Late toxicities burden in patients with radioiodine-refractory differentiated thyroid cancer treated with lenvatinib.

PURPOSE: Radioactive-iodine (RAI)-resistant differentiated thyroid cancer (DTC) patients benefit from multi-kinase inhibitors (MKIs), such as lenvatinib. Incidence of treatment-related (TR) late toxicities has been not yet described. METHODS: From January 2015 to June 2019 we retrospectively reviewed clinical records of patients with RAI-resistant DTC treated with lenvatinib at Istituto Nazionale dei Tumori (Milan, Italy). New side effect of any grade, appeared after 12 months of lenvatinib, was defined as late adverse event (AE). Descriptive analyses were performed. Survival curves were estimated with Kaplan-Meier method and compared with log-rank test. RESULTS: Thirty-seven patients were included, 65% had ≥65 years and 68% were female. Thirty patients received lenvatinib for >12 months. Lenvatinib was started at ≤20 mg/daily in 59% of patients, 64% were ≥65 years. The frequency of late AEs was 80% and cardiovascular toxicity was the most common (57%). There was no difference in the incidence of late AEs between younger/older population (77% and 82%, respectively). Median lenvatinib treatment duration (TD) was 39.96 months (95% CI 21.64-NR): 39.96 months for patients <65 years (95% CI: 13.25-NR) and 37.53 months for those ≥65 years, respectively (95% CI: 15.85-NR). Median overall survival (OS) was 39.96 months (95% CI: 21.84-NR), no statistically differences in OS was observed between younger (<65 years) and older patients (≥65 years) (HR 1.013; 95% CI 0.963-1.065; p = 0.62). CONCLUSION: Late toxicity burden of lenvatinib is not negligible. Cardiovascular toxicity remains the principal side effect even after a prolonged lenvatinib exposition.

Adjuvant androgen deprivation therapy for poor-risk, androgen receptor-positive salivary duct carcinoma.

AIM: Salivary duct carcinoma (SDC), an aggressive subtype of salivary gland cancer, is androgen receptor (AR)-positive in 67-96% of cases. In patients with locally recurrent and metastatic (R/M) AR-positive SDC, androgen deprivation therapy (ADT) has an overall response rate of 18-64.7%. In this study, we describe the efficacy of adjuvant ADT in patients with poor-risk (stage 4a) AR-positive SDC. METHODS: This is a retrospective cohort study in which patients with stage 4a AR-positive SDC were offered adjuvant ADT, i.e. bicalutamide, luteinizing hormone-releasing hormone (LHRH) analogue or a combination of these after tumour resection. In the control group, data were collected on patients with stage 4a SDC who underwent a tumour resection but did not receive adjuvant ADT. RESULTS: Twenty-two AR-positive SDC patients were treated with adjuvant ADT for a median duration of 12 months. The control group consisted of 111 SDC patients. After a median follow-up of 20 months in the ADT-treated patients and 26 months in the control group, the 3-year disease-free survival (DFS) was estimated as 48.2% (95% confidence interval [CI] 14.0-82.4%) and 27.7% (95% CI 18.5-36.9%) (P = 0.037). Multivariable Cox regression analysis showed a hazard ratio of 0.138 (95% CI 0.025-0.751, P = 0.022) for DFS and 0.064 (95% CI 0.005-0.764, P = 0.030) for overall survival (OS) in favour of the ADT-treated patients. CONCLUSION: Poor-risk, AR-positive SDC patients who received adjuvant ADT have a significantly longer DFS compared with patients in the control group, who did not receive adjuvant ADT. For OS, this was just below and above the significance level, in case there was or was no correction for confounders.

Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer.

BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial. METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC. RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup. CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.

Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients.

Four tyrosine kinase inhibitors (TKIs) have been recently licensed in thyroid cancer (TC), sorafenib and lenvatinib for differentiated TC, vandetanib and cabozantinib for medullary TC. Others TKIs such as axitinib, pazopanib, sunitinib, have been tested within phase II trials. The toxicity burden associated to TKIs is not negligible. Drug reductions and interruptions are common, definitive drug withdrawals have also been reported as well as toxic deaths in more rare cases. In this context, the prevention of toxicities is mandatory to allow patients to stay on treatment as long as possible without dose and schedule modifications. Both physicians and patients should be educated to recognize drug-related toxicities in order to manage them in an early phase. Tools (e.g. toxicities summary booklet) for physicians and patients could be considered to improve the knowledge on side effects management. Guidelines, whenever available, should be followed.

