The Erice 58 Charter on 'The health of migrants. An equity challenge for the public health system'.

Abstract: The Erice 58 Charter titled "The Health of Migrants: a Challenge of Equity for the Public Health System", was unanimously approved at the conclusion of the 58th Residential Course of the School of Epidemiology and Preventive Medicine 'Giuseppe D'Alessandro' entitled "The Health of Migrants: a Challenge of Equity for the Public Health System. Epidemiological, clinical-relational, regulatory, organisational, training and public communication aspects at international, national and local level', which took place from 28 March to 2 April 2022 in Erice (Sicily, Italy), at the 'Ettore Majorana' Foundation and Centre for Scientific Culture. The Course was promoted by the Italian Society of Migration Medicine (S.I.M.M.) and the Italian Society of Hygiene, Preventive Medicine and Public Health (SItI), with the collaboration and patronage of the Istituto Superiore di Sanità (ISS). 72 learners participated (mainly resident doctors in 'Hygiene and Preventive Medicine' but also other health service professionals), whose average age was 37 years; on the basis of territorial origin, 13 of the 20 Italian regions were represented. During the intense learning experience, which consisted of 18 frontal lessons (with 20 lecturers from the bio-medical, socio-anthropological and journalistic fields) and 7 working group sessions (supported by 4 classroom tutors in addition to the lecturers) in 'blended learning' mode, the various dimensions and critical issues related to the possibility of guaranteeing truly inclusive health policies for foreigners/migrants, throughout the country, were identified and discussed from an 'Health Equity' perspective. This enabled a small editorial group to draw up the basic document that, in the last session of the Course, was discussed and modified by all participants into the version of the 'Erice 58 Charter' presented here.

Effects of food-based interventions in the management of chemoradiotherapy-induced nausea and vomiting: a systematic review.

BACKGROUND: Cancer treatment-related nausea and vomiting continue to be common and distressing symptoms for patients, despite improvements in antiemetics. Dietary modifications could potentially improve this symptom experience. Clinicians frequently provide dietary advice to patients, although the evidence base of such suggestions or recommendations is not clear. PURPOSE: This systematic review aimed to examine the current literature on food interventions associated with improvements in cancer treatment-related nausea and vomiting. METHODS: Eight electronic databases were searched with a specific search term strategy covering trials without time or language limitations. Eligible studies focused on a food substance, defined as any nutritious substance that people eat or drink to maintain life and well-being. Trials in children and adults during chemotherapy or radiotherapy were included. Cochrane risk of bias tool was used to assess trial quality and GRADE was used to assess the certainty in the effect of each outcome. RESULTS: Seventeen trials were included, 3 focusing on children and 14 on adults. Two trials included patients receiving radiation. Ten out of 17 trials (59%) had a high risk of bias. Strongest evidence with highest certainty was found for dietary counseling to meet macronutrient requirements in reducing incidence of radiotherapy-related nausea and vomiting in adults (n=2 studies; n=124 participants; GRADE level: moderate). There was also moderate certainty in the beneficial effect of protein supplementation on nausea and vomiting incidence in adults during radiotherapy (n=2 studies; n=124 participants; GRADE level: moderate). A significant positive effect on CINV incidence and/or severity in adults was also found for dietary counseling to meet macronutrient requirements during chemotherapy, a peppermint drink, scaly wood mushroom, chamomile, protein with ginger, and a colorless odorless diet (GRADE level: low to very low). CONCLUSIONS: The review identified food-based approaches that could improve the nausea and vomiting experience in patients with cancer and provide guidance to clinicians. However, confidence in these findings was low and studies were heterogeneous and mostly of low quality, requiring further investigation before stronger recommendations can be made. Future research is needed to confirm efficacy and safety. TRIAL REGISTRATION: PROSPERO CRD42022341154.

Low-grade fever: how to distinguish organic from non-organic forms.

