Improved Survival and Quality of Life Through an Integrative, Multidisciplinary Oncological Approach: Pathophysiological Analysis of Four Clinical Cancer Cases and Review of the Literature.

Objectives: According to the National Cancer Institute, the integrative medicine (IM) approach to medical care combines standard medicine with complementary and alternative medicine practices that have proved safe and effective. Methods: We describe the clinical cases of four patients with malignant pleural mesothelioma (MPM), diffuse malignant peritoneal mesothelioma (DMPM), intrahepatic cholangiocarcinoma, and breast cancer (BC) who received supportive treatment (ST) according to an IM approach after the failure of standard cancer treatments or the appearance of serious adverse events caused by antiblastic chemotherapy. The critical role of complementary drugs in reducing the side effects of cancer treatments and normalizing the white cell count is especially apparent in the case of the patient with metastatic BC, who experienced prolonged neutropenia. Results: The IM approach was well-tolerated and had no adverse side effects. It improved the quality of life (QoL) of all patients and in two cases extended overall survival. Conclusion: The extended clinical and instrumental response to IM of the patients with malignant mesothelioma and the improved health-related QoL and good tolerance of the ST demonstrated in all cases support the value of this approach in patients whose cancer therapies have failed but who show a good performance status. Our data require confirmation in a well-designed prospective clinical trial.

The Easy Thing (ET) observational study: evaluation of adherence to Mediterranean diet and role of a program of nutritional intervention performed by North Naples 2 Local Health Unit.

OBJECTIVE: The present observational study has the aim to describe the nutritional habits and adherence to Mediterranean diet within a dietary intervention performed by North Naples 2 Local Health Unit in some areas of Campania region. PATIENTS AND METHODS: A semi-quantitative food frequency questionnaire which takes in consideration several kinds of food and the related daily or weekly portions has been administered to people evaluated in the study. An increased score reflects an increased adherence to Mediterranean diet. Patients have been grouped by age, body mass index, education, socio-economic level, income, and score reported to the administered survey. Nutritional intervention has also been evaluated as concerns weight reduction during time. RESULTS: Surveys were administered to 200 patients aged from 12 to 79 years from 21 November 2018 to 27 November 2019. Obese patients were 61.5% in this population. 67.7% of obese people participating to this study had primary/lower secondary school education. 61.5% of study population have been categorized as having a low or low-medium socio-economic level and 68% of them were obese. An intermediate adherence to Mediterranean Diet has been the most represented (76.5%), a significant difference has been found among the groups normal weight, overweight and obese for the variables age, education and income. Obese patients in the present study had metabolic diseases more frequently than normal-weight patients. CONCLUSIONS: A high rate of obese people requesting nutritional counseling showed intermediate/bad adherence to Mediterranean Diet, reflecting the diffuse change from Mediterranean Diet to Western habits in nutrition. The nutritional intervention was found to be effective, especially for overweight patients. These data underline the need for further larger epidemiological analysis and public health interventions.

Preliminary results of phase II study of capecitabine and gemcitabine (CAP-GEM) in patients with metastatic pretreated thymic epithelial tumors (TETs).

BACKGROUND: No previous prospective trials have been reported with capecitabine and gemcitabine (CAP-GEM) in patients with metastatic thymic epithelial tumors (TETs). We conducted a multicenter study to determine the activity and tolerability of this regimen in pretreated TETs. PATIENTS AND METHODS: A total of 15 patients were enrolled in the first stage of phase II study. All patients received CAP-GEM every 3 weeks. The primary end point was objective response rate (RR); secondary end points were toxicity, progression-free survival (PFS) and overall survival. RESULTS: Complete responses (CR) and partial responses were observed in three (20%) and three (20%) patients for a 40% RR, respectively. Grade 1-2 neutropenia, anemia and thrombocytopenia were the most common side-effects, noted in seven (46.7%), five (33.3%) and five (33.3%) patients, respectively. The most common grade 3 toxicity was neutropenia in three patients (20%). Median PFS was 11 months (95% confidence interval 4-17). The 1- and 2-year survival rates were 80% and 67%, respectively. CONCLUSION: We have decided to publish the preliminary results because this regimen was more active than that expected. Although our results are preliminary, CAP-GEM shows activity and safety in pretreated TETs. Furthermore, multicenter trials, also in first-line setting, are necessary to confirm our results.