The steroid response to human chorionic gonadotropin (hCG) stimulation in men with Klinefelter syndrome does not change using immunoassay or mass spectrometry.

PURPOSE: Liquid-chromatography tandem mass-spectrometry (LC-MS/MS) was developed in parallel to Immunoassays (IAs) and today is proposed as the "gold standard" for steroid assays. Leydig cells of men with Klinefelter syndrome (KS) are able to respond to human chorionic gonadotropin (hCG) stimulation, even if testosterone (T) production was impaired. The aim was to evaluate how results obtained by IAs and LC-MS/MS can differently impact on the outcome of a clinical research on gonadal steroidogenesis after hCG stimulation. METHODS: A longitudinal, prospective, case-control clinical trial. (clinicaltrial.gov NCT02788136) was carried out, enrolling KS men and healthy age-matched controls, stimulated by hCG administration. Serum steroids were evaluated at baseline and for 5 days after intramuscular injection of 5000 IU hCG using both IAs and LC-MS/MS. RESULTS: 13 KS patients (36 ± 9 years) not receiving T replacement therapy and 14 controls (32 ± 8 years) were enrolled. T, progesterone, cortisol, 17-hydroxy-progesterone (17OHP) and androstenedione, were significantly higher using IAs than LC-MS/MS. IAs and LC-MS/MS showed direct correlation for all five steroids, although the constant overestimation detected by IAs. Either methodology found the same 17OHP and T increasing profile after hCG stimulation, with equal areas under the curves (AUCs). CONCLUSIONS: Although a linearity between IA and LC-MS/MS is demonstrated, LC-MS/MS is more sensitive and accurate, whereas IA shows a constant overestimation of sex steroid levels. This result suggests the need of reference intervals built on the specific assay. This fundamental difference between these two methodologies opens a deep reconsideration of what is needed to improve the accuracy of steroid hormone assays.

Lymphoepithelioma-like carcinoma of the skin.

The term lymphoepithelioma-like carcinoma identifies a group of nasopharingeal epithelial tumors characterized by aggregates of malignant undifferentiated cells surrounded by a dense reactive lymphoplasmacellular infiltrate. Primary cutaneous localization is rare, with approximately 30 cases reported in literature. We describe a case of primary lymphoepithelioma-like carcinoma of the skin in a 92-year-old woman. Immunohistochemical examination was positive for cytokeratine (KL1 and EMA) as regards epithelial cells, while the lymphocitic infiltrate was positive for LCA and CD3. In situ hybridization for Epstein Barr virus in tumor cells was negative. Electron microscopy showed rounded and occasionally spindle-shaped poorly-differentiated squamous epithelial cells, and a lymphoid stroma consisting mostly of normal-appearing small lymphocytes. Examination of the nasopharynx did not show any tumoral mass and after a 7 years follow-up the patient is free of local and distant recurrences. This tumor affects people aged over 50 years and is localized to the face, but scalp, shoulder and forearm may be involved. Research of Epstein-Barr virus is always negative in this tumor, unlike nasopharingeal epithelial carcinoma. The differential diagnosis of lymphoepithelioma-like carcinoma of the skin may present some difficulties and includes squamous cell carcinoma. Lymphoepithelioma-like carcinoma of the skin is a malignant neoplasm which tends to relapse locally and has a moderate tendency to metastatize.

Expression of the high-affinity laminin receptor (67 kDa) in normal human skin and appendages.

The interaction of cells with extracellular matrix components plays a significant role in the regulation of cell biology. Laminin is a large glycoprotein involved in fundamental interactions between cells and the basement membrane. Several cell surface receptors are responsible for cell-matrix interactions. The 67 kDa high affinity laminin receptor, 67LR, is involved in the adhesion of normal cells to the laminin network and is also associated with the metastatic phenotype of some tumoral cells. We have investigated the expression of laminin and of the 67LR in normal human skin using immunoperoxidase staining. Twenty samples of skin were analyzed. Antibody against laminin reacted in a continuous linear band at the dermal-epidermal junction, as well as basement membranes of hair follicles, sebaceous and eccrine sweat glands, and dermal blood vessels. The epidermis and the follicular epithelium were negative for laminin. The 67LR seemed not to be expressed on the basal surface of basal keratinocytes. The major expression of this receptor may be detected in the upper half of the spinous layer and in the granular layer. The cells of the outer root sheath in hair follicle showed the same immunohistochemical pattern described for epidermis. In sebaceous glands and in eccrine sweat glands the secreting epithelium was positive. Endothelial cells of dermal blood vessels were routinely positive for 67LR. We observed that the expression of the 67LR in normal human skin is mostly located in epidermal areas in which the keratinizing process was particularly advanced.

