothesis that there are pharmacokinetic interactions between celecoxib and chemotherapeutic drugs. The aim of the study was to investigate the induction by celecoxib of some multidrug resistance proteins, MRP1, MRP2, MRP4 and MRP5, involved in the transport of irinotecan and 5-FU. WiDr and COLO-205 cells were treated with celecoxib at a clinically relevant concentration. A viability assay was performed by treating cells with chemotherapy alone and chemotherapy plus celecoxib. The expression of MRP1, MRP2, MRP4 and MRP5 was analysed by RT-PCR and Western blot analysis. The sub cellular localization of MRP4 and MRP5 was investigated by cryoimmunoelectron microscopy. In both cell lines celecoxib induced MRP4 and MRP5 over-expression at RNA and protein levels. No induction of MRP1 and MRP2 was observed in treated cells compared to controls. Cryoimmunoelectron microscopy showed increased MRP4 and MRP5 immunolabeling in celecoxib treated cells both at cytoplasmic level and along the plasma membrane. Our findings suggest that the low response rate observed in clinical trials using celecoxib added to 5-fluorouracil and irinotecan may reflect celecoxib-mediated extrusion of chemotherapeutic drugs from cancer cells through the up regulation of ATP-binding cassette proteins. Our findings, together with the results of clinical trials, may suggest that the combined use of celecoxib and drugs that are substrate for MRP4/MRP5 should be avoided.

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.

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.

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.

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.

ErbB2 immune response in breast cancer patients with soluble receptor ectodomain.

Investigation of ErbB2 immunity in human breast cancer employing recombinant expression sources in immunoblot analysis revealed ErbB2-specific antibodies of the IgG isotype in sera of 14 of 71 cancer patients and 1 of 31 normal donors. Reactivity was confirmed on ErbB2-specific immunoprecipitates. Independent evidence of existing ErbB2 immunity was obtained after in vitro transformation of peripheral blood leukocytes from six positive patients. Furthermore, in vitro immortalization of B-lymphocytes unmasked existent ErbB2 immunity in 1 of 8 patients negative for ErbB2 serum antibodies. Determining shed ErbB2 extracellular domain as an indirect measure of tumor burden in ErbB2-positive malignancy, elevated serum levels were observed in 16 of 71 breast cancer and 1 of 31 normal donor sera. Strikingly, existing ErbB2 immunity correlated significantly with elevated shed ErbB2 ectodomain among the patients analyzed. Incidence of both ErbB2 immunity and elevated ErbB2 extracellular domain increased with a progressed disease stage and was significantly associated with metastatic breast cancer. These observations implicate soluble ErbB2 amounts in vivo in the development of ErbB2 immunity in breast cancer. They further project serum analysis of ErbB2 immunity and soluble ectodomain as potential markers of disease progression in ErbB2-positive malignancy.

A neural network study of the correlation between metabolic-cardiovascular diseases and disability in elderly people.

Numerous studies have affirmed the existence of a correlation between various cardiovascular diseases and functional decline in elderly people. Not much information, however, is available concerning the overall effect of various, possibly coexisting, cardiovascular pathologies, or metabolic conditions notoriously related to them, on determining disability. We wanted to verify if it were possible to assess: (1) The overall importance of various metabolic and cardiovascular diseases which elderly people often suffer from contemporaneously in determining a condition of not self-sufficiency; (2) The possibility of predicting a condition of not self-sufficiency in relation to the above-mentioned pathologies. In order to achieve this aim, we used an artificial neural network: a statistical-mathematical tool able to determine the existence of a correlation between series of data and, once 'trained', to predict output data given the input data. Although artificial neural networks have been applied in various areas of medical research, they have not been previously applied in geriatrics. We have applied this method to a sample of 179 elderly people, demonstrating that seven clinical-biological variables concerning their metabolic and cardiovascular conditions are strictly related, all together, to the presence or otherwise of a functional impairment. When tested on a sample of 20 'unknown' elderly people, the trained network gave the correct answer-self-sufficiency or not self-sufficiency-in 95% of the cases. Despite the fact that the sample studied was relatively small, artificial neural networks are undoubtedly useful in predicting functional impairment in elderly people in relation to the presence of metabolic and cardiovascular diseases.

[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.

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.

Role of 99mTc-Sestamibi scintimammography by SPEM camera in the management of breast cancer in the elderly.

The incidence of breast cancer in the elderly is 10 fold higher than in the population younger than 65 years. Moreover, in this segment of the population there are not defined clear practice guidelines regarding patient management. X-ray mammography, the most widely used diagnostic technique, is often inadequate to differentiate benign from malignant lesions. 99mTc Sestamibi scintimammography plays an important role as complement to mammography; in fact it is a very sensitive and specific method for breast cancer detection, when cancers > 1 cm diameter are considered. However, sensitivity values fall to 50-60% in the case of small tumors (T1a and T1b). In this study we present the results of a new Small Field Of View (SFOV) Gamma Camera with very high spatial resolution that allows the first Single Photon Emission Mammography (SPEM). Eighteen patients aged 71 +/- 6 years with mammographically detected breast lesions were submitted to a Prone Scinti Mammography (PSM) by conventional Gamma Camera and to a SPEM on craniocaudal view. A final diagnosis was reached by histopathology. SPEM correctly diagnosed 15 of 16 cancers, while PSM was not able to recognize 5 malignant lesions with subcentimeter size. Both the techniques provided normal findings in the case of benign lesions. The 99mTc Sestamibi scintimammography, particularly when performed by SPEM camera, is a sensitive, specific, and non invasive method to define the nature of radiologically described breast masses and would be very useful as a complement to X-ray mammography in screening programs for breast cancer.

Performance status and comorbidity in elderly cancer patients compared with young patients with neoplasia and elderly patients without neoplastic conditions.

BACKGROUND: Elderly people constitute a heterogeneous group and are at an increased risk for the development of cancer. It is not clear whether comorbid conditions and functional status influence clinical decisions and the pattern of referral in elderly cancer patients. The current study investigated functional status measured by Eastern Cooperative Oncology Group performance status, comorbid conditions, and medication taken as well as social environment in three series of patients grouped according to age and diagnosis. METHODS: A total of 593 patients were involved: 138 neoplastic patients age > 70 years with breast, colon, or prostate carcinoma, 177 neoplastic patients age < 70 years with the same types of pathology, and 278 elderly patients with nonneoplastic conditions. Patients with neoplastic disease were recruited from cancer centers; patients with nonneoplastic disease were recruited from either geriatric or general medicine departments. Differences in the distribution of variables were analyzed by univariate and bivariate analyses. RESULTS: No significant differences in social environment, marital status, or education were observed. Statistical differences were noted when comparing the distribution of comorbidities, performance status, and medication taken, elderly neoplastic patients presented in poorer condition compared with younger patients but in better condition compared with elderly patients with nonneoplastic disease. CONCLUSIONS: The overall better health of older cancer patients compared with those without cancer needs to be assessed further. It is possible that cancer is more likely to be diagnosed in healthier elderly, or that primary care providers are reluctant to refer for cancer care patients in poor general health. Studies of comorbidity, function, and social resources are necessary to establish the impact of cancer on survival and quality of life of older patients and to determine the social resources necessary for adequate care.