Thymoma-associated immunodeficiency: a syndrome characterized by severe alterations in NK, T and B-cells and progressive increase in naïve CD8+ T Cells.

Thymomas are rare tumours that sustain T-lymphopoiesis and trigger a variety of autoimmune diseases and immunodeficiencies, including a fatal hypogammaglobulinemia, namely Goods Syndrome (GS). Due to its rarity, GS has been poorly investigated and immunological features, as well as pathogenetic mechanisms underlying this syndrome, are unclear. We studied 30 thymoma patients by performing an immunological assessment, including immunophenotype and analysis of T cell repertoire (TCR). Development of GS was characterized by a progressive decrease in B, CD4 T and NK lymphocytes. These alterations paired with accumulation of CD8+CD45RA+ T cells that showed a polyclonal repertoire without expansions of specific clonotypes. GS is defined as hypogammaglobulinemia with thymoma. Here, we show for the first time that this syndrome is characterized by a severe loss of CD4+, NK and B cells. Furthermore, the accumulation of CD8+CD45RA+ T lymphocytes parallels these changes; this accumulation may have a role in determining the disease and can be used to monitor clinical stages of immunodeficiency in thymoma.

Once-per-cycle pegfilgrastim in breast cancer patients treated with docetaxel/epidoxorubicin/cyclophosphamide.

The incidence of neutropenia following combination chemotherapy is significant in breast cancer and impairs patients' quality of life. Colony-stimulating factors significantly decrease the risk of febrile neutropenia (FN). Aim of the present study was to assess the efficacy and safety profile of once-per-cycle pegfilgrastim in reducing FN in breast cancer patients treated with docetaxel (75 mg/m(2)), epidoxorubicin (75 mg/m(2)), cyclophosphamide (500 mg/m(2)) administered every 3 weeks. Thirty-five breast cancer patients were enrolled. Chemotherapy was administered in adjuvant, neoadjuvant and metastatic setting respectively in 26, 4 and 5 patients. Toxicity was monitored with programmed clinical evaluation and blood sampling. All patients completed the therapeutic programme consisting of six cycles for overall 210 cycles. The FN appeared in 6 out of 35 patients (17%), requiring dose reduction in 3 patients. Hypertransaminasemia was registered in two patients. In one patient pegfilgrastim administration was stopped because of skin hypersensitivity reaction. In conclusion, pegfilgrastim was able to maintain doses and timing of docetaxel/epidoxorubicin/cyclophosphamide in almost all breast cancer patients treated in this series. The reduced need for daily administration of colony-stimulating factors, blood sampling, antibiotic therapy and hospitalization has a significant impact in terms of both quality of life and pharmaco-economic evaluations.

Vascular endothelial growth factor monitoring in advanced hepatocellular carcinoma patients treated with radiofrequency ablation plus octreotide: a single center experience.

Local therapies such as radiofrequency ablation (RFA) represent a valuable choice in limited hepatocellular carcinoma (HCC) and are increasingly used also in advanced tumors. Medical treatments generally gave frustrating results in advanced HCC especially if comorbidities exist. Several biologic non-chemotherapeutic drugs are currently tested in HCC and, among them, octreotide was evaluated in single series of HCC patients reporting conflicting results. We have treated a series of 35 patients affected by advanced HCC (26 M and 9 F; age range: 55-85 years, median: 73 years) with RFA followed by octreotide to primarily evaluate the safety of combined treatment and to give preliminary evaluation on its activity. We have also evaluated serum VEGF changes during the study. Child A and Child B represented 60% and about 34% of the cases, respectively. Only two patients with Child C compensated cirrhosis were included in this study. All patients have multiple liver HCC nodules and one had bone metastases. Two complete responses, 3 partial responses and 23 disease stabilization for at least three months were obtained (overall response rate, 14,2%; clinical benefit, 80%). Mean overall survival was 31.4 months. The combined treatment was well tolerated. Statistically significant correlation was found between serum VEGF and tumor progression. In conclusion, the combination of RFA and octreotide was active in advanced HCC, however, confirmation in a larger series is required.

