Claudia Scaringi

Multidose Stereotactic Radiosurgery (9 Gy × 3) of the Postoperative Resection Cavity for Treatment of Large Brain Metastases

PURPOSE To evaluate the clinical outcomes with linear accelerator-based multidose stereotactic radiosurgery (SRS) to large postoperative resection cavities in patients with large brain metastases. METHODS AND MATERIALS Between March 2005 to May 2012, 101 patients with a single brain metastasis were treated with surgery and multidose SRS (9 Gy × 3) for large resection cavities (>3 cm). The target volume was the resection cavity with the inclusion of a 2-mm margin. The median cavity volume was 17.5 cm(3) (range, 12.6-35.7 cm(3)). The primary endpoint was local control. Secondary endpoints were survival and distant failure rates, cause of death, performance measurements, and toxicity of treatment. RESULTS With a median follow-up of 16 months (range, 6-44 months), the 1-year and 2-year actuarial survival rates were 69% and 34%, respectively. The 1-year and 2-year local control rates were 93% and 84%, with respective incidences of new distant brain metastases of 50% and 66%. Local control was similar for radiosensitive (non-small cell lung cancer and breast cancer) and radioresistant (melanoma and renal cell cancer) brain metastases. On multivariate Cox analysis stable extracranial disease, breast cancer histology, and Karnofsky performance status >70 were associated with significant survival benefit. Brain radionecrosis occurred in 9 patients (9%), being symptomatic in 5 patients (5%). CONCLUSIONS Adjuvant multidose SRS to resection cavity represents an effective treatment option that achieves excellent local control and defers the use of whole-brain radiation therapy in selected patients with large brain metastases.

Health-related quality of life in elderly patients with newly diagnosed glioblastoma treated with short-course radiation therapy plus concomitant and adjuvant temozolomide

PURPOSE To describe the quality of life (QOL) in elderly patients with glioblastoma (GBM) treated with an abbreviated course of radiation therapy (RT; 40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide (TMZ). METHODS AND MATERIALS Health-related QOL (HRQOL) was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30, version 3) and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20). Changes from baseline in the score of 9 preselected domains (global QLQ, social functioning, cognitive functioning, emotional functioning, physical functioning, motor dysfunction, communication deficit, fatigue, insomnia) were determined 4 weeks after RT and thereafter every 8 weeks during the treatment until disease progression. The proportion of patients with improved HRQOL scores, defined as a change of 10 points or more, and duration of changes were recorded. RESULTS Sixty-five patients completed the questionnaires at baseline. The treatment was consistently associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time; mean score differed by 9.6 points between baseline and 6-month follow-up (P=.03). For social functioning and cognitive functioning, mean scores improved over time, with a maximum difference of 10.4 points and 9.5 points between baseline and 6-month follow-up (P=.01 and P=.02), respectively. By contrast, fatigue worsened over time, with a difference in mean score of 5.6 points between baseline and 4-month follow-up (P=.02). CONCLUSIONS A short course of RT in combination with TMZ in elderly patients with GBM was associated with survival benefit without a negative effect on HRQOL until the time of disease progression.

Radiation techniques for acromegaly

Radiotherapy (RT) remains an effective treatment in patients with acromegaly refractory to medical and/or surgical interventions, with durable tumor control and biochemical remission; however, there are still concerns about delayed biochemical effect and potential late toxicity of radiation treatment, especially high rates of hypopituitarism. Stereotactic radiotherapy has been developed as a more accurate technique of irradiation with more precise tumour localization and consequently a reduction in the volume of normal tissue, particularly the brain, irradiated to high radiation doses. Radiation can be delivered in a single fraction by stereotactic radiosurgery (SRS) or as fractionated stereotactic radiotherapy (FSRT) in which smaller doses are delivered over 5-6 weeks in 25-30 treatments. A review of the recent literature suggests that pituitary irradiation is an effective treatment for acromegaly. Stereotactic techniques for GH-secreting pituitary tumors are discussed with the aim to define the efficacy and potential adverse effects of each of these techniques.

Selection of Shigella flexneri candidate virulence genes specifically induced in bacteria resident in host cell cytoplasm