BACKGROUND AND AIM: Low-grade fever (LGF) is defined as a body temperature between 37.5 and 38.3 degrees C, which is below the classical value reported for fever of unknown origin (FUO). We attempted to characterise its epidemiology, aetiology and clinical aspects to improve the methodological approach to diagnosis. DESIGN AND METHODS: We reviewed and evaluated a survey of patients with LGF, followed as outpatients of our Department, a tertiary referral centre from 1997 to 2008. The same classifications were applied for classical FUO, and in the patients diagnosed with LGF, we also investigated for habitual hyperthermia (HH). RESULTS: Seventy-three patients were selected and divided into two groups: group A included 32 patients classified with organic fever and group B included 41 patients with HH. Aetiology of organic LGF was: infectious disease 59%; neoplasm 3.1%; inflammatory non-infectious disease 6.2%; miscellaneous 18.7%; undiagnosed 12.5%. Mean age was significantly higher in the organic fever than in the HH group (p < 0.02). Splenomegaly and loss of weight were significantly associated with organic fever (p < 0.05), while dizziness and general malaise were associated with HH. Lack of any pathological signs at physical examination was significantly more frequent in HH (p < 0.0001). Among the biochemical tests, white blood cells and C-reactive protein were more frequently above normal limits in group A than in group B (p < 0.05). CONCLUSIONS: In our experience, LGF requires the same methodological diagnostic approach as FUO, because there is no relationship between body temperature values and the severity of the underlying diseases, and the aetiological spectrum is also the same.

[Abnormal liver function in brucellosis]. / Alterazioni della funzione epatica in corso di brucellosi.

We assessed the prevalence of impaired liver function in 47 patients suffering from brucellosis consecutively admitted to our department over the last five years. Parameters of liver function and ultrasound of the upper abdomen were performed at entry and at the end of treatment. On admission, mean transaminase values were elevated and significantly higher than at recovery (p 0.001): 38 percent and 53 percent of patients had elevated baseline values of GOT and GPT vs 13 and 19% at the end of treatment, respectively. Mean serum values of alkaline phosphatase (AP) were within normal limits on admission, although in 12 of them serum values were elevated. The same proportion was seen for gamma-glutamyltranspeptidase. Both transaminases and AP were elevated in 8 patients (17 percent). There were no significant differences in serum values of albumin and bilirubin before and after therapy. The platelet count slightly decreased, but not significantly, during the acute phase of disease. At ultrasound one third of the patients showed hepatomegaly with a hepatitis-like pattern and 40 percent of patients had splenomegaly. In conclusion, this study confirms data in the literature showing a high frequency of liver impairment during the course of brucellosis, which is usually mild-moderate.

A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy.

The prognosis for patients with metastatic breast cancer remains poor. Metastatic breast cancer confined to the bones may have a better prognosis, especially hormone receptor-positive disease. We performed a prospective, randomized clinical trial to compare immediate consolidation with high-dose chemotherapy and hematopoietic support versus observation with high-dose consolidation at the time of disease progression in women with metastatic breast cancer and only bone metastases. The patients received chemotherapy with doxorubicin, 5-fluorouracil and methotrexate before randomization. In all, 85 patients were enrolled and 69 were randomized. The median follow-up is 8.1 years from randomization. The median event-free survival (EFS) for the immediate transplant arm is 12 months and for the observation arm is 4.3 months (P<0.0001). The median overall survival for the immediate transplant arm is 2.97 years and for the observation arm 1.81 years, a difference that is not statistically significant. Immediate high-dose chemotherapy and radiation therapy as consolidation offers a clinically and statistically significant improvement in EFS compared with radiation therapy alone following induction chemotherapy for women with metastatic breast cancer confined to the bones.

Safe and successful endoarterial infusion of liposomal amphotericin B in treatment of mucormycosis.

