Platin desensitizations in thoracic malignancies and risk factors for breakthrough reactions.

Although platin desensitization is a safe and effective alternative for patients with hypersensitivity reactions (HSRs), sometimes breakthrough reactions (BTRs) can be encountered. However, data about the risk factors for BTRs are limited. The aim of this study is to define the outcomes of desensitization, the characteristics of BTRs, and to identify the risk factors for BTRs with platins in thoracic malignancies. This is a retrospective report of patients with thoracic malignancies who underwent platin desensitization. Patients' demographics, initial HSR characteristics, skin test results, desensitization outcomes, and BTR characteristics were recorded. Thirty-three lung cancer and 14 malignant pleural mesothelioma (MPM) patients were included in the study. The culprit drug was cisplatin in 29 and was carboplatin in 18 patients. Skin test positivity was 43.5% with cisplatin, 50% with carboplatin, and it was found to be higher if the interval between the initial HSR and skin testing (ST) was ˃20 days (p = 0.027). One hundred and five desensitization courses were performed. Twenty-two patients had 33 BTRs. Skin test positivity was higher in the BTR-positive group (p = 0.025). BTRs (18.2%; n = 6) were more severe than initial HSR. In the case of epinephrine administration during initial HSR, epinephrine administration during the first BTR was found to be more (p = 0.036). The target dose was achieved in 92.4% of desensitization courses. The number of previous platin infusions ≥10 was found to be an independent risk factor for BTR development (p = 0.036 OR:17.641, 95% CI: 1.211-256.971). Identification of risk factors for BTR will guide appropriate management and desensitization approaches for platin HSRs.

Cigarette smoking and hOGG1 Ser326Cys polymorphism are associated with 8-OHdG accumulation on mitochondrial DNA in thoracic esophageal squamous cell carcinoma.

BACKGROUND: We examined whether cigarette smoking affects the degrees of oxidative damage (8-hydroxyl-2'-deoxyguanosine [8-OHdG]) on mitochondrial DNA (mtDNA), whether the degree of 8-OHdG accumulation on mtDNA is related to the increased total mtDNA copy number, and whether human 8-oxoguanine DNA glycosylase 1 (hOGG1) Ser326Cys polymorphisms affect the degrees of 8-OHdG accumulation on mtDNA in thoracic esophageal squamous cell carcinoma (TESCC). METHODS: DNA extracted from microdissected tissues of paired noncancerous esophageal muscles, noncancerous esophageal mucosa, and cancerous TESCC nests (n = 74) along with metastatic lymph nodes (n = 38) of 74 TESCC patients was analyzed. Both the mtDNA copy number and mtDNA integrity were analyzed by quantitative real-time polymerase chain reaction (PCR). The hOGG1 Ser326Cys polymorphisms were identified by restriction fragment length polymorphism PCR and PCR-based direct sequencing. RESULTS: Among noncancerous esophageal mucosa, cancerous TESCC nests, and metastatic lymph nodes, the mtDNA integrity decreased (95.2 to 47.9 to 18.6 %; P < 0.001) and the mtDNA copy number disproportionally increased (0.163 to 0.204 to 0.207; P = 0.026). In TESCC, higher indexes of cigarette smoking (0, 0-20, 20-40, and >40 pack-years) were related to an advanced pathologic N category (P = 0.038), elevated mtDNA copy number (P = 0.013), higher mtDNA copy ratio (P = 0.028), and increased mtDNA integrity (P = 0.069). The TESCC mtDNA integrity in patients with Ser/Ser, Ser/Cys, and Cys/Cys hOGG1 variants decreased stepwise from 65.2 to 52.1 to 41.3 % (P = 0.051). CONCLUSIONS: Elevated 8-OHdG accumulations on mtDNA in TESCC were observed. Such accumulations were associated with a compensatory increase in total mtDNA copy number, indexes of cigarette smoking, and hOGG1 Ser326Cys polymorphisms.

Development of hibernomas in rats dosed with phentolamine mesylate during the 24-month carcinogenicity study.

Phentolamine is a reversible competitive alpha-adrenergic antagonist with similar affinities for alphal and alpha2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora cavernosa. Phentolamine mesylate was administered to rats by oral gavage at daily doses of 10, 50, and 150 mg/kg for 24 months. A dose-related increase in mortality, ascribed to an exaggerated pharmacologic effect, was seen at high doses. Systemic exposure as measured by plasma drug concentration increased with dose and duration of dosing and slight drug accumulation occurred, particularly in high-dose males. In the treated groups, 10 males and 1 female were diagnosed with hibernomas, neoplasms of brown adipose tissue, which appeared in the thoracic cavity or retroperitoneal area as circumscribed, tan to reddish-brown lobulated masses. Histologically, the masses were well circumscribed with variably sized lobules defined by a rich capillary network and consisted of closely apposed oval to polygonal cells with large amounts of cytoplasm and a centrally located nucleus. The cytoplasm's appearance varied from multivacuolated to univacuolated to granular eosinophilic. In a few cases, neoplastic emboli were observed in capsular vessels. Ultrastructurally, the neoplastic cells contained numerous mitochondria with transverse parallel cristae that occupied over 60% of the cytoplasm and lipid droplets. This study documents the previously unreported development of hibernomas in rats treated with phentolamine mesylate.

[Carcinomas of internal organs and their relationship to arsenical drinking water in the Republic of Argentina]. / Los carcinomas de los órganos internos y su relación con las aguas arsenicales de consumo en la República Argentina.

Presently exist only four regions where the supply of drinking water with an abnormally high content of arsenic and/or its salts, produces cutaneous signs generically termed "arsenical toxidermias" or "chronic arsenism"; they are: Mexico, Taiwan, Chile and Argentina. In this paper details are given of the typical skin lesions of hydroarsenism and the generally multiple epitheliomas of varied histological and clinical pattern in 340 patients; the diseases characterized for not being acute but chronic and the relanodermia holds a secondary place. Among histologically diagnosed carcinomas, deep basal-cell (276) and superficial multiple basal-cell (130) carcinomas predominate over the squamous-cell carcinomas (239) and Bowen disease (113); 18 mixed carcinomas were found. In these 340 patients, 51 carcinomas of the internal organs (15%), 34 of lungs, 8 of larynx, 3 of stomach, 2 of liver and 1 of pharynx, trachea, esophagus and breast in a man were diagnosed, which evolved in a similar manner to that of not arsenical patients.

Morphological aspects of mesotheliomas after intratracheal instillations of fibrous dusts in Syrian golden hamsters.

After intratracheal instillation of glass fibres and crocidolite in male Syrian golden hamsters, besides lung carcinomas a number of mesotheliomas of the epitheloid type occurred. These were examined with light microscopy (LM) and scanning electron microscopy (SEM); the characteristics of the tumours are described.

[The oncogenic effect of fibrous dust. Animal experiments and their relationship with human carcinogenesis]. / L'effet oncogène des poussières fibreuses. L'expérimentation animale et ses relations avec la carcinogénèse humaine

The results after intraperitoneal injection of fibrous and granular dusts in rats suggest, that the fibrous shape of asbestos is the cause of its cancerogenicity. Fibrous dusts other than asbestos (for example glass fibers) may induce tumours, when their diameters are like that of asbestos and the fibres are invariable in tissue. It is supposed, that a fibre with a diameter less than 1 mum and a length greater than 3 mum has a cancerogenic effect. The interpretation of the experimental results considering the cancerogenesis in humans is discussed, especially concerning the effect of fibrous glass.