We describe an in vivo expression technology (IVET)‐like approach, which uses antibiotic resistance for selection, to identify Shigella flexneri genes specifically activated in bacteria resident in host cell cytoplasm. This procedure required construction of a promoter‐trap vector containing a synthetic operon between the promoterless chloramphenicol acetyl transferase   (cat)   and   lacZ  genes   and   construction of a library of plasmids carrying transcriptional fusions between S. flexneri genomic fragments and the cat–lacZ operon. Clones exhibiting low levels (<10 µg ml−1) of chloramphenicol (Cm) resistance on laboratory media were analysed for their ability to induce a cytophatic effect – plaque – on a cell monolayer, in the presence of Cm. These clones were assumed to carry a plasmid in which the cloned fragment acted as a promoter/gene which is poorly expressed under laboratory conditions. Therefore, only strains harbouring fusion‐plasmids in which the cloned promoter was specifically activated within host cytoplasm could survive within the cell monolayer in the presence of Cm and give a positive result in the plaque assay. Pai (plaque assay induced) clones, selected following this procedure, were analysed for intracellular (i) β‐galactosidase activity, (ii) proliferation in the presence of Cm, and (iii) Cm resistance. Sequence analysis of Pai plasmids revealed genes encoding proteins of three functional classes: external layer recycling, adaptation to microaerophilic environment and gene regulation. Sequences encoding unknown functions were also trapped and selected by this new IVET‐based protocol.

Standard (60 Gy) or short-course (40 Gy) irradiation plus concomitant and adjuvant temozolomide for elderly patients with glioblastoma: A propensity-matched analysis

PURPOSE To evaluate 2 specific radiation schedules, each combined with temozolomide (TMZ), assessing their efficacy and safety in patients aged ≥65 years with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS Patients aged ≥65 years with Karnofsky performance status (KPS) ≥60 who received either standard (60 Gy) or short-course (40 Gy) radiation therapy (RT) with concomitant and adjuvant TMZ between June 2004 and October 2013 were retrospectively analyzed. A propensity score analysis was executed for a balanced comparison of treatment outcomes. RESULTS A total of 127 patients received standard RT-TMZ, whereas 116 patients underwent short-course RT-TMZ. Median overall survival and progression-free survival times were similar: 12 months and 5.6 months for the standard RT-TMZ group and 12.5 months and 6.7 months for the short-course RT-TMZ group, respectively. Radiation schedule was associated with similar survival outcomes in either unadjusted or adjusted analysis. O(6)-methylguanine-DNA methyltransferase promoter methylation was the most favorable prognostic factor (P=.0001). Standard RT-TMZ therapy was associated with a significant rise in grade 2 and 3 neurologic toxicity (P=.01), lowering of KPS scores during the study (P=.01), and higher posttreatment dosing of corticosteroid (P=.02). CONCLUSIONS In older adults with GBM, survival outcomes of standard and short-course RT-TMZ were similar. An abbreviated course of RT plus TMZ may represent a reasonable therapeutic approach for these patients, without loss of survival benefit and acceptable toxicity.

Stereotactic Irradiation of GH-Secreting Pituitary Adenomas

Radiotherapy (RT) is often employed in patients with acromegaly refractory to medical and/or surgical interventions in order to prevent tumour regrowth and normalize elevated GH and IGF-I levels. It achieves tumour control and hormone normalization up to 90% and 70% of patients at 10–15 years. Despite the excellent tumour control, conventional RT is associated with a potential risk of developing late toxicity, especially hypopituitarism, and its role in the management of patients with GH-secreting pituitary adenomas remains a matter of debate. Stereotactic techniques have been developed with the aim to deliver more localized irradiation and minimize the long-term consequences of treatment, while improving its efficacy. Stereotactic irradiation can be given in a single dose as stereotactic radiosurgery (SRS) or in multiple doses as fractionated stereotactic radiotherapy (FSRT). We have reviewed the recent published literature on stereotactic techniques for GH-secreting pituitary tumors with the aim to define the efficacy and potential adverse effects of each of these techniques.

Fractionated stereotactic radiotherapy for large and invasive non-functioning pituitary adenomas: Long-term clinical outcomes and volumetric MRI assessment of tumor response

OBJECTIVE We describe the use of fractionated stereotactic radiotherapy (FSRT) for the treatment of large, invasive, nonfunctioning pituitary adenomas (NFPAs). FSRT is frequently employed for the treatment of residual or recurrent pituitary adenomas. PATIENTS AND METHODS Sixty-eight patients with a large residual or recurrent NFPAs were treated between April 2004 and December 2012, including 39 males and 29 females (median age 51 years). Visual defects were present in 34 patients, consisting of visual field defects (n=31) and/or reduced visual acuity (n=12). Forty-five patients had evidence of partial or total hypopituitarism before FSRT. For most of the patients, the treatment was delivered through 5-10 noncoplanar conformal fixed fields using a 6-MV linear accelerator to a dose of 45 Gy in 25 fractions. RESULTS At a median follow-up of 75 months (range 12-120 months), the 5- and 10-year actuarial local control were 97 and 91%, respectively, and overall survival 97 and 93%, respectively. Forty-nine patients had a tumor reduction, 16 remained stable, and three progressed. The relative tumor volume reduction measured using three-dimensional (3D) magnetic resonance imaging (MRI) was 47%. The treatment was well tolerated with minimal acute toxicity. Eighteen patients developed partial or complete hypopituitarism. The actuarial incidence of new anterior pituitary deficits was 40% at 5 years and 72% at 10 years. No other radiation-induced complications occurred. CONCLUSIONS Our results suggest that FSRT is an effective treatment for large or giant pituitary adenomas with low toxicity.

