High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study.

BACKGROUND: In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). PATIENTS AND METHODS: Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m(2)), 2 courses of cisplatin and HD-etoposide (2.4 g/m(2)) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. RESULTS: From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7-165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8-72.8] and 54.8% (95% CI 41.6%-72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9-79.0) and 59.3% (95% CI 46.1-76.3). One toxic death (PEB arm) was recorded. CONCLUSIONS: The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. CLINICALTRIALS.GOV: NCT02161692.

Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes.

BACKGROUND: Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. PATIENTS AND METHODS: A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus <30 Gy), and PEB/EP regimens only. RESULTS: Thirteen studies have been selected for MA on relapse outcome. No randomized trials compared RT and CT. There were 4 prospective and 9 retrospective studies, with a total of 607 patients receiving RT and 283 patients CT. The pooled relapse rate (RR) was similar between the RT [0.11, 95% confidence interval (CI) 0.08-0.14, P for heterogeneity = 0.096, I(2) = 38%] and CT groups (0.08, 95% CI 0.01-0.15, P for heterogeneity <0.001, I(2) = 82.5%). However, in the sensitivity analysis, the pooled RR for RT in CSIIB was 0.12 (95% CI 0.06-0.17) while it was 0.05 (95% CI 0-0.11) for CT. Long-term side-effects and incidence of second cancers were more frequently reported following RT. The overall incidence of nontesticular second malignancies was 0.04 (95% CI 0.01-0.02) in the RT group and 0.02 (95% CI 0.003-0.04) in the CT group. CONCLUSIONS: Although RT and CT appeared to be equal options in CSIIA and IIB seminoma, a trend in favor of CT for a lower incidence of side-effects and RR in CSIIB was found. This evidence is limited by the retrospective quality of studies and their small sample size.

Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ cell tumors: long-term efficacy and safety outcomes.

BACKGROUND: Since 1985, we introduced a modified combination of etoposide, ifosfamide, and cisplatin (PEI) as second-line therapy of adult male germ cell tumors with the aim to reduce toxic effect while maintaining efficacy over the original regimen. PATIENTS AND METHODS: Patients received four cycles of ifosfamide at 2.5 g/m(2) on days 1-2, etoposide, and cisplatin at 100 and 33 mg/m(2), respectively, on days 3-5 every 21 days, followed by surgery. Results were stratified according to the International Germ Cell Consensus Classification Group-2 (IGCCCG-2). RESULTS: From February 1985 to January 2012, 189 patients were treated. 72.6% were IGCCCG-2 intermediate-to-very high risk. Thirty-five patients (18.5%) had a complete response, 67 (35.4%) a marker normalization (PRm-). Median follow-up was 122.1 months (inter-quartile range [IQR]: 71.4-232.0). Two-year progression-free and 5-year overall survival were 34.3% [95% confidence interval (CI) 28.1% to 41.9%] and 42.1% (95% CI 35.3% to 50.2%), respectively. Survival estimates compared favorably with those obtained by conventional dose chemotherapy (CDCT) regimens in each prognostic category. 70.4% of grade 3-4 neutropenia (25.5% febrile neutropenia), 48.1% thrombocytopenia, 21.2% anemia, 3.2% neurotoxic effect, and no severe renal toxic effect were recorded. CONCLUSION: Dose-modified Italian PEI should be considered as an appropriate benchmark for CDCT in the first salvage setting.

CT-guided percutaneous cryoablation of renal masses in selected patients.

PURPOSE: We analysed our experience with computed tomography (CT)-guided percutaneous cryoablation (PCA) in patients who were not surgical candidates or refused surgery for small to medium-sized renal masses. MATERIALS AND METHODS: Two freezing cycles were applied and separated by a passive warming cycle using 1.7- and 2.4-mm cryoprobes under either general anaesthesia or sedation based on patient positioning and respiratory status. Postoperative monitoring included haematological and biochemistry evaluation and CT scan 24 h after PCA. Follow-up consisted of a multislice CT scan at 1 month and every 3 months in the first year then every 6 months thereafter. RESULTS: Thirty-seven patients (38 lesions) underwent 40 PCA procedures; 5/37 (13.5%) had a solitary kidney. Median mass size was 35 (range 12-70) mm. No complications occurred during the procedure. Clavien grade ≥2 anaemia occurred in two patients (5.4 %): one patient required 1 U of packed red blood cells; the other required an arterial embolisation. Serum creatinine did not increase in any case. Two patients showed persisting or recurrent disease at 1 and 9 months, respectively, and both could be re-treated with PCA. All other patients showed a hypodense mass 3 months after PCA, with no contrast enhancement. Subsequent examinations showed that lesion sizes decreased and CT densitometry remained stable or increased minimally, also with no contrast enhancement. CONCLUSIONS: PCA proved relatively easy and safe and could be considered an effective alternative for patients who are not surgical candidates or refuse surgery, as well as in patients with medium-sized lesions.

