Aflibercept, ranibizumab and bevacizumab upcoming biosimilars: a general overview.

Anti-vascular endothelial growth factors currently are the first-line treatment option for neovascular age-related macular degeneration (nAMD) and other retinal vascular disorders, and their clinical use is associated with high financial burden. Biosimilars are a type of biological product highly similar to referral biologic drugs; they are increasing competition among biologics and have the potential to reduce the overall expenditures on biologics. In this comprehensive literature review, the current investigational biosimilars acting on retinal diseases are discussed. The authors review the results of clinical studies and highlight ongoing trials. Several biosimilar candidates are under evaluation and the pipeline will rapidly change in the future, as soon as each patent expires. Clinicians have to know these new therapeutic agents, which might come in the mainstream clinical practice as a more cost-efficient option.

Birth by cesarean section and mood disorders among adolescents of a birth cohort study in northern Brazil.

The increasing number of cesarean sections worldwide has encouraged research on the long-term effects of this birth type on the offspring's mental health. The objective of this study was to investigate whether there is an association between birth by cesarean section and the development of mood disorders (depression and bipolar disorders) in adolescents. A cohort study was carried out with 1603 adolescents from 18 to 19 years old who participated in the third phase of a birth cohort study in São Luís, MA, in 2016. Information on birth type and weight, prematurity, mother's age and schooling, parity, marital status, and smoking behavior during pregnancy, were collected at birth. The study outcomes were depression, bipolar disorder, and "mood disorder" construct. A Directed Acyclic Graph (DAG) was developed to select the variables for minimal adjustment for confounding and collision bias. Associations were estimated through propensity score weighting using a two-step estimation model, and confounders for cesarean birth were used in the predictive model. There was no significant association in the relationship between birth type and depression (95%CI: -0.037 to 0.017; P=0.47), bipolar disorder (95%CI: -0.019 to 0.045; P=0.43), and mood disorder (95%CI: -0.033 to 0.042; P=0.80) in adolescents of both sexes. Birth by cesarean section was not associated with the development of mood disorders in adolescents.

Birth by cesarean section and mood disorders among adolescents of a birth cohort study in northern Brazil

The increasing number of cesarean sections worldwide has encouraged research on the long-term effects of this birth type on the offspring's mental health. The objective of this study was to investigate whether there is an association between birth by cesarean section and the development of mood disorders (depression and bipolar disorders) in adolescents. A cohort study was carried out with 1603 adolescents from 18 to 19 years old who participated in the third phase of a birth cohort study in São Luís, MA, in 2016. Information on birth type and weight, prematurity, mother's age and schooling, parity, marital status, and smoking behavior during pregnancy, were collected at birth. The study outcomes were depression, bipolar disorder, and "mood disorder" construct. A Directed Acyclic Graph (DAG) was developed to select the variables for minimal adjustment for confounding and collision bias. Associations were estimated through propensity score weighting using a two-step estimation model, and confounders for cesarean birth were used in the predictive model. There was no significant association in the relationship between birth type and depression (95%CI: -0.037 to 0.017; P=0.47), bipolar disorder (95%CI: -0.019 to 0.045; P=0.43), and mood disorder (95%CI: -0.033 to 0.042; P=0.80) in adolescents of both sexes. Birth by cesarean section was not associated with the development of mood disorders in adolescents.

Pharmacological, Surgical and Diagnostic Innovations in Meniere's Disease: A Review.

PURPOSE: To investigate literature about pharmacological, surgical, and diagnostic innovations for Meniere's Disease (MD). SUMMARY: Meniere's disease is an inner ear disorder characterized by the presence of endolymphatic hydrops in the inner ear and symptomatology of recurrent and debilitating vertigo attacks, tinnitus, aural fullness, and fluctuating sensorineural hearing loss. Although many therapeutic options for MD have been proposed during years, no consensus has been reached by the scientific community. In the last decade, many therapeutic options have been proposed, as intratympanic steroid, intratympanic gentamicin, and intravenous glycerol. Recently, the role of the antisecretory factor in the diet of MD patients have been investigated. Surgery is recommended for intractable MD; some authors proposed new approaches including transcanal endoscopic infracochlear vestibular neurectomy, new marsupiliazation technique in sac surgery, and tenotomy of the stapedius and tensor tympani muscles.

When tumor doesn't read textbook. Third case of TTF1 and p40 co-expression in the same tumour cells in a non-small cell carcinoma. A potential new entity to consider?

