Economic preferences in the health setting. Three case studies concerning the needs of breast cancer patients, pain management in oncology and extreme end-of-life decisions

The thesis describes three studies concerning the role of the Economic Preference set investigated in the Global Preference Survey (GPS) in the following cases: 1) the needs of women with breast cancer; 2) pain undertreament in oncology; 3) legal status of euthanasia and assisted suicide. The analyses, based on regression techniques, were always conducted on the basis of aggregate data and revealed in all cases a possible role of the Economic Preferences studied, also resisting the concomitant effect of the other covariates that were considered from time to time. Regarding individual studies, the related conclusion are: 1) Economic Preferences appear to play a role in influencing the needs of women with breast cancer, albeit of non-trivial interpretation, statistically "resisting" the concomitant effect of the other independent variables considered. However, these results should be considered preliminary and need further confirmation, possibly with prospective studies conducted at the level of the individual; 2) the results show a good degree of internal consistency with regard to pro-social GPS scores, since they are all found to be non-statistically significant and united, albeit only weakly in trend, by a negative correlation with the % of pain undertreated patients. Sharper, at least statistically, is the role of Patience and Willingness to Take Risk, although of more complex empirical interpretation. 3) the results seem to indicate an obvious role of Economic Preferences, however difficult to interpret empirically. Less evidence, at least on the inferential level, emerged, however, regarding variables that, based on common sense, should play an even more obvious role than Economic Preferences in orienting attitudes toward euthanasia and assisted suicide, namely Healthcare System, Legal Origin, and Kinship Tightness; striking, in particular, is the inability to prove a role for the dominant religious orientation even with a simple bivariate analysis.

Uremic Neuropathy: Epiemiological Study in Hemodialysis Patients

Background/Aims. Uremic Neuropathy (UN) highly limits the individual self-sufficiency causing near-continuous pain. An estimation of the actual UN prevalence among hemodialysis patients was the aim of the present work. Methods. We studied 225 prevalent dialysis patients from two Italian Centres. The Michigan Neuropathy Score Instrument (MNSI), already validated in diabetic neuropathy, was used for the diagnosis of UN. It consisted of a questionnaire (MNSI_Q) and a physical-clinical evaluation (MNSI_P). Patients without any disease possibly inducing secondary neuropathy and with MNSI score  3 have been diagnosed as affected by UN. Electroneurographic (ENG) lower limbs examination was performed in these patients to compare sensory conduction velocities (SCV) and sensory nerve action potentials (SNAP) with the MNSI results. Results. Thirtyseven patients (16.4%) were identified as being affected by UN, while 9 (4%) presented a score <3 in spite of neuropathic symptoms. In the 37 UN patients a significant correlation was found between MNSI_P and SCV (r2 = 0.1959; p<0.034) as well as SNAP (r2 = 0.3454; p=0.027) both measured by ENG. Conclusions. UN is an underestimated disease among the dialysis population even though it represents a huge problem in terms of pain and quality of life. MNSI could represent a valid and simple clinical-instrumental screening test for the early diagnosis of UN in view of an early therapeutic approach.

Biomedicine and pain

The focus of my research is on contemporary biomedical construction of pain as an object, i.e. the different ways in which pain has been conceptualized and approached as a specific site of investigation in biomedicine. A significant shift in the scientific conception of pain occured in the second half of XXth century. In 1965, Ronald Melzack and Patrick D. Wall propose the Gate Control theory of pain mechanism. This theory denies a fixed and direct relationship between stimulus and pain perception, and emphazises the role played by psychological factors in pain. The IASP utilizes this perspective on the phenomenon, describing pain as “an unpleasant sensory and emotional experience associated to an actual or potential tissue damage or described in the terms of such a damage.” The relationship between pain and damage is pivotal in the definition of pain as a pathological entity. In particular, the biomedical approach to pain appears to be strongly characterized by a dualistic view of its aetiology. Disease conceptions such as “psychogenic pain” and chronic pain are deeply influenced by the ways in which psychological factors have been interpreted as components, or as causes of pain. In the second part of my dissertation, I focus on fibromyalgia, which is emblematic of the problematic acknowledgment of chronic pain as a disease. Even if fibromyalgia is actually treated in Rheumatology, its status as a disease is blurred, mainly because of its complex symptomatology including both physiological manifestations and psychological ones. In the conclusion, I present a scenario of the different ways in which this disease is dealt with in biomedical knowledge, through medical literature, clinical practice, and patients’ accounts. The findings of an ethnographic enquiry in the Rheumatology Division of a local clinic and a visual research on patients’ experiences are analyzed and discussed.

Evaluation of Antitumoral activity of bone targeted drugs/conventional chemotherapies and identification of biomarkers for the selection of patients with breast cancer for the bone targeted therapy in adjuvant setting

Bone metastases are responsible for different clinical complications defined as skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, hypercalcaemia, bone marrow infiltration and severe bone pain requiring palliative radiotherapy. The general aim of these three years research period was to improve the management of patients with bone metastases through two different approaches of translational research. Firstly in vitro preclinical tests were conducted on breast cancer cells and on indirect co-colture of cancer cells and osteoclasts to evaluate bone targeted therapy singly and in combination with conventional chemotherapy. The study suggests that zoledronic acid has an antitumor activity in breast cancer cell lines. Its mechanism of action involves the decrease of RAS and RHO, as in osteoclasts. Repeated treatment enhances antitumor activity compared to non-repeated treatment. Furthermore the combination Zoledronic Acid + Cisplatin induced a high antitumoral activity in the two triple-negative lines MDA-MB-231 and BRC-230. The p21, pMAPK and m-TOR pathways were regulated by this combined treatment, particularly at lower Cisplatin doses. A co-colture system to test the activity of bone-targeted molecules on monocytes-breast conditioned by breast cancer cells was also developed. Another important criticism of the treatment of breast cancer patients, is the selection of patients who will benefit of bone targeted therapy in the adjuvant setting. A retrospective case-control study on breast cancer patients to find new predictive markers of bone metastases in the primary tumors was performed. Eight markers were evaluated and TFF1 and CXCR4 were found to discriminate between patients with relapse to bone respect to patients with no evidence of disease. In particular TFF1 was the most accurate marker reaching a sensitivity of 63% and a specificity of 79%. This marker could be a useful tool for clinicians to select patients who could benefit for bone targeted therapy in adjuvant setting.