Intracellular distribution and stability of a luminescent rhenium(i) tricarbonyl tetrazolato complex using epifluorescence microscopy in conjunction with X-ray fluorescence imaging.

Optical epifluorescence microscopy was used in conjunction with X-ray fluorescence imaging to monitor the stability and intracellular distribution of the luminescent rhenium(i) complex fac-[Re(CO)3(phen)L], where phen = 1,10-phenathroline and L = 5-(4-iodophenyl)tetrazolato, in 22Rv1 cells. The rhenium complex showed no signs of ancillary ligand dissociation, a conclusion based on data obtained via X-ray fluorescence imaging aligning iodine and rhenium distributions. A diffuse reticular localisation was detected for the complex in the nuclear/perinuclear region of cells, by either optical or X-ray fluorescence imaging techniques. X-ray fluorescence also showed that the rhenium complex disrupted the homeostasis of some biologically relevant elements, such as chlorine, potassium and zinc.

Unprecedented staining of polar lipids by a luminescent rhenium complex revealed by FTIR microspectroscopy in adipocytes.

Fourier transform infrared (FTIR) microspectroscopy and confocal imaging have been used to demonstrate that the neutral rhenium(i) tricarbonyl 1,10-phenanthroline complex bound to 4-cyanophenyltetrazolate as the ancillary ligand is able to localise in regions with high concentrations of polar lipids such as phosphatidylethanolamine (PE), sphingomyelin, sphingosphine and lysophosphatidic acid (LPA) in mammalian adipocytes.

The first world war drives rehabilitation toward the modern concepts of disability and participation.

The First World War produced a huge number of disabled soldiers. During the war, surgeons realized that it was not enough to merely treat the limbs of the wounded soldiers; it was also necessary to train them to use their remaining abilities to their greatest capacity. Governments at the same time realized that such a high number of veterans created a financial burden, by entitling disabled veterans to full healthcare, raising the issues of social welfare. Both in the US and Europe, programs of rehabilitation were instituted, providing injured soldiers with long-term medical care and vocational training aimed at restituting soldier's independence for a speedy return to work. In Italy at the Istituto Ortopedico Rizzoli, one of the most renowned Hospitals for the treatment of orthopedic deformities, Putti set up a technologically advanced Orthopedic Workshop, and a Rehabilitation House. The so called "reconstruction programs" addressed all aspects of rehabilitation (including physiotherapy, curative workshops and vocational therapy), seeing disability in terms of function. The experience gained in the treatment of war victims markedly enriched rehabilitation techniques, but overall the First World War helped engender the concept of rehabilitative programs to assist disabled veterans reintegrate in the workplace, thus laying the foundations of the modern concept of participation at a social level. In the centenary of Italy's entry into the First World War, it is worth underlining just how much hindsight affords us a new perspective on Physical Medicine and Rehabilitation. It reminds us that rehabilitation is not merely the role of medicine, but forms part of a multifaceted approach involving societal roles and expectations, regardless of the psychological and physical impairments suffered by the individuals concerned.

Epidemiology of neuromuscular disorders in the under-20 population in Bologna Province, Italy.

A retrospective epidemiological survey of the principal neuromuscular disorders was undertaken in the population under the age of 20 yr in Bologna city and province. The incidence of Duchenne muscular dystrophy (DMD) proved to be 25.8 x 10(-5), that is, comparable with the outcome of neonatal screening studies. The incidence of spinal muscular atrophy (SMA) was very high (11.2 x 10(-5), probably the result of our greater awareness and recognition of this disorder. The prevalence of neuromuscular disorders in the 0-19 yr population is 1.5 times that in the general population; that of DMD is 28 x 10(-5) vs 6.3 x 10(-5) and that of the SMA 6.5 x 10(-5) vs 1.2 x 10(-5). Our results indicate that neuromuscular disorders, particularly DMD and SMA I and II, have a much higher prevalence in the first two decades of life than is generally thought. Awareness of the higher prevalence of neuromuscular disorders among the under-20s is essential to the adequate planning of medical services.

Spinal muscular atrophy: natural history and orthopaedic treatment of scoliosis.