INTRODUCTION: The 2011 WHO Classification for lung adenocarcinoma enlightened the need for a wise use of immunohistochemistry to preserve tissue for both diagnosis and molecular studies. The current recommendation is to use a panel comprising TTF1 and p40 to classify tumors with no clear squamous or glandular differentiation as many studies have showed the higher specificity of p40 over p63 as marker of squamous differentiation. However, the co-expression of both markers opens a new scenario with subsequent classification and potentially treatment issues. MATERIALS AND METHODS: We report a case of a non-small lung cell carcinoma (NSCLC) with coexistent expression of TTF1 and p40 in the same tumour cells. To our knowledge, this peculiar immunohistochemical profile is very rare, and thus a review of the clinical and molecular features including molecular variances of the tumour was performed. Review of the pertinent literature was also carried out. RESULTS: Two additional articles describing unusual cases of NSCLC with coexistent expression of TTF1 and p40 were found and compared to our case. Interestingly, they all carried out aberrant mutation in TP53 oncogene and were of advance stage. CONCLUSION: The positivity for both "squamous" and "adenocarcinomatous" markers and mutations of TP53 could be the expression of a not fully recognized variant of NSCLC with possible implications for classification, diagnosis and therapy.

Pleural chondroid metaplasia in a background of IgG4 plasma cell rich chronic inflammatory infiltrate: report of a rare case with review of literature.

Mesothelial reactive and degenerative changes secondary to inflammatory conditions, toxin exposure, neoplastic and non-neoplastic disease are often encountered in routine histopathology practice. Herein, we report a very rare case of pleural chronic inflammation with features suggestive for IgG4-related disease associated with the formation of a nest of mature, benign looking cartilage in the pleura of a middle age male patient. The review of the pertinent literature reveals that to date, only few cases of chondroid metaplasia or benign tumor (choristoma) are reported in mesothelium and only occasionally in this change is found in the pleura.

Cellular fibroma in the Douglas cavity, mimicking a malignant neoplasia: fibroma, fibrosarcoma or mitotically active cellular fibroma?

INTRODUCTION: Ovarian fibroma is a benign stromal tumour composed of spindle/ovoid fibroblastic cells producing collagen. Approximally 10% of fibromas are densely cellular with small amount of collagen. In these cases, if mild nuclear atypia is present, they are best addressed as cellular fibroma. However cellular fibroma may show a greater mitotic activity and therefore they should be referred as mitotically active cellular fibromas. Mostly benign, it is necessary to differentiate them from malignant tumours such as fibrosarcomas. METHODS: We report a case of an unusual presentation of mitotically active cellular fibroma, detected in the Douglas cavity of a young woman, with normal appearing ovaries and uterus, mimicking a malignant neoplasia clinically and on imaging. In fact abdominal mass may be associated with acute pain, resulting in clinical emergency, really difficult to distinguish from a frank malignancy, before surgical procedure. RESULTS: We described the clinical, radiological and pathological characteristics of our case and we make a comparison of what previously described in literature. DISCUSSION: The differential diagnosis among those entities is based on the microscopic features such as atypia and the number of mitoses. However, according to their dimensions, it may be necessary to generously sample these tumours and sometimes, to perform a panel of immunohistochemical markers, in order to make a correct diagnosis, establish the best treatment and the right follow-up. In fact, the prognosis is not certain, due to the possible recurrence, especially if not completely excised.

Solitary plasmacytoma of the tonsillar site associated with actinomyces infection: the possible role of IL-6.

ExtraMedullary Plasmacytoma (EMP) is a rare plasma cell tumor. It can occur in the upper aerodigestive tract and presents as a large nodule causing local compressive symptoms. A 79-year old woman presented to Otorhinolaryngology Department with progressive hearing loss and no other symptoms. Following PET/TC examination due to the suspicion of a lymphoproliferative disease, the patient underwent tonsillectomy and the diagnosis of solitary EMP was formulated. In addition to that, the histological examination of the tonsillar tissue revealed large colonies of filamentous bacteria, showing abundant sulphur granules and Splendore-Hoeppli phenomenon; these evidences indicating the presence of a chronic Actinomyces infection. Immunohistochemical analysis demonstrated a marked IL-6 immunoreactivity of the neoplastic plasma cells. Interestingly, a marked IL-6 immunoreactivity was also found in the tissue surrounding the Actinomyces colonies. In the present study we report for the first time a solitary EMP associated with Actinomycosis. It is tempting to speculate that the unsuspected and untreated Actinomyces infection, through chronic IL-6 production, could contribute to the neoplastic transformation of plasma cells.

Combined uterine smooth muscle tumour: a challenging case.