Mucormycosis is a rare invasive mycotic infection treated by antifungini or amphotericin B. We describe the case of a patient with septic fever and a necrotic lesion, with phlegmon of medial left thigh. Surgery was performed to drain the abscess content and to remove the necrotic tissue; mucormycosis was diagnosized by histological and culture tests and treated by intravenous amphotericin B. Since the lesion worsened, liposomal amphotericin B was directly infused into the left common iliac artery, with progressive improvement, and treatment was continued until complete recovery. Therefore, the endoarterial infusion of liposomal amphotericin B was a safe and successful treatment of advanced lesions of mucormycosis. In such lesions, intravenous general antibiotic administration probably is not sufficient to reach the whole infected area.

Phase I study of Gliadel wafers plus temozolomide in adults with recurrent supratentorial high-grade gliomas.

Both Gliadel wafers [1,3-bis(2-chloroethyl)-1-nitrosourea] and temozolomide (TEMO) have been shown in independent studies to prolong survival of patients with recurrent malignant glioma following surgery and radiotherapy. On the basis of preclinical evidence of synergism between Gliadel wafers and TEMO, a phase I study was designed to evaluate the toxicity of combining these 2 agents in the treatment of patients with recurrent supratentorial malignant glioma. All patients had surgical resection of the tumor at relapse, and up to 8 Gliadel (3.85%) wafers were placed in the surgical cavity following resection. Two weeks after surgery, TEMO was given orally daily for 5 days. Cohorts of 3 patients received TEMO at daily doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2, respectively. Patients were assessed for toxicity 4 weeks after start of the first course of TEMO. Contrast-enhanced MRI of the brain was used to assesstumor response after the first cycle of TEMO. Patients with stable disease or response after the first cycle of TEMO were allowed to continue treatment at the same dose every 4 weeks for 12 cycles or until disease progression or unacceptable toxicity. Ten patients with a median age of 47 years (range, 22-66 years) were enrolled in this study. There were 7 patients with glioblastoma multiforme and 3 patients with anaplastic astrocytoma. Three patients were treated with TEMO at the first dose level of 100 mg/m2, 4 at the second dose level of 150 mg/m2, and 3 at the third dose level of 200 mg/m2. The 10 patients received a median of 3 cycles (range, 1-12 cycles) of TEMO following placement of Gliadel wafers. The treatment was well tolerated, with only 1 patient suffering grade III thrombocytopenia at the highest dose level. Two patients at each dose level had no evidence of disease progression after treatment. Four patients suffered progressive disease on therapy. Our study demonstrates that TEMO can be given safely after placement of Gliadel (3.85%) wafers. The recommended dosage for TEMO for a phase II study of this combination is 200 mg/m2 per day for 5 days.

The acute phase response in Sicilian patients with boutonneuse fever admitted to hospitals in Palermo, 1992-1997.

OBJECTIVES: To study the modifications of some components of the acute phase response (APR) in Sicilian patients with boutonneuse fever (BF) caused by Rickettsia conorii. METHODS: Sera from 500 Sicilian patients with confirmed BF were studied at the time of diagnosis and every week after treatment, and after recovery for the presence of various inflammatory mediators. Tumour necrosis factor alpha (TNFalpha), interleukin(IL)-6, IL-1alpha, IL-8, soluble TNF receptors (sTNF-R) and sIL-6R were assayed by commercially ELISA kits. C3, C4, factor B, C-reactive protein (CRP), fibrinogen, ceruloplasmin (Cp) and alpha(1)-antitrypsin (AAT) were assayed by a rate nephelometry. RESULTS: Interferon gamma (IFNgamma), IL-6, TNFalpha, and IL-10 cytokines were significantly modified, whereas IL-1 and IL-8 were not detectable in the blood in any phase of infection. sTNF-RI, sTNF-RII and sIL-6 were significantly increased in the first 2 weeks of infection, but sTNF-R levels were not related to the plasma levels of TNFalpha, whereas sIL-6 was directly related to serum IL-6 concentrations. C3, C4, factor B and CRP were significantly increased in the first 2 weeks of infection, but afterwards returned to the normal range, even though CRP was still high in the third week and C3 persisted high after the fourth week. Fibrinogen was high only in the first week in relation to the injury to the endothelial cells (ECs). The anti-inflammatory proteins, Cp and AAT, were extremely high in the first 2 weeks of infection acting as a buffer of APR activation. CONCLUSIONS: These results suggest that R. conorii is able to elicit, after invasion and proliferation in the ECs, the activation of APR. Further work is required to establish if active inhibitory mechanisms are operating during APR, or if there is a spontaneous decay in the initiation events.

