Dose distribution in 3-dimensional conformal radiotherapy for prostate cancer: comparison of two treatment techniques (six coplanar fields and two dynamic arcs).

PURPOSE: To compare dose distribution for two techniques of 3-dimensional conformal radiotherapy (RT): 6-field technique (6F) and 2-dynamic arc therapy (2DA). METHODS AND MATERIALS: Thirty nonmetastatic prostate cancer patients were included. In each patient, two treatment plans were prepared: with six coplanar fields (45 degrees , 90 degrees , 135 degrees , 225 degrees , 270 degrees , 315 degrees ) and with two dynamic lateral 100 degrees -wide arcs (40-140 degrees , 220-320 degrees ). Dose-volume histograms (DVHs) were computed and mean area under curve (AUC) values were calculated for the DVHs of Planning Target Volume (PTV), rectum, urinary bladder and femoral heads. Doses given to 30% of rectum (DR(30)), to 60% of rectum (DR(60)), to 50% of bladder (DB(50)), to 50% of femoral head (DF(50)) and to 95% of PTV (DPTV(95)) were reported as a percentage of the total dose. RESULTS: Mean DR(30) and DR(60) for 6F and 2DA were 75.8%, 51.5% and 72.2%, 37.2%, respectively. Mean DB(50) for 6F and 2DA were 68% and 64.2%, respectively. Mean right DF(50) for 6F and 2DA were 35.4% and 45.5%, respectively. Mean DPTV(95) for 6F and 2DA were 99% and 99.2%, respectively. Mean AUCs of DVHs of rectum and urinary bladder were significantly higher for 6F (this was more evident for small PTV and in the intermediate dose range). Mean AUC of DVHs of PTV and femoral heads were significantly higher for 2DA. CONCLUSIONS: Both 6F and 2DA offer good dose distribution for PTV. 2DA allows for significantly better sparing of rectum and urinary bladder with slightly worse femoral head dose distribution. Further study is warranted in order to establish the clinical relevance of these differences.     

Efficacy of the novel camptothecin gimatecan against orthotopic and metastatic human tumor xenograft models.

PURPOSE: Gimatecan, a novel oral lipophilic camptothecin characterized by favorable features at molecular/cellular level and by a promising profile of preclinical activity, is currently in clinical phase I/II. The aim of the study was to additionally investigate the therapeutic potential of the drug in human tumor xenografts growing in different organs as models representative of tumor growth in the clinical setting. EXPERIMENTAL DESIGN: The models include two orthotopic central nervous system tumors, two melanomas growing intracranially, and an ovarian carcinoma growing i.p. In addition, gimatecan was tested against experimental lung metastases of two tumor types (lung and ovarian carcinomas). Gimatecan was delivered by oral gavage according to various schedules (daily or intermittent). The time (in days) mice required to show evident signs of disease was used as end point for drug efficacy. RESULTS: Gimatecan was highly effective in delaying disease manifestations in all tumor systems investigated. In the intracranially growing tumors, a significant time increase (versus control mice) was achieved by the drug administered according to all of the schedules. In addition, almost all treated mice were alive and tumor-free at the end of the experiment in the metastatic models and in the ascitic ovarian tumor. The daily prolonged treatment schedule was the best one. CONCLUSIONS: In all tumor systems investigated, including orthotopic tumor growth models and lung metastases, the oral administration of gimatecan showed a therapeutic benefit in terms of survival increase. The good oral availability allowed a prolonged daily treatment regimen, which seems the most promising to exploit the therapeutic potential of the drug.     

Inhibition of hepatocellular carcinomas in vitro and hepatic metastases in vivo in mice by the histone deacetylase inhibitor HA-But.