An outbreak of vancomycin-resistant Enterococcus faecium in liver transplant recipients.

Vancomycin-resistant Enterococcus faecium (VREF) has become a significant nosocomial pathogen for immunosuppressed patients. During a 5-month period in 1993, 8 cases of invasive infection with VREF (7 with bacteremia) were identified in liver transplant recipients, half of whom were adults. Epidemiology and microbiology studies were designed to identify the source and to determine the risk factors for this infection. Overall mortality was 50% (3 adults and 1 child). Mortality in bacteremic patients was 57%. A case-control study showed that cases were more likely to have been treated with a third-generation cephalosporin or vancomycin and to have undergone more than four biliary tract procedures. Environmental surveillance cultures yielded only one VREF isolate from a rectal temperature probe, but this device was used in only 2 of the cases. Cultures from all surgery and radiology suites were negative. All VREF isolates were genotyped by contour-clamped homogenous electric field electrophoresis of chromosomal DNA restriction fragments. These studies showed that a single clone was responsible for the outbreak, although other clones could be detected in the hospital. After implementing strict contact isolation on the liver transplant unit, only 1 additional patient with VREF was identified during this outbreak. In conclusion, it was found that antibiotic use and biliary tract manipulation were risk factors for developing invasive infections with VREF after liver transplantation. Optimal treatment is still unclear but most likely includes a combination of two or more antibiotics. Prompt institution of infection control measures can preclude rapid spread of this nosocomial pathogen.

Anaplastic progression of classic Kaposi's sarcoma.

We describe a case of classic Kaposi's sarcoma (KS) in an Italian HIV-negative patient, with bone involvement and progression to anaplastic histotype. At the age of 22, violaceous patches of KS appeared on his feet. At the age of 50, he noted the appearance of a violaceous firm nodule on his right wrist. The lesions grew rapidly and became ulcerated. Radiotherapy led to a complete remission of symptoms. At the age of 55, a subcutaneous nodule developed on the proximal third of the right forearm associated with a wide painful edema of the right forearm and the proximal third of the right arm. The nodule enlarged rapidly, and an X-ray of the right forearm revealed the presence of a large osteolytic area of the ulna. A biopsy specimen from the right ulna showed bone erosion by a mesenchymal neoplasia with a high degree of malignancy. The right arm was amputated, and histologic examination of the surgical material confirmed the diagnosis of undifferentiated spindle-cell malignant neoplasia strongly positive for factor-VII-related antigen and CD34 antigen. Three years after surgical treatment, no recurrences have been observed.

[Eosinophilic pustular folliculitis and Ofuji disease. A case report]. / Le follicoliti pustolose eosinofiliche e la malattia di Ofuji. Caso clinico.

We describe the case of a young man of Calabrian origin, who came to our observation for the appearance of erythematous pustular, intensely itching, lesions on the arms, trunk and, in a less extent, on the face. The blood count revealed a differential cell count of 16.8% eosinophils. Serum IgE levels were elevated (1000 IU/ml), and T cell subsets showed an increase in CD8+ and a decrease in CD4+ with an inversion of CD4+/CD8+ ratio (= 0.78). The result of the following investigations were either normal or negative: anti-(ds)DNA antibody, anti-nuclear antibody, anti-smooth muscle antibody, anti-striated muscle antibody, serological tests for viral, bacterial, fungal and parasitic diseases and cultural examination of the material from lesion. Histopathological examination of a biopsy specimen from the left arm showed the presence of abundant perivascular inflammatory infiltrate in the dermis and inflammatory infiltrate, with numerous eosinophils, around sebaceous glands. Taken together, all these data suggest the diagnosis of eosinophilic pustular folliculitis, a dermatosis of unknown etiology, with a histopathological picture identical to Ofuji's disease. Eosinophilic pustular folliculitis can be associated with HIV infection or haematological diseases (as non-Hodgkin lymphomas, myeloma, etc.); it was also reported in adult immunocompetent healthy individuals and in children. On the basis of our findings, we propose that this case should be classified as an idiopathic form, as we were not able to demonstrate any associated disease.

[Cutaneous tuberculosis: a case of difficult classification]. / Tubercolosi cutanea: un caso di difficile classificazione.