Prognostic and predictive factors for patients with metastatic breast cancer undergoing aggressive induction therapy followed by high-dose chemotherapy with autologous stem-cell support.

PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses. RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P =.0041), smaller metastatic foci ( 2 cm) (P =. 0165), a longer disease-free interval from initial diagnosis to diagnosis of metastases ( 2 years) (P =.0051), and prior treatment with tamoxifen (P =.0152) were good prognostic signs for overall survival. Patients who had received prior adjuvant therapy (P =.0001) and those who developed liver metastases (P =.0001) had decreased long-term survival. In the subgroup of responders to AFM induction, multivariate analysis showed that those with visceral metastases did less well (P =.0006), as did patients who had received prior adjuvant therapy (P =.0023). However, those who had received tamoxifen therapy in the adjuvant setting did better (P =. 0143). CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive-patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.

Modifications of general parameters of immune activation in the sera of Sicilian patients with Boutonneuse fever.

The serum levels of beta2-microglobulin (beta2-M), soluble HLA class I antigen (sHLA-I), soluble CD4 (sCD4) and CD8 (sCD8) were studied in 98 Sicilian patients with Boutonneuse fever (BF). In different stages of infection all markers were significantly increased in sera from Sicilian patients with acute BF compared with healthy controls. sCD8 and sHLA-I reached the peak in the second week after the onset of symptoms, whereas sCD4 and beta2-M reached the peak in the first week. Afterwards sCD8 decreased to the levels of controls within the third week, the other parameters decreased later and were unmodified until the third week of infection. Significant correlations were found between sCD4 and sCD8 and the sIL-2R, as well as between serum levels of beta2-M and sCD8. The reduction of CD3+ and CD4+ and the increase of CD8+ T cells in the blood indicate that these cells are involved in the response to rickettsia, and their activation might be in part responsible for the release of sCD4 and sCD8. Our data suggest that these soluble markers, indexes of immune activation of T cells both in the circulation and the affected tissues, may be used in monitoring BF evolution.

Evaluation of GM-CSF mouthwash for prevention of chemotherapy-induced mucositis: a randomized, double-blind, dose-ranging study.

Uncontrolled clinical trials have shown that parenteral administration of GM-CSF reduces the frequency of chemotherapy-induced mucositis. The mechanism of this effect could be related to acceleration of haematopoiesis and/or increase in functional activation of WBC. We conducted a double-blind, placebo-controlled, dose ranging study of GM-CSF (mol-gramostim) mouthwash in patients with breast cancer during the first treatment cycle of a combination chemotherapy regimen which has historically produced dose-limiting (grade > or = 3) mucositis in approximately 39% of patients. Subjects were randomized to receive either placebo mouthwash (0.1 percent albumin) or one of four concentrations of GM-CSF mouthwash (0.01, 0.1, 1.0 or 10 mcg/ml). The primary endpoint was to evaluate the relationship between dose of GM-CSF mouthwash received and probability of grade > or = 3 mucositis using a logistic model. Solutions were administered four times daily starting within 24 hours of chemotherapy initiation and continuing until the end of the cycle (day 21). Mucositis was assessed on days 1-6, 10, 15 and 21. Day 6 plasma samples were assayed for GM-CSF. Forty-five patients were evaluable for response (nine per dosing group). A 42% risk (15/36) of mucositis grade > or = 3 was evident on day 15 in patients receiving GM-CSF compared to 2 of 9 patients on the placebo arm. No evidence of dose response was found by logistic regression. Five patients had a detectable plasma concentration of GM-CSF (56-209 pg/ml). A positive correlation between GM-CSF dose and leukocyte recovery was noted (P = 0.04).

Bone metastases from breast cancer: value of CT bone windows.