PURPOSE: The purpose is to evaluate the CD44-mediated cellular targeting of HA-But, a hyaluronic acid esterified with butyric acid (But) residues, to hepatocellular carcinoma cell lines in vitro and to hepatic tumor metastases in vivo. EXPERIMENTAL DESIGN: In vitro, the CD44-dependent cytotoxicity in two human hepatocellular carcinoma cell lines (HepB3 and HepG2) with high and low CD44 expression was investigated; in vivo, the effect on liver metastases originating from intrasplenic implants of Lewis lung carcinoma (LL3) or B16-F10 melanoma in mice was compared with the pharmacokinetics of organ and tissue distribution using different routes of administration. RESULTS: HepB3 and HepG2 cell lines showed different expression of CD44 (78 and 18%, respectively), which resulted in a CD44-dependent HA-But inhibitory effect as demonstrated also by the uptake analysis performed using radiolabeled HA-But ((99m)Tc-HA-But). Pharmacokinetic studies showed different rates of (99m)Tc-HA-But distribution according to the route of administration (i.v., i.p., or s.c.): very fast (a few minutes) after i.v. treatment, with substantial accumulation in the liver and spleen; relatively slow after i.p. or s.c. treatment, with marked persistence of the drug at the site of injection. The effect of s.c. and i.p. treatment with HA-But on liver metastases originating from intrasplenic implants of LL3 carcinoma or B16-F10 melanoma (both CD44-positive: 68 and 87%, respectively), resulted in 87 and 100% metastases-free animals, respectively (regardless of the route of administration), and a significant prolongation of the life expectancy compared with control groups. CONCLUSIONS: HA-But tends to concentrate in the liver and spleen and appears to be a promising new drug for the treatment of intrahepatic tumor lesions.     

Low-Grade Intraductal Carcinoma of the Parotid Gland: A Case Report and Literature Review

Low-grade intraductal carcinoma is a rare neoplasia with an excellent prognosis, previously classified as low-grade cribriform cystadenocarcinoma and low-grade salivary duct carcinoma. The tumor mainly occurs in the parotid gland and presents a ductal phenotype and an intraductal/intracystic growth pattern. It resembles intraductal breast lesions such as atypical ductal hyperplasia, papillary and cribriform ductal carcinoma in situ. Despite its infrequency, discriminating low-grade intraductal carcinoma from other salivary gland tumors is crucial, especially because of its favorable prognosis. A 74-year-old woman with a history of neurofibromatosis underwent a superficial parotidectomy to remove a sharply demarcated multi-cystic mass, diagnosed as category 4 at FNAC. The histological examination revealed a demarcated but unencapsulated lesion composed of a bigger cyst surrounded by several smaller cysts, lined by a monolayer or bilayer epithelium alternated with a cribriform proliferation, characterized by “Roman-bridges”, with occasional micro-papillae. A myoepithelial component, with a basal disposition, was present, confirmed by intense staining for protein p63 and SMA. Immunohistochemical stains showed intense, strong uniform positivity for pan-cytokeratin, protein S100, and SOX10. The Ki67 proliferation index was low (< 10%). A diagnosis of Low-grade Intraductal Carcinoma (LGIC) of the parotid was made. We performed a literature search in PUBMED for “Intraductal carcinoma”, “Low-grade Intraductal Carcinoma”, “Cribriform Cystadenocarcinoma”, “Salivary Duct Carcinoma”, and “Low-Grade Salivary Duct Carcinoma”. We selected 17 papers published between 1983 and 2020; the most affected anatomical site was the parotid gland (77/90), followed by minor salivary glands (6/90), the intraparotid lymph nodes (3/90) and the submandibular gland (4/90). Their main histopathological features are reported in the paper. Here we present a case report and a review of scientific literature on this topic to provide some essential diagnostic tools to discriminate this rare entity.     

Severe liver impairment in a cystic fibrosis-affected child homozygous for the G542X mutation

The clinical and laboratory findings of a cystic fibrosis (CF) patient homozygous for the G542X mutation are described. This is the first case, among the 7 G542X homozygous CF subjects described so far who shows severe liver involvement, associated pancreatic insufficiency, and moderate pulmonary expression of the disease, as demonstrated by laboratory and imaging data. This case adds to the conclusion that genotype/phenotype correlation in cystic fibrosis is more complex than formerly suspected. Am. J. Med. Genet. 69:155–158, 1997. © 1997 Wiley-Liss, Inc.     