Mediastinal images resembling thymus following 131-I treatment for thyroid cancer.

The follow-up of Differentiated Thyroid Cancer conventionally includes serum thyroglobulin and periodic Whole Body Scans. The uptake of 131-I in normal and pathological tissues different from metastatic thyroid cancer sites is a cause of false-positive scans. Among them, mediastinal uptake caused by thymic hyperplasia can be observed. The aim of the present study was to review a series of 573 patients with differentiated thyroid cancer treated with 131-I after surgery between 1992 and 2003 looking above all for those with mediastinal images resembling thymus. This evaluation is presented together with some hypotheses on the relationships between thymus and thyroid. Moreover, some considerations are made on the differential diagnosis between thymus and mediastinal tumour thyroid residues.

Interferon alpha-2b at low doses as long-term antiangiogenic treatment of a metastatic intracranial hemangioendothelioma: a case report.

We describe a case of intracranial haemangioendothelioma in a 20-year old female patient who presented severe neurological symptoms and relapsed after two surgical interventions. The patient was treated with low doses of recombinant interferon alpha-2b (1 MUI three times a week) after surgical resection which led to recovery of daily function and work activity. To our knowledge, this is the ninth patient reported with intracranial hemangioendothelioma, but the only one having diffuse and painful bone metastases resolved by treatment with interferon. After 30 months the patient is free from symptoms and recurrence. The effectiveness shown by recombinant interferon alpha-2b against vascular neoplasms prompted us to look for the possible biological basis of such a property.

[Thymoma and somatostatin analogs. Biology, diagnostic and clinical practice]. / Timomi e analoghi della somatostatina. Biologia, diagnostica e clinica.

Thymic tumours are rare neoplasms which generally follow a slow pattern of growth, showing their aggressiveness locally through the infiltration of adjacent organs and they rarely metastasise hematogenically. In the presence of locally advanced, metastatic or inoperable disease, combined strategies including chemotherapy, radiotherapy and surgery are now being evaluated. Scintigraphy with 111In DTPA-D-Phe 1 octreotide was used for the first time in a relevant series of patients with thymic tumour (13 cases) by our research group. The presence of somatostatin receptors (ss-R) assayed in vivo provided the rationale for the use of a treatment based on the octreotide analog in a patient with thymoma and aplasia of the erythroid series (pure red cell aplasia, PRCA) in whom a complete response for the tumour and the remission of anemia was obtained. The efficacy of this treatment was confirmed by our series of patients with chemoresistant thymic tumour and by national and international confirmations. These data, ranging from in vivo diagnosis to treatment and the in vitro study of receptor expression, confirm that somatostatin plays a major role in thymic tumours.

Prevalence, age distribution and aetiology of bronchiectasis: a retrospective study on 144 symptomatic patients.

The incidence of bronchiectasis (BCT) has probably decreased in developed countries in recent years, but reliable statistical data on its occurrence are still lacking. The aim of the present study was to retrospectively evaluate the prevalence, age distribution and aetiology of BCT, diagnosed in a selected series of symptomatic patients of a Western country by using bronchography. The authors analysed the main known predisposing and associated conditions (PACs), and the occurrence and age distribution of BCT in 144 consecutive patients who underwent bronchological examination (fibreoptic bronchoscopy and bronchography) in the years 1987-1994 because of recurrent purulent bronchitis and/or haemoptysis. The overall prevalence of BCT was 34% (49/144); its age distribution was: 17.2% (0-10 yrs), 43.7% (11-20 yrs), 38% (21-30 yrs), 37.5% (31-40 yrs), 33.3% (41-50 yrs), 40% (51-60 yrs), and 20% (61-70 yrs). Thirty-one PACs were found in 29/144 patients of the whole study group. The prevalence of BCT was significantly higher in the subgroup of 29 patients with PACs than in the subgroup of 115 patients without PACs (75.9% versus 23.5%; p < 0000001). The aetiology of BCT was mainly unexplained, as it was only possible to detect 24 PACs in 22/49 patients with BCT (44.9%): congenital, genetic and immune disorders (eight), localized airways obstructive diseases (five), pulmonary infections (three), bronchial asthma (two), pulmonary lobar fibrosis (two), ulcerative colitis (two), dermatomiositis (one), and toxin inhalation (one). The authors conclude that bronchiectasis still occurs in a large percentage of symptomatic patients of a developed country in the post-antimicrobial era, especially in the second to sixth decades, as well as in the presence of predisposing and associated conditions; its aetiology remains unknown in more than half of cases.