A pilot study was organized to compare the utility of scintigraphy, radiographic bone surveys, and conventional CT bone windows (CTBWs) in judging therapeutic response of bone lesions in patients with metastatic breast carcinoma. Twenty-six patients with stage IV disease and documented bone metastases were evaluated over a 2 year period. Discordance in the assessment of therapeutic response was greatest (56% discordance) between bone scans (BSs) and conventional CTBWs. In 77% of the discordant observations, the assessment by conventional CTBWs agreed with the patients' clinical response to therapy. Our preliminary results suggest that posttherapy review of conventional CTBWs provides useful clinical information about therapeutic response and exceeds the contribution of BSs in this regard.

4-Hydroperoxycyclophosphamide purging of breast cancer from the mononuclear cell fraction of bone marrow in patients receiving high-dose chemotherapy and autologous marrow support: a phase I trial.

We designed an ex vivo bone marrow treatment for breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support (ABMS), using 4-hydroperoxycyclophosphamide (4-HC), an active derivative of cyclophosphamide with known activity against breast cancer. This phase I bone marrow purging trial used ficoll-separated mononuclear cells (MNC) (devoid of granulocytes and RBCs), as opposed to the buffy coat. Twenty-five patients with metastatic breast cancer were studied. Patients received three cycles of the Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), fluorouracil, and methotrexate (Duke AFM) regimen, followed by marrow harvest. An MNC fraction of marrow was prepared and treated with 4-HC in concentrations of 20 micrograms/mL (four patients), 40 micrograms/mL (four patients), 60 micrograms/mL (nine patients), or 80 micrograms/mL (eight patients) and cryopreserved. Patients then received high-dose systemic cyclophosphamide, cisplatin, and carmustine, followed by infusion of the purged marrow. The study end point was marrow engraftment, defined as WBC count greater than 1,000 cells per microliter. At the first three dose levels (20, 40, and 60 micrograms/mL 4-HC), there was no significant delay in time to engraftment (19, 20, and 23 days, respectively) compared with the unpurged historical controls (17 days). At 80 micrograms/mL, engraftment was significantly delayed compared with the lower concentrations (P = .027), and further escalation of 4-HC was not attempted. A significant correlation was observed between the time of leukocyte engraftment and the 4-HC concentration (P = .017). With a methylcellulose-based tissue culture assay, we demonstrated a statistically significant correlation between the colony-forming unit-granulocyte-macrophage (CFU-GM) content in the purged marrow and the days to engraftment. Ninety-five percent of patients responded clinically to the entire program, 55% of them completely. Longer follow-up is required to assess the ultimate benefit of intensive therapy on long-term survival.

The Duke AFM Program. Intensive induction chemotherapy for metastatic breast cancer.

Forty-five patients have completed treatment with AFM, an intensive induction chemotherapy regimen composed of Adriamycin (doxorubicin, Adria Laboratories, Columbus, Ohio), 5-fluorouracil, and methotrexate with folinic acid rescue. This regimen was designed to produce rapid and extensive tumor shrinkage prior to high-dose alkylating agent chemotherapy with autologous marrow support. The overall response rate was 91%, and 38% of patients achieved complete clinical responses after a mean of 70 days on treatment. Hematologic and mucosal toxicity were extensive, but no toxic deaths were noted. AFM is a potent remission induction regimen for metastatic breast cancer, but its considerable toxicity suggests caution in its use for routine breast cancer treatment.

High-dose carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support: excessive hepatic toxicity.

Intensive doses of carboplatin, cyclophosphamide, and BCNU with autologous bone marrow support were given to four patients with advanced melanoma. Three developed clinically diagnosed, severe veno-occlusive liver disease, which was fatal in two cases. The dose of carboplatin (450 mg/m2) was comparable with that used in ambulatory regimens. At the doses and schedule employed, this three-drug combination produced excessive hepatic toxicity. Caution is suggested when giving carboplatin in combination with intensive doses of other chemotherapeutic agents with known hepatotoxic potential.