We describe a case of cutaneous tuberculosis in a 25-year-old Philippine man. Erythematous papulo-nodular lesions, measuring 0.5 to 1 cm, were present on lower limbs; a 2 cm nodule was located on the left flank. The examination of the skin biopsy showed the presence of a superficial and deep perivascular dermatitis with histiocytes, lymphocytes and plasma cells. Ziehl-Nielsen stain for mycobacterium were negative, while the cultural examination led to the isolation of M. tuberculosis. Direct smear and cultural examination of sputum for M. tuberculosis were negative; chest and skeletal roentgenograms, syphilis and HIV infection serology, haematological and hematochemical examinations and urinalysis were negative. Specific treatment with isoniazid, rifampin and ofloxacin led to a rapid remission of cutaneous lesions. This case was particularly difficult to classify, but the Authors think it would be considered a tuberculid.

[Mastocytosis. A case of urticaria pigmentosa with a systemic malignant evolution]. / Mastocitosi. Un caso di urticaria pigmentosa ad evoluzione sistemica maligna.

A case of systemic mastocytosis with a malignant course, started as urticaria pigmentosa in adult age, is reported. The progression from cutaneous to systemic involvement has been marked by increasing hypereosinophilia which can be considered an important sign of adverse prognosis.

Effect of a dressing radiation field on the laser-induced collisional energy-transfer line shape.

We describe a new scheme suitable for the study of strong-field effects on the laser-induced collisional energytransfer process. The use of two independently tuned radiation fields, to induce the interatomic transition and to modify the energy levels, is found to give rise to a splitting of the excitation spectrum peak, similar to the Autler-Townes doublet. Owing to the resonant coupling, an observable splitting of a few inverse centimeters can be induced by a dressing laser intensity of the order of 10 MW/cm(2).

Whole-lung tomography in urologic malignancy.

The place of whole-lung tomography in urologic malignancy has not been established. We reviewed 88 cases of known or suspected urologic malignancy in which tomography was used. Most patients had renal, bladder, or testicular tumors. Of the 68 patients with negative screening chest roentgenograms, all but 2 had negative tomograms. One of these 2 patients had a normal chest film (the other had extrapulmonary metastasis), and he did not have the renal carcinoma initially suspected. Tomography discovered no metastases from urologic malignancy that was not already known about from the screening x-ray film. In 20 cases with a positive screening x-ray film, tomography was of limited value. It cleared two suspicious chest films and added information on extent of metastatic involvement in three. We conclude that whole-lung tomography adds little information not available by chest roentgenogram in our selected population, and with a negative screening chest film no additional chest study is needed.

[Cancer of the colon and cholelithiasis: bile bacteria, composition of the stones and the bile]. / Cancro del colon e colelitiasi: bactibilia, composizione dei calcoli e della bile.

Our recent studies have shown a significant association between lithiasic biliary disease and colorectal cancer. This could be due to the existence of risk factors common to both disease or to a cause-effect correlation between them. This latter hypothesis is supported by the observation in gallstone patients of the increase of biliary and fecal concentrations in secondary biliary acids. These could have co-carcinogenic effect on the colon. With a view to singling out further elements which might help us to understand more clearly the possible cause-effect correlation between cholelithiasis and colon cancer, we examined 12 patients affected by both diseases. In these, we evaluated the composition of the gallbladder stones, by means of spectrophotometry and diffractometry. Bile samples were taken from the gallbladder and used to examine the lipidic composition and the cholesterol saturation index according to Carey. In addition bacteriological examinations were carried out. The results were compared with those of 10 patients with cholelithiasis but not cancer, 10 with cancer but not cholelithiasis and 10 with neither. Analysis of the results did not reveal significant differences in gallstone and bile composition between colon cancer patients with concomitant gallstones and control groups. However, in cancer patients with gallstones a higher incidence of bile bacteria (35.7%) was observed than in the other groups. Bile bacteria were observed more frequently in right colon cancer patients who had pigment stones in 75% of the cases. The results seem to evidence peculiarities in patients with a cancer of right colon.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcitonin inhibition of growth hormone-releasing hormone-induced GH secretion in normal men.

