The importance of molecular markers for diagnosis and selection of targeted treatments in patients with cancer.

The past 30 years have seen the introduction of a number of cancer therapies with the aim of restricting the growth and spread of primary and metastatic tumours. A shared commonality among these therapies is their targeting of various aspects of the cancer hallmarks, that is traits that are essential to successful tumour propagation and dissemination. The evolution of molecular-scale technology has been central to the identification of new cancer targets, and it is not a coincidence that improved therapies have emerged at the same time as gene expression arrays and DNA sequencing have enhanced our understanding of cancer genetics. Modern tumour pathology is now viewed at the molecular level ranging from IHC biomarkers, to gene signature classifiers and gene mutations, all of which provide crucial information about which patients will respond to targeted therapy regimens. In this review, we briefly discuss the general types of targeted therapies used in a clinical setting and provide a short background on immunohistochemical, gene expression and DNA sequencing technologies, before focusing on three tumour types: breast, lung and colorectal cancers. For each of these cancer types, we provide a background to the disease along with an overview of the current standard therapies and then focus on the relevant targeted therapies and the pathways they inhibit. Finally, we highlight several strategies that are pivotal to the successful development of targeted anti-cancer drugs.

Lung abscess in a child secondary to Mycoplasma pneumoniae infection.

We present a case of a lung abscess in a child 6-year-old admitted with a history of right hemithorax pain lasting for 15 days and the onset of mild fever in the last two days. Etiological research showed positivity of IgM antibodies to Mycoplasma pneumoniae after seven days of admission. The child has been successfully treated with antibiotic therapy, without the use of macrolides, for a duration of 4 weeks. Our study suggests that the Mycoplasma pneumoniae infection may predispose to severe infections, such as lung abscess, caused by typical respiratory pathogens. The reported case of lung abscess is one of the few reported in the literature in the modern antibiotic era and is the first preceded by Mycoplasma pneumoniae infection.

Two cases of neonatal adrenal hemorrhage presenting with persistent jaundice.

The adrenal hemorrhage is a relatively rare event in newborns but must be considered in the presence of a persistent unexplained jaundice, especially in presence of predisposing factors. Serial ultrasonography is the modality of choice for initial diagnosis and follow-up of neonatal adrenal hemorrhage. We report two cases of neonatal adrenal hemorrhage presenting with persistent jaundice. The causes of the neonatal adrenal hemorrhages were a difficult vaginal delivery in macrosomic infant and a neonatal infection.

Chronic massive fetomaternal hemorrhage in a newborn from immigrants. Clinical and organizational implications.

Fetomaternal hemorrhage (FMH) refers to the entry of fetal blood into the maternal bloodstream before or during delivery. FMH of more than 30 mL occurs with the frequency of about 1/300. Fetal outcomes may be compromised by still births, hydrops fetalis, cardiac complications, and increased rates of postpartum infant death. In most cases, the cause is not identified. Clinical manifestations of FMH depend on the volume of blood lost and the rate that it occurred. We report a case of chronic massive FMH in a newborn of an immigrant mother with a favorable outcome. Medical visits and tests during pregnancy, including ultrasound scans, were not performed. The baby was hemodynamically stable after birth, manifesting only pallor. The complete blood count revealed severe hypochromic anemia (hemoglobin 3,8 g/dl, hematocrit 14,4%) and reticulocytosis (reticulocyte 25,2%). There was no ABO blood type incompatibility and the result of direct Coomb's test was negative. The Kleihauer-Betke test revealed 5% of fetal erythrocytes in the maternal bloodstream equivalent to 180 mL. The fact that FMH can occur without prior risk factors, and the diagnosis is often postnatal, underscores the importance of heightened of medical suspicion particularly in infants born to immigrants where there is often the lack of prenatal visits.

Management of brain metastasized non-small cell lung cancer (NSCLC) - From local treatment to new systemic therapies.