Uterine smooth muscle tumours that cannot be diagnosed unequivocally as benign or malignant should be termed 'smooth muscle tumours of uncertain malignant potential' (STUMP). Since there are no unequivocal morphological and ancillary criteria to differentiate this group of tumours, we present a case of a 49-year-old woman with a combined, benign and borderline lesion, which could have different clinical management strategies, and discuss the diagnostic issues.

Portal dose measurements by a 2D array.

A 2D array (PTW, type 10024), equipped with 729 vented plane parallel ion-chambers, has been calibrated as a detector for the in vivo comparison between measured and predicted portal doses for head-neck tumors. The comparison of absolute portal doses measured to ones predicted by a commercial treatment planning system within the field of view of the CT scanner, can help the delivered dose verification during different treatment fractions, in particular when the patient's present weight loss. This paper reports the preliminary results of the comparison of the portal doses measured by a PTW 2D array during several radiotherapy fractions and the predicted portal doses for seven patients undergoing head-neck tumor radiotherapy. The gamma index analysis supplied an agreement of more than 95% of the dose-point P(gamma)>95% within acceptance criteria, in terms of dose difference, DeltaD(max), and distance-agreement, Deltad(max), equal to 5% and 4mm, respectively. After the third week, one patient showed a decrease of P(gamma) values due to the markedly reduced patient's thickness. Even if the spatial resolution of the 2D array was 1cm, there were two advantages in the use of this 2D array as a portal dose device for IMRT quality control. The first one was the use of a stable and efficient absolute dosimeter for in vivo verification, although its construction and behavior for other gantry angles need to be tested, and the second one was the time efficiency in verifying the correct dose delivery in several fractions of the therapy. This study presents acceptance criteria for the comparison of TPS-predicted portal dose images with in vivo 2D ion-chamber measurements for IMRT. In particular, portal dose measurements offer clues for additional studies as to which indicators can signal the need for replanning during treatment.

Experimental dosimetry of a 32P catheter-based endovascular brachytherapy source.

The experimental dosimetry in a water phantom of a 32P linear source, 20 mm in length, used for the brachytherapy of coronary vessels is reported. The source content activity, A, was determined by means of a calibrated well ion-chamber and the value was compared with the contained activity reported in the manufacturer's certification. In this field of brachytherapy dosimetry, radiochromic film supplies a high enough spatial resolution. A highly sensitive radiochromic film, that presents only one active layer, was used in this work for the source dosimetry in a water phantom. The radiochromic film was characterized by electron beams produced by a clinical linac. A Monte Carlo calculation of beta spectra in water at different distances along the source transverse bisector axis allowed to take into account the low dependence of film response from the electron beam energy. The adopted experimental set-up, with the source in its catheter positioned on the film plane inside the water phantom, supplies accurate dosimetric information. The measured dose rate to water per unit of source activity at reference distance, D(r0, theta0)/A, in units of cGy s(-1) GBq(-1), was in agreement with the value reported in the manufacturer's certification within the experimental uncertainty. The radial dose function, g(r), is in good agreement with the literature data. The anisotropy function F(r, theta) is also reported. The analysis of the dose profile obtained at 2 mm from the source longitudinal axis shows that the uniformity is within 10% along 75% of the 20 mm treatment length. The adopted experimental set-up seems to be adequate for the quality control procedure of the dose homogeneity distribution in the water medium.

The wall correction factor for a spherical ionization chamber used in brachytherapy source calibration.

The effect of wall chamber attenuation and scattering is one of the most important corrections that must be determined when the linear interpolation method between two calibration factors of an ionization chamber is used. For spherical ionization chambers the corresponding correction factors A(w) have to be determined by a non-linear trend of the response as a function of the wall thickness. The Monte Carlo and experimental data here reported show that the A(w) factors obtained for an Exradin A4 chamber, used in the brachytherapy source calibration, in terms of reference air kerma rate, are up to 1.2% greater than the values obtained by the linear extrapolation method for the studied beam qualities. Using the Aw factors derived from Monte Carlo calculations, the accuracy of the calibration factor N(K,Ir) for the Exradin A4, obtained by the interpolation between two calibration factors, improves about 0.6%. The discrepancy between the new calculated factor and that obtained using the complete calibration curve of the ion-chamber and the 192Ir spectrum is only 0.1%.

Multi-modal volume registration by maximization of mutual information.