Combining molecular targeted agents with radiation therapy for malignant gliomas

The expansion in understanding the molecular biology that characterizes cancer cells has led to the rapid development of new agents to target important molecular pathways associated with aberrant activation or suppression of cellular signal transduction pathways involved in gliomagenesis, including epidermal growth factor receptor, vascular endothelial growth factor receptor, mammalian target of rapamycin, and integrins signaling pathways. The use of antiangiogenic agent bevacizumab, epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib, mammalian target of rapamycin inhibitors temsirolimus and everolimus, and integrin inhibitor cilengitide, in combination with radiation therapy, has been supported by encouraging preclinical data, resulting in a rapid translation into clinical trials. Currently, the majority of published clinical studies on the use of these agents in combination with radiation and cytotoxic therapies have shown only modest survival benefits at best. Tumor heterogeneity and genetic instability may, at least in part, explain the poor results observed with a single-target approach. Much remains to be learned regarding the optimal combination of targeted agents with conventional chemoradiation, including the use of multipathways-targeted therapies, the selection of patients who may benefit from combined treatments based on molecular biomarkers, and the verification of effective blockade of signaling pathways.

Radiation therapy after breast reconstruction: outcomes, complications, and patient satisfaction

PurposeThe aim of this study was to evaluate treatmentrelated complications, outcomes, and patient satisfaction in women with locally advanced breast cancer who received post-mastectomy radiation therapy (PMRT) after breast reconstruction (BR).Materials and methodsBetween October 2007 and November 2010, 46 patients with locally advanced breast cancer who underwent mastectomy followed by BR received PMRT at our Department. Radiotherapy was delivered to the chest wall with a dose of 50 Gy in 25 fractions over 5 weeks.ResultsThe median follow-up was 19 months. Skin erythema grade 1 and 2 was seen in 44 (96%) and two (4%) patients, respectively. Major complications, requiring additional corrective surgical procedure, occurred in three (7%) patients (one patient with prosthesis, one patient with tissue expander and one patient with deep inferior epigastric perforator flap). At univariate analysis, smoking, chemotherapy, hormone therapy with tamoxifen and reconstruction with implant were associated with overall complications (capsular contracture and reconstruction failure). Forty (86%) patients were very satisfied or satisfied with the cosmetic outcome of reconstruction.ConclusionsRadiotherapy can be safely delivered after BR, with a low complication rate and good patient satisfaction. Further randomised studies are needed to better define the optimal timing of breast reconstruction and post-mastectomy radiation therapy.RiassuntoObiettivoScopo del nostro lavoro è stato valutare le complicanze del trattamento e il livello di soddisfazione del risultato in pazienti con tumore della mammella localmente avanzato sottoposte a trattamento radioterapico post-mastectomia e ricostruzione mammaria.Materiali e metodiTra ottobre 2007 e novembre 2010, presso il nostro Dipartimento, 46 pazienti affette da neoplasia della mammella sono state sottoposte a trattamento radioterapico dopo intervento di mastectomia radicale e ricostruzione mammaria. La dose totale somministrata sulla parete toracica è stata di 50 Gy in 25 frazioni.RisultatiA un follow-up mediano di 19 mesi, si è osservata la comparsa di eritema cutaneo di grado 1 e 2 rispettivamente in 44 (96%) e in 2 (4%) pazienti. Complicanze maggiori, che hanno richiesto un ulteriore intervento chirurgico correttivo, sono state osservate in 3 pazienti (7%). All’analisi univariata il fumo, la chemioterapia, il tamoxifene e la ricostruzione con protesi risultano associate a un maggior rischio di complicanze generali (contrattura capsulare e fallimento della ricostruzione). Quaranta pazienti (86%) si sono mostrate soddisfatte o molto soddisfatte dei risultati estetici.ConclusioniLa radioterapia dopo ricostruzione mammaria è un trattamento sicuro associato a una bassa incidenza di complicanze e a un buon livello di soddisfazione da parte delle pazienti. Sono necessari ulteriori studi per definire meglio la sequenza ottimale di trattamento tra ricostruzione mammaria e radioterapia.

Temozolomide-Related Hematologic Toxicity

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of recurrent or newly diagnosed malignant gliomas with significant survival benefit. TMZ is generally well tolerated and safe. The most common side effects are mild to moderate, and are represented by fatigue, nausea, vomiting, thrombocytopenia, and neutropenia. However severe hematologic adverse events (HAEs), including myelodysplastic syndrome and aplastic anemia, have also been reported. In this review we present an overview of the available literature of HAEs after exposure to TMZ.