Spatially defined peptidomimetics for pain relief and for targeted cancer therapy and diagnostics

Cancer is a disease that has plagued scientists for decades, and how to treat cancer and its complications are inevitable topics in current scientific research. Cancer pain is a major factor that reduces the quality of life of patients. Therefore, the development of analgesic agents with minimal adverse side effects, especially with low addiction, has attracted more and more attention. Among them, opioid analgesics are widely used to alleviate cancer pain and improve the quality of life of patients with advanced cancer, such as in the palliative therapy. Although peptide drugs are efficient, selective and safe, they have several unignorable disadvantages such as poor biological stability, rapid excretion, difficulty in penetrate blood brain barrier. In order to solve these problems, peptidomimetics were developed by introducing unnatural/modified amino acids, decorated peptide backbone, conformational restrictions and secondary structure mimics in peptide sequence. Compared with peptides, peptidomimetics have improved biological stability, increased bioavailability, high affinity and selectivity for receptor binding, and decreased adverse side effects. As the second part of this thesis, I explored the opportunity to design peptide-functionalized responsive biomaterials for the detection of cancer cell and the selective delivery of cytotoxic drugs. The conjugation of peptides with biomaterials enhanced the stability of the loaded drugs, improved targeted delivery, decreased side effects, and increased bioavailability. The precise and controllable drug delivery platform has profound application prospects in cancer treatment. Grafting specific peptides sequence on the surface of biomaterials can satisfy different drug delivery demands according to the characteristics of both peptides and biomaterials. For example, the introduction of tumor-targeting peptides can guide biomaterials into tumor lesions, and blood-brain barrier (BBB) shuttle peptides can lead biomaterials to penetrate the BBB, etc.

Psychological characterization of hypertensive patients: associations with adherence to pharmacological treatment and self-management

Introduction: The role of psychosocial factors in the onset and progression of essential hypertension has been object of a large body of literature, yet findings appear to be controversial. Aims: We assessed the predictive role of psychosomatic syndromes, affective symptomatology, psychological reactance, psychological distress, well-being and quality of life on adherence to antihypertensive medications, lifestyle behaviors, hypertension severity and absolute cardiovascular risk grading, as well as their temporal stability at 1-year follow-up, in a sample of hypertensive patients. In addition, we aimed to validate the Italian version of the Hong Psychological Reactance Scale (HPRS). Methods: Eighty consecutive hypertensive outpatients treated with antihypertensive medications were compared to 80 controls. Psychosocial variables were assessed using clinical interviews and self-rating questionnaires at baseline and at 1-year follow-up. Cardiac parameters were also collected. One-hundred and fifty individuals from general population provided data for the HPRS validation. Results: Hypertensive patients reported significantly higher levels of psychological distress and lower levels of psychological well-being at baseline compared to controls. Among hypertensive patients, allostatic overload (AO) was the most frequently reported psychosomatic syndrome at baseline. Patients with AO displayed significantly greater levels of psychological distress and lower levels of well-being and quality of life than those without. Further, patients with illness denial were significantly more likely to report poor adherence to pharmacological treatment and, as well as those with higher levels of affective symptomatology, were less likely to follow a balanced diet. At follow-up, patients displayed significantly higher levels of well-being and lower levels of stress, mental pain and quality of life. Conclusions: Findings suggest the clinical relevance of psychosocial factors and psychosomatic syndromes in the progression of hypertension, with important implications for its management. As to the Italian validation of the HPRS, results support previous findings, even though a confirmatory factor analysis should be carried out.

[In search of] Digital biomarkers for objective pain assessment

Pain is a highly complex phenomenon involving intricate neural systems, whose interactions with other physiological mechanisms are not fully understood. Standard pain assessment methods, relying on verbal communication, often fail to provide reliable and accurate information, which poses a critical challenge in the clinical context. In the era of ubiquitous and inexpensive physiological monitoring, coupled with the advancement of artificial intelligence, these new tools appear as the natural candidates to be tested to address such a challenge. This thesis aims to conduct experimental research to develop digital biomarkers for pain assessment. After providing an overview of the state-of-the-art regarding pain neurophysiology and assessment tools, methods for appropriately conditioning physiological signals and controlling confounding factors are presented. The thesis focuses on three different pain conditions: cancer pain, chronic low back pain, and pain experienced by patients undergoing neurorehabilitation. The approach presented in this thesis has shown promise, but further studies are needed to confirm and strengthen these results. Prior to developing any models, a preliminary signal quality check is essential, along with the inclusion of personal and health information in the models to limit their confounding effects. A multimodal approach is preferred for better performance, although unimodal analysis has revealed interesting aspects of the pain experience. This approach can enrich the routine clinical pain assessment procedure by enabling pain to be monitored when and where it is actually experienced, and without the involvement of explicit communication,. This would improve the characterization of the pain experience, aid in antalgic therapy personalization, and bring timely relief, with the ultimate goal of improving the quality of life of patients suffering from pain.