Calcitonin has been shown to modulate pituitary hormone secretion in a variety of ways. In this study we examined the effects of a salmon calcitonin infusion on GHRH-induced GH secretion in 5 normal men. In addition, in vitro experiments were performed using primary cultures of rat anterior pituitary cells in order to examine whether there is a direct pituitary effect of CT. Infusion of CT significantly blunted the GH response to GHRH in all subjects without affecting basal GH secretion or plasma calcium levels. Infusion of CT was accompanied by significant increases in ACTH, beta-endorphin, cortisol and free fatty acid levels, and by a significant decrease in serum insulin levels. The addition of CT to primary cultures of rat pituitary cells did not alter basal or stimulated secretion of GH or ACTH. These results indicate that: 1) CT blunts the GH response to GHRH; 2) CT infusion results in the stimulation of the hypothalamic-pituitary-adrenal axis, and 3) this effect is probably exerted at the hypothalamic level, since no direct activity of CT was documented in vitro on either GH or ACTH secretion.

Laser dentistry: root canal diagnostic technique based on ultraviolet-induced fluorescence spectroscopy.

A diagnostic technique to detect residual tissues at different levels of the root canal during an endodontic treatment is presented. The diagnostic system is based on ultraviolet-induced fluorescence spectroscopy and uses suitable optical fibers for local delivery of excitation light and to collect back fluorescence spectra. Spectra of root canal tissues have been obtained from split teeth by labeling with a fluorescent solution. Residual tissue can be discriminated in respect to healthy dentin because of their different spectral responses: the spectral shape of the first response shows a clear peak at 530 nm because of a selective absorption of the fluorescent dye, whereas for the second response, the spectral curve monotonically increases toward ultraviolet wave-lengths with no particular structure. This technique has been tested on unsplit teeth simulating operative conditions. A compact spectroscopic system has been devised that can be easily integrated in an excimer laser system to perform residual tissue detection during laser cleaning of the canals.

Induction of ovulation for gamete intrafallopian transfer (GIFT) using a gonadotropin-releasing hormone agonist and "pure" FSH: results obtained in 30 normally menstruating women.

About 30% of the ovulation induction cycles in GIFT and FIVET programmes are cancelled due to an inadequate response of patients to gonadotropins and/or clomiphene citrate. GnRH agonist-gonadotropins and/or "pure" FSH combination has been successful in inducing ovulation in patients with a previous history of cycle cancellation and/or alterations in the menstrual cycles. In order to reduce the number of cycle cancellations and obtain more homogeneous oocytes, GnRH agonist-gonadotropins and/or "pure" FSH combination in all candidates for GIFT and FIVET has been recently hypothesised. The Authors report results obtained from GnRH agonist-"pure" FSH combination in 30 normally menstruating patients of the GIFT programme: in 93% of cases the harvested oocytes were preovulatory, in 27.6% of cycles and in 28.6% of the GIFTs respectively an ongoing pregnancy was obtained. While the results obtained must be considered preliminary, they nevertheless suggest that the use of a combination of GnRH-agonist "pure" FSH in all patients in the GIFT programme may be of real clinical validity.

Evidence of neurologic dysfunction related to long-term ethylene oxide exposure.

Eight hospital workers with chronic ethylene oxide exposure were age-sex matched with eight nonexposed controls with no significant differences in educational backgrounds and vocabulary scores. The exposed group performed more poorly on all eight measures of cognition, memory, attention, and coordination, with 71.3% less accuracy on the Hand-Eye Coordination Test. There was a dose-response relationship between exposure and the following: Continuous Performance Test and sural velocity. These findings suggest that neurologic dysfunction may result from long-term low-dose exposure to ethylene oxide, and that these effects may occur at exposure levels common in hospital sterilizer operations.

[Acute respiratory syndromes caused by viruses in a pediatric department. Clinical and epidemiological studies of a series of cases admitted in the period from February to May, 1979]. / Le sindromi respiratorie acute da virus in un reparto pediatrico. Studi clinico-epidemiologici su una casistica raccolta nel periodo febbraio-maggio 1979.

In the period between February and May 1979, in concomitance with a sharp increase in admittance to the pediatric Division of the Parma General Hospital for acute respiratory infections, we carried out a virologic and serologic investigation on hospitalized children aged 21 days-12 years. The investigation was carried out on 137 patients with respiratory diseases: 33 with bronchiolitis, which occurred mainly (32/33) between February and March in children that were prevalently (30/33) in the first year of life; 27 with upper respiratory tract infections; 54 with mid respiratory tract infections; 23 with pneumonia. Forty-eight controls (without respiratory infections) were also investigated. In the months of February and March there was a high circulation of respiratory syncytial virus (RSV): throughout the entire period there was a lower incidence of Adenovirus infections and more uniformly distributed.