A new information-theoretic approach is presented for finding the registration of volumetric medical images of differing modalities. Registration is achieved by adjustment of the relative position and orientation until the mutual information between the images is maximized. In our derivation of the registration procedure, few assumptions are made about the nature of the imaging process. As a result the algorithms are quite general and can foreseeably be used with a wide variety of imaging devices. This approach works directly with image data; no pre-processing or segmentation is required. This technique is, however, more flexible and robust than other intensity-based techniques like correlation. Additionally, it has an efficient implementation that is based on stochastic approximation. Experiments are presented that demonstrate the approach registering magnetic resonance (MR) images with computed tomography (CT) images, and with positron-emission tomography (PET) images. Surgical applications of the registration method are described.

Patients' assessment of quality of care: a survey of a group of breast cancer patients in Italy.

Patients' assessment of quality of care was investigated in 825 women with breast cancer treated in a group of specialized and non-specialized institutions in Italy. A 10-page mail questionnaire explored patients' adjustment to the disease, satisfaction with care, and quality of the information on diagnosis and treatment. Most of the 428 (52%) responders reported good or acceptable adjustment to the disease (as reflected by acceptable performance in some daily living activities), and favorable judgment about care providers, but many women complained of hospital organizational deficiencies. A contradictory picture emerged regarding the quality of information. Completeness and thoroughness appeared seriously deficient when examined objectively using a series of explicit predefined criteria, but patients' assessments showed in most cases moderate or high satisfaction. The paper presents these results and discusses pros and cons in the use of patients' opinions for evaluation of quality of care.

Follow-up after mastectomy for breast cancer. Observations in 96 patients.

From 1978 to 1982 at the Oncology Unit of the Rho Hospital, we followed 96 women who had been operated for breast cancer. In 22 cases (23%) the first signs of recurrence were changes in the following: physical examination (9), symptoms (7), ESR (3), bone scan (2), alkaline phosphatase (1), chest X-ray (1). An adequate follow-up schedule is based on the following: a) limited examinations causing little disturbance to the patient, easily feasible, sensitive, specific, and of limited cost; b) lead-intervals of various tests set according to the risk of relapse; c) critical periodic review of the series, with constant updating of information in the literature.

Anionic glycoproteins and their hexosamine content in neoplastic patients: relationships with the clinical stage and the course of the disease.

In 40 healthy subjects, in 47 non-cancer patients, and in 142 cancer patients, perchloric acid soluble glycoproteins (PASG) and hexosamines were determined to investigate their tumor specificity and correlation with the tumor mass. Cancer patients were divided into three subgroups: CI, no evidence of cancer (after radical surgery); CII, locoregional disease; CIII, widespread metastatic disease. There was no statistically significant difference in PASG among normals, non-cancer and CI patients; hexosamines in non-cancer and in CI patients were higher (P less than 0.002) than in normals; both PASG and hexosamines were significantly higher in CII and CIII patients than in normals (P less than 0.001). In the CI group, 62% of patients who relapsed within 10 months after surgery had high hexosamine values, whereas 69% of patients who did not relapse showed normal levels (P less than 0.05). PASG and hexosamines significantly increased with cancer progression and decreased when objective response to treatment was achieved. They are not tumor specific, but seem to be related to the tumor burden; hexosamines seem to have some prognostic value.

[Epidemiological study of congenital heart diseases in the province of Parma during the years 1972-80 (author's transl)]. / Studio epidemiologico delle cardiopatie congenite nei nati in Parma e provincia negli anni 1972-80.

We have carried out an epidemiological-statistical study about congenital heart disease on 33.245 live-born infants in Parma from 1972 to 1980. 327 newborns with congenital heart disease were found; the incidence was 9,8/1000 live-born. The lowest value was 5,8/1000 live-born in 1972, the highest was 14,5/1000 live-born in 1977. In the majority of cases diagnosis was only clinical VSD, PDA, ecc.), whereas in the more complex cardiac malformations and in patients with severe congestive heart failure diagnosis was confirmed at cardiac catheterization and at surgery. In 60 cases diagnosis was confirmed also at autopsy. The congenital heart disease most frequently observed was VSD (33%), followed by PDA (13,4%) and TGA (8,8%), ecc. Clinical status at 1 year of age in all patients was evaluated. The Authors think that infant cardiac program is necessary to improve the results on congenital heart disease control.

Carcinogenicity studies on vinylidene chloride.

Results of a study on Wistar rats regarding a possible carcinogenic effect of vinylidene chloride (VDC) were presented previously by one of the authors. Due to the unclear character of these results, a second inhalation study was initiated with Sprague-Dawley rats. Groups of 60 animals were exposed to 100 and 75 ppm VDC, along with one control group. A final report on the pathological results must await completion of the microscopic examination of the tissues and organs from all the animals. Nevertheless, it seems clear that there is no grossly observable interrelation between tumor production and VDC inhalation.