Retention rates of different Janus kinase inhibitors in rheumatoid arthritis: experience from a large monocentric cohort.

OBJECTIVE: The efficacy of Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) has been clearly shown. However, information on comparative drug retention rates (DRRs) of different JAKi is heterogeneous. The aim of this study was to compute and compare DRRs of different JAKi in a large cohort of RA patients. METHOD: Patients with RA treated with at least one JAKi and followed up at our centre were retrospectively identified. DRRs of each JAKi were computed at 24 months. The association of baseline features with drug persistence was tested. Variations in 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP) and Clinical Disease Activity Index (CDAI) scores between baseline and 12 months were analysed. RESULTS: The study included 365 patients, with a total of 463 therapy courses. Tofacitinib was the most prescribed JAKi (33%), followed by baricitinib (25%), upadacitinib (24%), and filgotinib (21%). The mean treatment duration was 24 ± 17 months, with a maximum of 70 months. At 24 months, the overall DRR was 86%. DRRs were not significantly different across different JAKi. The only baseline predictor of treatment discontinuation was previous treatment with a biological disease-modifying anti-rheumatic drug (bDMARD) (hazard ratio 1.65, 95% confidence interval 1.08-2.53; p = 0.021). There were significant reductions in DAS28-CRP and CDAI 1 year after treatment start. CONCLUSIONS: In our large, monocentric cohort, the overall 24 month DRR for JAKi was greater than 80%. No significant differences in retention were found among different JAKi. Persistence was lower in patients who had previously been treated with other bDMARDs.

Long-term sequelae of breast cancer surgery.

BACKGROUND: Quality of care is today a major issue in oncology, and much attention is given to research on the outcome of breast cancer care. Too little attention has been devoted in the scientific literature to the consequences of treatment in long-term survivors, and in particular to the possible side effects. The specific aim of this contribution is to present population-based data about the long-term impact of breast cancer care in women who had an incident cancer in 1985/1986. PATIENTS AND METHODS: The cases are 476 breast cancers incident in the City of Florence in 1985-86. Women still living 5 years later were invited to have an interview and a physical examination. Lymphedema, peripheral nerve lesions and damage to the shoulder were assessed. RESULTS: Of the 346 5-year survivors, 238 accepted our invitation: 35.2% of the women reported some early postoperative sequelae, 30.2% had a chronic lymphedema and 18.9% a shoulder deficit. Comparing breast-conserving surgery with radical mastectomy, the risk of chronic lymphedema (OR = 1.62; 95% C1: 0.91-2.88) and other lesions was higher for women who had a radical surgery. Women who had a breast-conserving surgery more often reported an early lymphedema (OR = 1.60; 95% Cl: 0.88-2.88). CONCLUSIONS: The proportion of women who complained of (or manifested at the physical examination) a minor or major disability of the arm in our study was high. The impact of these functional problems in terms of quality of life should also be assessed, but it is our impression that there is need for much greater attention to the issue of long-term survivor sequelae.

The efficacy of intensive follow-up testing in breast cancer cases.

BACKGROUND: A preliminary inquiry into the follow-up practices of Italian breast cancer centers revealed a considerable diversity of policy. It is clear that accurate follow-up examinations supply important information about the development of metastases, but there is no clinical proof that they extend survival time. It is possible that the effects of early diagnosis are only negative, extending the period over which the patient is aware of her illness and leading to over-diagnosis, overtreatment and increased health-care costs. PATIENTS AND METHODS: In a study involving the national oncological centers, patients were randomized into two groups: an intensive follow-up group (6 monthly chest X-rays and bone scans) and a control group (clinical examination only). RESULTS: An excess of isolated bone and intrathoracic metastases were observed in the intensive follow-up group. The survival curves showed no difference between the two groups. CONCLUSIONS: Six monthly X-rays and bone scans provide occasion for early diagnosis of intrathoracic and bone metastases without, however, influencing overall 5-year survival. Recourse to diagnostic tests only in the presence of symptoms appears to be the most appropriate follow-up procedure. However, other studies considering long term effects of early diagnosis and the effects of considering long term effects of early diagnosis and the effects of new diagnostic tests and/or treatment modalities are clearly needed.

Independent double reading of screening mammograms.

OBJECTIVE: To evaluate the cost effectiveness of independent double reading of screening mammograms. SETTING: Prospective study of 18,817 women undergoing first or repeat screening in a population based programme in the Florence district. METHODS: Mammograms were independently double read by experienced radiologists. Subjects with mammographic abnormalities reported by at least one reader were recalled for diagnostic assessment. The mean increase in recall rate, cancer detection rate, and screening costs attributable to double reading was calculated. RESULTS: Eleven of 125 cancers were detected by only one reader. The mean increase in cancer detection rate attributable to double reading compared with single reading was 4.6% (95% confidence interval (CI) 1.1 to 8.9). From a total of 748 cases referred for diagnostic assessment, 196 subjects were referred by one reader only. The mean increase in referral rate attributable to double reading compared with single reading was 15.1% (CI 12.3 to 17.8). Double reading caused a marked increase in the cost for each woman screened -8.5% at the first screening and 6.2% at repeat screening and a more limited increase in the cost for each cancer detected -3.5% at the first screening and 2.7% at repeat screening. Cancers detected by only one screener were at an earlier stage than those detected by both screeners (P = 0.6, not significant). CONCLUSIONS: Independent double reading results in only a modest increase in the detection of cancers and therefore may not be cost effective.

Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up.

OBJECTIVE: To evaluate the effectiveness of early detection of intrathoracic and bone metastases in reducing mortality in breast cancer patients. DESIGN: Randomized clinical trial allocating breast cancer patients to two alternative follow-up protocols (intensive vs clinical) for at least 5 years. SETTING: Twelve breast clinics (referral centers) in different areas in Italy. PATIENTS: A total of 1243 consecutive patients (either premenopausal or postmenopausal) surgically treated for unilateral invasive breast carcinoma with no evidence of metastases. The two study groups were well balanced in terms of clinical and prognostic characteristics. INTERVENTION: Patients in both treatment groups had physical examination and mammography, while patients of the intensive follow-up group had, in addition, chest roentgenography and bone scan every 6 months. MAIN OUTCOME MEASURES: Vital status at 5 years was the main outcome; information was available for all except five patients (0.4%). Relapse-free survival was also analyzed. RESULTS: Overall, 393 recurrences (104 local and 289 distant) were observed during the study. Increased detection of isolated intrathoracic and bone metastases was evident in the intensive follow-up group compared with the clinical follow-up group (112 vs 71 cases), while no difference was observed for other sites and for local and/or regional recurrences. The 5-year relapse-free survival rate was significantly higher for the clinical follow-up group, with patients in the intensive follow-up group showing earlier detection of recurrences. No difference in 5-year overall mortality (18.6% vs 19.5%) was observed between the two follow-up groups. CONCLUSIONS: Periodic chest roentgenography and bone scan allow earlier detection of distant metastases, but anticipated diagnosis appears to be the only effect of intensive follow-up, and no impact on prognosis is evident after 5 years. Periodic intensive follow-up with chest roentgenography and bone scan should not be recommended as a routine policy.

Radial scars of the breast: review of 38 consecutive mammographic diagnoses.

The authors report 38 consecutive cases of histologically proved breast radial scars (RSs) detected at mammography. In a retrospective review of mammograms in 30 matched cases of nonpalpable RS and nonpalpable scirrhous cancer, the characteristic mammographic features of RS were confirmed: (a) the absence of a central opacity, often substituted by a radiolucent area; (b) the presence of multiple elongated thin spicules radiating from the center of the lesion; (c) the infrequency of any palpable finding, even for superficial lesions of relatively large size. Microcalcifications with aspecific structure were found in the lesions on mammograms of 14 of the 38 cases and in 24 of the histologic specimens. The typical mammographic features of RS were not specific to RS, being present in a minority of cancer cases. For two blinded readers, sensitivity was 86.7% and 76.7% and specificity was 78% and 80%, respectively. Although some specific mammographic features may suggest the presence of RS, the final differential diagnosis from scirrhous cancer should be based on histologic evidence, and surgical biopsy should be advised for any stellate lesion detected at mammography.

Histopathologic classification of breast cancer in Sweden and Italy: a comparison between two pathologists.

Two large series of breast cancers (BC), identified in the Pathology Departments of Malmö (Sweden) and Florence (Italy), were independently reviewed by two experienced pathologists, one from each department. Overall, comparison of diagnoses of 372 BCs according to a simplified WHO histologic classification system (in four combined categories) revealed agreement for 74% of the cases. Concordance, as measured by the kappa statistic, was relatively good (0.53 overall). Kappa values for specific categories were also acceptable, being highest for "invasive lobular" BC (0.63) and lowest for "other types" (0.45). The kappa value for "noninvasive" versus all other categories of invasive BC was 0.53. Some BCs were systematically classified as "noninvasive" by one pathologist and as "invasive ductal with a predominant intraductal component" by the other. Invasive lobular BCs were also diagnosed more frequently by one pathologist. These findings suggest that when planning geographical or temporal comparisons of distribution for BC histologic categories, standardization of classification and a centralized review may play an important role.

[Chronobiological study of ischemic attacks in angina pectoris at rest]. / Studio cronobiologico degli attacchi ischemici nell'angina a riposo.