Endobronchial metastasis from stomach carcinoma.

We describe the case of a 57-yr-old female with endobronchial metastasis from stomach carcinoma. Respiratory symptoms began 3 months before the diagnosis of the gastric cancer. Chest computed tomography revealed a reticular lymphangitic carcinomatosis pattern with hilar and mediastinal lymphadenopathy. Fibreoptic bronchoscopy showed a spread submucosal infiltration which narrowed the apical segment of the left lower lobar bronchus. The biopsy specimen at that level was histologically identical to the gastric primitive cancer. To the authors' knowledge, stomach carcinoma has rarely been reported to give rise to airway metastases.

Oxidative stress and ERK1/2 phosphorylation as predictors of outcome in hepatocellular carcinoma patients treated with sorafenib plus octreotide LAR.

We reported a relevant activity of the combination between sorafenib and octreotide long-acting release (LAR) in advanced hepatocellular carcinoma (HCC) patients. In this work, we have studied if oxidative stress in both serum and peripheral blood mononuclear cells (PBMC) and pERK activation status in PBMC could be predictive of response. In the 20 responsive patients, the decrease of reactive oxygen species levels was already detectable after 10 days (T10) from the beginning of sorafenib administration, and this effect was enhanced by the combined treatment with sorafenib+octreotide LAR (T21). This effect correlated with the modulation of superoxide dismutase (SOD) activity (physiological scavenger of O(2-)) and of serum nitric oxide (NO) levels. Sorafenib alone induced an increase of about 40% of NO levels and of about two-fold of SOD activity in responsive patients, and both effects were significantly potentiated by the combined treatment. We found a gradual reduction of Erk1/2 activity, as evaluated by cytofluorimetric analysis, in 15 responsive patients reaching about 50% maximal decrease at T21. On the other hand, in 17 resistant patients, Erk1/2 activity was about 80% increased at T21. The determination of both the oxidative stress status and pERK activity in PBMC has high value in the prediction of response to sorafenib+octreotide therapy in HCC patients.

Depletion study of PCDD/Fs and dioxin-like PCBs concentrations in contaminated home-produced eggs: preliminary study.

Dioxins (PCDD/Fs) and polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants. The contamination of food products with dioxins and PCBs is a well studied issue, because food is generally considered the major source of dioxin intake for humans. In Italy, the Regional Monitoring Plan (part of the national residue monitoring plan) used in the field for 2009 has also included the control of environmental pollutants in small egg producers. Following an irregular result, 12 laying hens were transferred into a laboratory controlled environment. Eggs were collected for 60 days and they were weekly analysed for the evaluation of dioxins, dioxin-like PCBs (DL-PCBs), and non-dioxin-like PCBs (NDL-PCBs, six congeners) levels. The dioxins and PCBs contents were determined, according to EPA methods, by gas chromatography ic determination coupled with high resolution mass spectrometry (HRGC-HRMS). The content of PCDD/Fs, DL-PCBs and NDL-PCBs was evaluated weekly by mean from week to week. The concentration of dioxins was lower than DL-PCBs (2.5 pg TEQ g(-1) of fat against 4.5 pg TEQ g(-1) of fat), but we observed the same depletion trend for both pollutants. On the opposite, NDL-PCBs had a different course: we noted there was an increase between weeks 6 and 7, but the mean levels remained very low (about 20 ng g(-1) of fat). The dioxins, and sum of dioxin and DL-PCBs concentration were below the fixed European limits (i.e. 3 pg TEQ g(-1) of fat for dioxins and 6 pg TEQ g(-1) of fat for sum of dioxins and DL-PCBs), beginning from the 3rd week of trial.

Somatostatin analogues, a series of tissue transglutaminase inducers, as a new tool for therapy of mesenchimal tumors of the gastrointestinal tract.