Lung cancer has the highest frequency of brain dissemination compared to all other solid tumours. Classical treatment options such as brain irradiation have started to be questioned due to lack of survival benefit and risk for severe side effects. Oncogenic driven tumours have the highest frequency of brain dissemination among NSCLC patients and available targeted therapies have shown activity both intra-and extracranially, with an acceptable toxicity profile. The recent approval of immune checkpoint inhibitors for the treatment of NSCLC has complicated treatment selection even more. Data regarding efficacy of immune therapy in the CNS are limited, though promising, and data from larger cohorts are eagerly expected. The purpose of this review is to summarize all available treatment options for brain metastatic NSCLC with an emphasis on oncogenic driven tumours. Treatment selection for brain metastasized NSCLC patients is challenging because of the detrimental effect of potential treatment related CNS side effects in patients' quality of life. Clinical decision making should be done in an individualised way, taking both clinical and molecular factors into consideration.

Second-line chemotherapy for non-small cell lung cancer.

Despite being considered a standard of care, administration of second-line chemotherapy for non-small cell lung cancer is limited to patients in good performance status (ECOG PS 0-1) and to selected patients with PS 2. Drugs currently approved by FDA in this setting are docetaxel, gefitinib, erlotinib and pemetrexed, while in Europe those registered with this indication are only docetaxel and pemetrexed. This short review will focus on the role of pemetrexed, from the controlled phase II trial, to the development of the vitamin supplementation strategy to decrease toxicity, to the large phase III registration trial undertaken vs. the standard docetaxel. Moreover, the huge patient material collected during this latter trial has lead to further analyses to clarify several aspects of second-line treatment, from toxicity to quality of life assessment, to its role in elderly patients and to the direct translation in terms of costs. Finally, we will give a brief overview on current trials, that mainly explore the possibility to raise pemetrexed dose, and thus to increase its activity while maintaining an acceptable toxicity.

Neoadjuvant chemotherapy for stage IIIA-N2 non-small cell lung cancer.

Neoadjuvant chemotherapy in potentially resectable stage IIIA-N2 non-small cell lung cancer (NSCLC) has become standard of treatment in the last years. Two randomised pioneer phase III trials conducted with second generation platinum combinations had demonstrated an advantage in survival of induction chemotherapy followed by surgery versus surgery alone. Subsequently, a wide number of phase II studies with third generation platinum-based doublets or triplets have increased the evidence of the activity as well as the good tolerability of this approach. Nowadays, the main topics of ongoing clinical research are to assess the role of induction chemotherapy in early stage disease, and the role of induction radiotherapy, as well as definite chemo-radiotherapy in stage IIIA NSCLC. This report review these issues and focuses on current treatment options for resectable stage IIIA-N2 NSCLC.

[Combined treatment of thymoma. State of the art and our experience]. / Trattamento integrato del timoma. Stato dell'arte e nostra esperienza.

Thymoma is the most common neoplasm of the anterior mediastinum and is frequently associated with paraneoplastic syndromes. Surgery is the first therapeutic option, but in advanced disease a multidisciplinary approach is feasible, because of chemosensitivity and radiosensitivity of the disease. The natural history of thymoma after surgery points to local recurrence. Adjuvant radiotherapy seems to improve local control and survival. Chemotherapy based on cisplatin plus anthracyclines could be performed in advanced and metastatic disease. The optimal sequence of chemotherapy, radiation therapy and surgery is yet to be defined. In our experience, primary chemotherapy seems to give best results in advanced thymoma with good tolerability.

[Peritoneal papillary serous carcinoma: clinical report]. / Il carcinoma papillare sieroso del peritoneo: caso clinico.

Peritoneal papillary serous carcinoma (PPSC) is a rare tumour that involves the surface of the peritoneum, with prevalence in female patients and can originate from a single or multicentric focus is here described. A primary peritoneal serous carcinoma is here described. The patient has been treated with paclitaxel 175 mg/m2 and carboplatinum AUC 6.