To study the natural history of scoliosis in spinal muscular atrophy (SMA), 63 spinal radiographs of affected patients who attended the Muscle Clinic of Rizzoli Orthopaedic Institute between 1974 and 1988 were reviewed. All but one of the intermediate SMA patients, and all of the mild SMA patients who stopped walking had a scoliosis that ranged from 10 degrees to 165 degrees. Out of the 19 mild SMA patients still able to walk, 12 had a scoliosis ranging from 10 degrees to 45 degrees. Mean age at the onset of scoliosis was 4 years 4 months in intermediate SMA, and 9 years 10 months in mild SMA. Data on characteristics of the scoliotic curve are reported. The effectiveness of orthopaedic treatment in the prevention of scoliosis is discussed.

[Continence problems after radical prostatectomy: role of rehabilitation of the pelvic floor]. / Problemi di continenza dopo prostatectomia radicale: ruolo della rieducazione del piano perineale.

Continence mechanisms can be compromised after radical prostatectomy. Relatively low percentages of urinary incontinence are reported (2-15%). Perineal floor physiotherapy is considered an actual method of treatment of urinary incontinence in females. It is based on pelvic floor muscles exercises, biofeedback and functional electrical stimulation. The aim of physiotherapy is to improve pelvic floor muscles proprioception, to increase tone of levator ani and to favour automatization of these muscles in daily life. The reports in Literature on perineal floor physiotherapy in treating incontinence after radical prostatectomy are scarce. In this paper we present our experience about 9 patients with incontinence post radical prostatectomy (out of 74 patients operated on at our Institution). We obtained an improvement or a complete cure in 78% of the treated patients. We believed that pelvic floor physiotherapy can be considered a good and safe method of treatment of incontinence after radical prostatectomy, at least in less serious cases.

[Extracorporeal SWL in the treatment of reno-ureteral calculosis in day hospital]. / Trattamento extracorporeo SWL della calcolosi reno-ureterale (SWL) in Day Hospital.

Eighteen years after the first clinical shock wave lithotripsy (SWL), no doubt remains as to its therapeutic efficacy in ureterorenal lithiasis. The advent of lithotriptors with a large shock wave energy range and integration of both ultrasound and radiologic imaging equipment at the shock wave source has meant that outpatients treatment of urolithiasis is now feasible in a good proportion of cases. In our lithotripsy center, from January 1995 to August 1996, 208 out of 310 patients who underwent SWL treatment for renal and ureteral stones, were outpatients. Pretreatment manoeuvres were performed in 10.6% of the patients. No major complications occurred during the treatment. Only three patients (1.4%) were admitted to hospital because of fever, colics or perirenal haematoma in the first two days after SWL therapy. The stone free rate was 67 and 84% respectively one and three months after treatment. In our experience, the possibility of performing SWL treatments without anesthesia and even analgosedation, the absence of complications and the high success rate, make outpatient treatment of urolithiasis safe and suitable in a large number of patients.

[Therapeutic alternatives in the treatment of class T1N0 squamous cell carcinoma of the penis: indications and limitations]. / Alternative terapeutiche nel trattamento del carcinoma spinocellulare del pene di categoria T1N0: indicazioni e limiti.

At INT of Milan between 1964 and 1990, 204 consecutive native patients suffering from penile cancer have been treated. 101 (59%) patients out of 171 with invasive cancer (23 affected with Tis were excluded) have been classified T1N0M0. 74 patients have been treated with penis conserving methods, such as circumcision, radiotherapy, laser excision and primary chemotherapy + conserving surgery. Overall local failure and/or nodal relapses occurred in 27% (20/74). Relapses are significantly related with grading but there isn't any relationship with macroscopical aspect or size of the tumor. The conservative treatment had been possible in 80% of patients. In our experience T1N0 clinical stage conservative therapy does not worsen the prognosis.

Fractures in myopathies.

The paper reports the results obtained in a study on the frequency of fractures in patients affected with Duchenne Muscular Dystrophy and Spinal Muscular Atrophy, types II and type III; the patients were observed between 1974 and 1988 at the muscle clinic of the Rizzoli Orthopaedic Institute. Out of a total of 238 cases, 36 (15.1%) reported one or more fractures during the follow-up period. For each fracture, age, functional capacity, the particular circumstances in which fractures occurred, site and type of fracture, medical treatment and consequences were all considered. A protocol for fracture prevention in neuromuscular patients is proposed, and suitable methods of treatment suggested.

[Pyeloureteral junction syndrome caused by "anomalous vessel"]. / Sindrome del giunto pieloureterale da "vaso anomalo".