Imatinib, a tyrosine kinase inhibitor directed against the enzymatic domain of KIT protein, was found to produce dramatic clinical responses in metastatic gastrointestinal stromal tumors (GISTs). However, resistance usually develops thus determining treatment failure. The present study was performed to analyse the expression of somatostatin receptor (SSTR) subtypes, modulators of tissue transglutaminase, in a series of GISTs and leiomyosarcomas by immunohistochemistry to identify a new potential therapeutic target. Sixteen cases (8 males and 8 females, age range: 38-73; 11 GISTs, 4 leiomyosarcomas, 1 leiomyoma) were studied. Immunohistochemical detection of the relevant SSTRs was performed on paraffin-embedded tissue sections, stained with polyclonal antibodies directed against the five somatostatin receptor subtypes. We found 7 out of 16 (44%) tumors expressing all SSTRs and 14 out of 16 (87%) tumors positive for at least 3 subtypes. SSTR2A was the most represented subtype in the tumors studied, being expressed in approximately 70% of cases exhibiting an intense labeling in most of these cases. The significant expression of SSTRs shown in this series of GISTs and gastrointestinal leiomyosarcomas suggests a potential therapeutic target to be explored alone and/or in combination with other therapeutic agents in the setting of refractory GI stromal tumors.

Persistent Cryptococcus neoformans pulmonary infection in the rat is associated with intracellular parasitism, decreased inducible nitric oxide synthase expression, and altered antibody responsiveness to cryptococcal polysaccharide.

Fungal pathogens are notorious for causing chronic and latent infections, but the mechanism by which they evade the immune response is poorly understood. A major limitation in the study of chronic fungal infection has been the lack of suitable animal models where the infection is controlled and yet persists. Pulmonary Cryptococcus neoformans infection in rats results in a diffuse pneumonitis that resolves without dissemination or scarring except for the persistence of interstitial and subpleural granulomas that harbor viable cryptococci inside macrophages and epithelioid cells. Infected rats are asymptomatic but remain infected for as long as 18 months after inoculation with C. neoformans. Containment of infection is associated with granuloma formation that can be partially abrogated by glucocorticoid administration. Using this model, we identified several features associated with persistent infection in the rat lung, including (i) localization of C. neoformans to discrete, well-organized granulomas; (ii) intracellular persistence of C. neoformans within macrophages and epithelioid cells; (iii) reduced inducible nitric oxide synthase expression by granulomas harboring C. neoformans; and (iv) reduced antibody responses to cryptococcal polysaccharide. The results show that maintenance of persistent infection is associated with downregulation of both cellular and humoral immune responses.

Phenotypic switching in the human pathogenic fungus Cryptococcus neoformans is associated with changes in virulence and pulmonary inflammatory response in rodents.

High-frequency reversible changes in colony morphology were observed in three strains of Cryptococcus neoformans. For one strain (SB4, serotype A), this process produced three colony types: smooth (S), wrinkled (W), and serrated (C). The frequency of switching between colony types varied for the individual colony transitions and was as high as 10(-3). Mice infected with colony type W died faster than those infected with other colony types. The rat inflammatory response to infection with colony types S, W, and C was C > S > W and ranged from intense granulomatous inflammation with caseous necrosis for infection with type C to minimal inflammation for infection with type W. Infection with the various colony types was associated with different antibody responses to cryptococcal proteins in rats. Analysis of cellular characteristics revealed differences between the three colony types. High-frequency changes in colony morphology were also observed in two additional strains of C. neoformans. For one strain (24067A, serotype D) the switching occurred between smooth and wrinkled colonies. For the other strain (J32A, serotype A), the switching occurred between mucoid and nonmucoid colonies. The findings indicate that C. neoformans undergoes phenotypic switching and that this process can affect virulence and host inflammatory and immune responses. Phenotypic switching may play a role in the ability of this fungus to escape host defenses and establish chronic infections.

B-cell lymphopenia and hypogammaglobulinemia in thymoma patients.