Locally advanced non-small cell lung cancer: role of induction chemotherapy in resectable N2 disease.

Patients with resectable stage IIIA-N2 non-small cell lung cancer should receive induction chemotherapy before surgery. The aim is to early control systemic disease, eventually cure the mediastinal tumor spread and improve patients' survival. A recent metanalysis of randomized trials with second-generation platinum-based combinations has reinforced the evidence concerning the benefit of induction chemotherapy followed by surgery versus surgery alone in resectable disease. Moreover a large number of phase II trials have explored the activity and feasibility of platinum-based combinations with third-generation drugs in the same setting. Still opened questions to address with current clinical research are the eventual role of radiotherapy as induction treatment, the impact of definite chemoradiation versus induction treatment followed by surgical resection on local control and survival and finally the non-easy choice between neo-adjuvant and adjuvant chemotherapy.

Treatment of advanced non-small cell lung cancer.

In the last decade the treatment of advanced-metastatic non-small cell lung cancer has substantially improved. If in the early 90s there was still concern about the real efficacy of chemotherapy over best suppotive care alone in the advanced setting, constant developments in clinical research have demonstrated the survival advantage of active anti-cancer drugs not only in the first-line setting, but, lately, even in patients with recurrent disease after failure of two previous chemotherapy lines. With the premises of high throughput technologies, translational research is aiming to characterize patients and tumors on a molecular basis. With pharmacogenomics it would then be possible to accurately predict patient outcome and tailor the treatment strategy according to the geno-phenotype of single patients.

Cell volume regulation and transport mechanisms across the blood-brain barrier: implications for the management of hypernatraemic states.

UNLABELLED: Onset and correction of hypernatraemia constitute major hypertonic stresses for mammalian cells. Cells respond by activating specific osmoregulatory mechanisms allowing to preserve their volume and to adapt to their new environmental conditions. These processes have major implications in the management of hypernatraemia. In particular, cells chronically exposed to hypertonic conditions progressively accumulate organic osmolytes to maintain optimal intracellular electrolyte concentrations. During treatment of hypernatraemia, elevated intracellular organic osmotic content exposes cells to cellular oedema if sodium concentrations are rapidly corrected. In addition, circulating ions equilibrate slowly across the blood-brain barrier during acute changes in plasma osmolality. This can generate major brain water shifts and severe cerebral lesions related to brain shrinking or cerebral oedema. CONCLUSION: The basic mechanisms involved in brain ion and water transport are reviewed. A proper understanding of these processes is essential to develop appropriate treatment strategies in managing children with hypernatraemia.

Renal mass dosing and graft function in children transplanted from pediatric donors.

It has been suggested that "renal mass dosing" may affect graft evolution. Between 1993 and 1999, 43 children, aged 4-17 years, received 43 pediatric cadaveric grafts. The ratio between graft volume (calculated by ultrasound within the first 24 h from transplantation, by ellipsoid formula) and the recipient's body surface area (BSA) ranged between 14.1 and 110 ml/m(2). Three groups were identified: group 1, 14-29 ml/m(2) (13 patients); group 2, 30-39 ml/m(2) (16 patients); group 3, 40-110 ml/m(2) (14 patients). As a consequence of the different renal volume increments in the three groups during the first year after transplant, no differences in the absolute renal volume were observed at the end of follow-up. The average follow-up was 38 months (range 12-80). In the 37 routine graft biopsies, performed on average 13 months after transplantation and with more than five glomeruli, maximum mean glomerular diameters were mostly above normal values. There were no significant differences among the three groups. At the end of follow-up, the three groups did not differ in microalbuminuria, proteinuria, glomerular function or in incidence of hypertension. From this retrospective study, we conclude that the very wide range of renal mass dosing did not cause differences in medium-term graft evolution. A longer follow-up will be necessary to ascertain the possible influence of disproportion between pediatric donors and recipients, on a long-term graft outcome.