The aims of this study were to determine if the hourly distribution of ischaemic episodes differed as regards ST segment elevation or ST segment depression during ischaemic attacks and differed as regards the degree of coronary atherosclerotic involvement. Twenty-four in-patient drug free subjects with angina at rest underwent ECG continuous Holter monitoring for periods varying from 24 to 168 hours. Four groups of patients were identified: group 1A: 6 patients with ST elevation and 0-1 vessel disease; group 1B: 6 patients with ST elevation and 2-3 vessel disease; group 2A: 3 patients with ST depression and 0-1 vessel disease; group 2B: 9 patients with ST depression and 2-3 vessel disease. During Holter monitoring, 301 ischaemic episodes were registered in group 1A during 576 hours; 173 episodes were registered in group 1B during 624 hours; 41 episodes were registered in group 2B during 528 hours. Using the single and population mean cosinor tests on the episodes of each group, considered as a whole, the following results were found: group 1A showed a circadian rhythm with acrophase at 4:03 a.m. (Fig. 2), group 1B showed a circadian rhythm with acrophase at 10:51 a.m. (Fig. 3), group 2A showed a circadian rhythm with acrophase at 11:15 p.m. (Fig. 5), while group 2B showed ultradian rhythms which lasted 7 and 13 hours (Fig. 6). The chronobiologic analysis of the distribution of the ischaemic attacks confirmed the existence of a circadian rhythm of ischaemic episodes in patients with ST elevation.(ABSTRACT TRUNCATED AT 250 WORDS)

Prominent circadian absorption of intranasal salmon calcitonin (SCT) in healthy subjects.

In young healthy subjects salmon calcitonin (SCT), intranasally administered, increased in serum as a function of the drug administration time. The serum concentration of a 400 IU SCT dose monitored 10 min after dosing was statistically more significant when inhaled at 0000 than at other, more conventional, administration times (morning or evening). Following dosing at certain times during the day, the serum SCT was less or even questionable with the dose and under the study conditions selected. Dosing without consideration of timing may lead to reduced effect or lack of effect or perhaps ambiguity or controversy regarding the possible circumstance of a "non-absorbent subject". The circadian frequency appears to be a critical determinant of intranasal SCT absorption suggesting administration time to be an important factor in the cost/benefit ratio without the unpleasant side effects sometimes experienced through parenteral routes.

Further steps toward a neonatal chronocardiology.

The study of 53 series of blood pressures at half-hour intervals from clinically healthy full-term newborns during the first days of life reveals various classifiers correlating with a history of high blood pressure: the circadian amplitude of diastolic blood pressure, the 50% range of systolic blood pressure and the standard deviation of heart rate.

Intragastric pH continuously monitored in health and in gastric diseases: chronobiologic assessment.

Some gastric diseases clinically show ultradian, circadian, and circannual periodicities. We continuously monitored, during a single 24-hr span, with a fully electronic, solid-state portable recorder, endoluminal gastric pH in five healthy subjects, in some patients with gastric diseases including duodenal ulcer and gastric cancer, and in high-risk persons prone to develop duodenal ulcer and gastric cancer. The daily schedule and the timing of standardized meals for each subject were strictly verified. All stored data (300 time points/subject) were decoded, read, and analyzed by an inferential statistical method to estimate the rhythm parameters. The intragastric dense pH samples showed highly significant circadian and ultradian (8-hr) rhythms in all investigated subjects, but rhythm parameters differed in pre- and in overt pathology.

Serum gastrin and pepsinogen in shift workers.

Gastrointestinal complaints, including peptic ulcer, are believed to be associated and enhanced by shift work (SW). However, there are no clear reports in the literature about this acquired pathology. Serum gastrin (G) and group I pepsinogen (PG1) are thought to play a role in the pathogenesis of peptic ulcer and may be considered a useful test of the gastric function. Five adult male foundry shift workers, without any demonstrated gastrointestinal pathology, were studied over a month's span during the following weekly rotating shift schedule: 07.45-16.45, 06.00-14.00, 14.00-22.00, 22.00-06.00. Six adult, day-working males acted as controls. Blood samples drawn at the beginning and at the end of each weekly shift were assayed for G and PG1 utilizing RIA kits. Our data showed that SW causes a prominent change in the gastrin/acidopepsin secretion system.

Toward a medical prolepsis by chronobiology.

Medicine today strongly aims at prevention and optimization of diagnosis and therapy Studies tried staging and standardization of clinical trials in diseases and made search of markers for early diagnosis, prognosis and therapy. Moreover, risk factors and other variables such as predictors are now investigated more often in groups or populations of apparently healthy subjects, especially for such diseases as atherosclerosis and neoplasia. This new aspect of increasing interest may be defined as medical prolepsis (from the Greek pi rho ómicron lambda eta psi iota zeta = anticipated idea). It includes early signals of disease (protopathology) as well as other signals the host shows as defence or alarm reaction. Hence, we suggest a chronobiological approach in this field, which allows to quantify health and reveals more subtle differences in many physiological variables. According to these views, we reported studies concerning humoral markers and other parameters considered as risk factors both in atherosclerosis and in some endocrine tumors.