In presenting and describing the pathogenesis of the pyeloureteral junction syndrome, the Authors report their recent experience with four cases due to an "abnormal vessel". Symptoms, diagnosis, and surgical techniques are discussed.

[Anatomical and surgical considerations on the internal spermatic venous system]. / Considerazioni anatomiche e chirurgiche sul sistema venoso spermatico interno.

The surgical anatomy of the spermatic venous system is described. Thereafter an experimental evaluation performed on cadavers by the vascular mould technique using plastic materials is reported. The resulting data point out the complex variability of the spermatic venous circulation, stressing the value of preoperative phlebography in the surgical approach to varicocele.

[Conservative elective surgery in kidney neoplasms]. / Chirurgia conservativa di elezione nelle neoplasie renali.

After the good results of "necessary" conservative surgery in the treatment of kidney neoplasms (bilateral neoplasms, congenital, acquired or functional solitary kidney), conservative surgery itself has been employed as elective treatment in selected cases presenting without the overmentioned problems. The authors report two cases of elective conservative surgery in kidney neoplasm with good results after 18 and 24 months.

A minimally invasive treatment for lumbar disc herniation: DiscoGel® chemonucleolysis in patients unresponsive to chemonucleolysis with oxygen-ozone.

A multitude of therapies is available to treat disc herniation, ranging from conservative methods (medication and physical therapy) to minimally invasive (percutaneous) treatments and surgery. O2-O3 chemonucleolysis (O2-O3 therapy) is one of the minimally invasive treatments with the best cost/benefit ratio and lowest complication rate. Another substance recently made available exploiting the chemical properties of pure ethanol is DiscoGel®, a radiopaque gelified ethanol more viscous than absolute alcohol 8,9. The present study aimed to assess the therapeutic outcome of DiscoGel® chemonucleolysis in patients with lumbar disc herniation unresponsive to O2-O3 therapy. Thirty-two patients aged between 20 and 79 years were treated by DiscoGel® chemonucleolysis between December 2008 and January 2010. The treatment was successful (improvement in pain) in 24 out of 32 patients. DiscoGel® is safe and easy to handle and there were no complications related to product diffusivity outside the treatment site. The therapeutic success rate of DiscoGel® chemonucleolysis in patients unresponsive to O2-O3 therapy was satisfactory. Among other methods used to treat lumbar disc herniation, DiscoGel® chemonucleolysis can be deemed an intermediate procedure bridging conservative medical treatments and surgery.

[Retroperitoneal surgery in the treatment of germ-cell tumors of the testis: retroperitoneal lymph node dissection (RPLND)]. / La linfoadenectomia retroperitoneale (RPLND) nel trattamento delle neoplasie germinali del testicolo.

Germ-cell tumors of the testis (GCTT) are rare, but have a high social impact. In fact they represent no more than 1% of male tumors (about 700 new cases per year in Italy), but electively occur in young patients, 20 to 40 years old, during their fully mature social and working life. More than 80% of patients are cured and return to a normal social, sexual, and working life. Improvements achieved both in diagnosis, with the use of scans (CT, MRI, US and recently PET) and of serum tumor markers alpha-fetoprotein (AFP), beta-fraction of human chorionic gonadotropin (b-HCG) and lactate dehydrogenase (LDH), and mainly in treatment, through the amelioration of radiotherapy and surgical techniques and, especially, with the introduction of Cisplatin, Etoposide and Ifosfamide in chemotherapic regimens, have made germ-cell tumor a model of "curable disease". Retroperitoneal lymph node dissection (RPLND) has indications in patients with clinical stage I (CS1) as well as in advanced disease, where it is integrated in the multimodality treatment. Anatomical studies, as well as a long-term experience, have gradually but consistently modified the surgical techniques of RPLND. Currently, "nerve sparing" RPLND represents a safe management of CS1 nonseminomatous germ cell testicular tumor with minimal morbidity and excellent outcomes. Nonetheless, surveillance and adjuvant chemotherapy are as effective as RPLND, but, in our opinion, associated with some discomforts for the patients. Laparoscopic retroperitoneal lymph node dissection (Lap-RPLND) is gaining popularity as a minimally invasive staging procedure for clinical stage I nonseminomatous testicular carcinoma, but its therapeutic role is still under investigation.

[State of the art and controversies in the treatment of testis germ-cell tumors (TGT)].

Many different, intersecting strategies are available for managing germ-cell cancers,particularly in early-stage disease. Which is 'right' remains a matter of debate, and requires balancing efficacy against late effects, bearing in mind the complexity of treatment strategies and the available expertise.