Thymic tumors represent a unique neoplastic disease associated with various immune-mediated syndromes. Immune impairment is generically recognized to be associated with thymoma. Hypogammaglobulinemia and recurrent pulmonary infections in thymoma patients define Good's syndrome. Apart from sporadic reports focusing on this topic, there is still a lack of knowledge on immune assessment and clinical sequelae in thymoma patients. The present study was performed to evaluate immunoglobulin levels, CD19(+) B lymphocytes, and CD3(+) T lymphocytes in a large series of thymoma patients from a single institution. The occurrence of recurrent severe infections was related to immunological findings to identify the possible correlation with the immunodeficiency status. Eighteen patients (eight males, ten females, mean age: 56 years, range: 19-75) with a pathological diagnosis of thymic tumor were studied. Six patients suffered from clinical recurrent pulmonary infections. Blood samples were collected to measure serum immunoglobulins and analyze immunophenotype. Low T lymphocyte number was found in 22% of the patients. T lymphocytosis was present in one patient. Panhypogammaglobulinemia was found in 4 of 18 patients (22%). Conversely B lymphopenia was a frequent finding in this series of thymoma patients (9 of 18, 50%). Five of six patients (83%) with recurrent infections had B lymphopenia, while only two (33%) had panhypogammaglobulinemia. B lymphopenia often occurred in this series of thymoma patients and was related to susceptibility to recurrent infections more than hypogammaglobulinemia. Therefore, immunophenotype has to be monitored in follow-up of thymoma patients because it may reveal significant abnormalities.

Role of surgery in thymic disorders.

Thymomas are relatively slow-growing neoplasms that should be considered malignant tumours. When treated in the early stages, however, they have an excellent prognosis for long-term survival. Surgery, radiation therapy and chemotherapy all play a role in the management of these neoplasms. Surgery is the treatment of choice in thymoma patients and has become an increasingly accepted procedure in the treatment of myasthenia gravis (MG) since 1936, when thymectomy was performed for this disease for the first time. Improvement in myasthenic symptoms is nearly always observed following thymectomy, but the rates of complete remission vary from 7% to 63%. We have studied the potential preoperative factors predicting the evolution of MG.

Role of somatostatin analogue-based therapy in unresponsive malignant thymomas.

Thymomas are rare neoplasms that are usually associated with parathymic syndromes, pure red cell aplasia, myasthenia gravis, hypogammaglobulinaemia and other mainly immunological disorders. Therefore, the management of thymoma patients is often complex and presents many diagnostic and therapeutic issues. Controversies concerning the definition of the histological subtypes and the role played by thymoma-associated syndromes are of primary importance in determining the oncological approach. Although low-stage thymomas have a high percentage of recovery, thymomas which are locally advanced, metastatic or previously treated with standard therapeutic options have no well-defined and effective treatment approaches. The data previously described by us on somatostatin receptor scintigraphy showing high uptake of indium-labelled octreotide by thymic masses and the successful treatment of a patient with thymoma and pure red cell aplasia with octreotide and prednisone has provided us the rationale for using such treatment in patients with advanced thymoma.

Immunological findings in thymoma and thymoma-related syndromes.

Human thymoma is a neoplasm of thymic epithelial cells associated with several clinical syndromes ranging from autoimmune disease to immunodeficiency. The aim of our research was to investigate T cell-mediated immune response in patients with thymoma. Initially eight patients were enrolled in this study. Four patients underwent surgical removal of the thymus, while four were submitted to diagnostic procedures only. Inversion of the CD4:CD8 ratio was found in three patients. Only one subject displayed a normal CD19 count in peripheral blood. The mean value (+/-SD) of the CD19 percentage in the patient group was 2 +/- 2.2. Notably, the patients with thymoma had fewer mature B lymphocytes than the thymectomized patients. The T-cell receptor (TCR) repertoire was investigated in three individuals affected by thymoma: one underwent thymectomy, while the two others, one of which presented with lymphocytosis, were submitted to diagnostic biopsies only. The preliminary results showed a marked alteration in the CD8 repertoire of the thymectomized patient but not in that of the lymphocytotic patient. However, alterations in the TCR repertoire were also found in one patient with thymoma. Altogether, these preliminary findings reveal that loss of CD19+ lymphocytes in peripheral blood is a frequent phenomena in thymoma patients. In this article we discuss this aspect in the context of alterations of the TCR repertoire.