A multi‐centre randomized trial of two different doses of nicotinamide in patients with recent‐onset Type 1 diabetes (the IMDIAB VI)

Background

Intensive insulin therapy is the gold standard by which Type 1 diabetes is treated. In addition to this therapy, administration of nicotinamide (NA) can be beneficial. This concept is reinforced by the results of a recent meta‐analysis of the use of NA in patients with recent‐onset Type 1 diabetes.

Methods

In this study we compared two different doses of NA in 74 patients with duration of Type 1 diabetes <4 weeks (mean age 13 years). Patients were randomly allocated in blind to two treatment groups: 38 patients received a dose of 25 mg/kg (b.w.) of NA and 36 patients received a dose of 50 mg/kg (b.w.) of NA. Intensive insulin therapy was carried out in order to optimize metabolic control as soon as possible after diagnosis and to maintain blood glucose level as near to normal as possible. Response to therapy was monitored throughout the study by investigating the occurrence of clinical (complete) remission defined, according to the recommendations of the International Diabetes Immunotherapy Group, as restoration of normal fasting and post‐prandial blood glucose without any insulin administration for more than 2 weeks. Moreover, the integrated measures of metabolic control (C‐peptide, HbA_1c and insulin dose) were analysed at 3‐ month intervals up to 1 year after diagnosis.

Results

There were no significant differences in the integrated measures of metabolic control between the two NA treated groups either at onset of the disease or at each 3‐month interval up to 1 year after diagnosis, although there was a tendency toward higher insulin dosages in the 50 mg NA group. No significant differences were observed in the rate of clinical remission between the two groups.

Conclusion

We conclude that patients with recent‐onset Type 1 diabetes treated with two different doses of NA, in addition to intensive insulin therapy, show similar residual beta‐cell function 1 year later. Since both doses of NA are likely to be effective in reducing beta‐cell dysfunction, the smaller dose of 25 mg/kg NA would be sufficient as a higher dose may induce insulin resistance. Copyright © 1999 John Wiley & Sons, Ltd.

     

Liquid Biopsy Testing for the Management of Patient with Non-Small Cell Lung Cancer Carrying a Rare Exon-20 EGFR Insertion

Increasing evidence suggests that liquid biopsy might play a relevant role in the management of metastatic non-small cell lung cancer (NSCLC) patients. Here, we show how the Molecular Tumor Board (MTB) in our cancer center employed liquid biopsy to support therapeutic decisions in a patient with NSCLC carrying a rare EGFR mutation. A 44-year-old woman, never-smoker with an EGFR, ALK, and ROS1-negative lung adenocarcinoma and multiple brain metastases received systemic therapy and surgery before being referred to our Institute. The MTB suggested NGS testing of tumor biopsy that revealed a rare exon-20 EGFR insertion (p.His773dup; c.2315_2316insCCA) and EGFR amplification. The MTB recommended treatment with erlotinib and follow-up with liquid biopsy, by using both cell-free DNA (cfDNA) and circulating tumor cells (CTCs). An increase of EGFR mutation levels in cfDNA revealed resistance to treatment about 6 months before clinical progression. Extremely low levels of EGFR p.T790M were detected at progression. Based on preclinical data suggesting activity of osimertinib against EGFR exon-20 insertions, the MTB recommended treatment with brain and bone radiotherapy and osimertinib. A dramatic reduction of EGFR mutation levels in the cfDNA was observed after 4 weeks of treatment. The PET scan demonstrated a metabolic partial remission that was maintained for 9 months. This case supports the evidence that liquid biopsy can aid in the management of metastatic NSCLC. It also suggests that treatment with osimertinib might be a therapeutic option in patients with EGFR exon-20 insertions when a clinical trial is not available.     

EFFECTIVENESS OF ROBOTIC BALANCE TRAINING ON POSTURAL INSTABILITY IN PATIENTS WITH MILD PARKINSON’S DISEASE: A PILOT,SINGLE-BLIND,RANDOMIZED CONTROLLED TRIAL

ObjectiveTo examine whether tailored robotic platform training could improve postural stability compared with conventional balance treatment in patients with mild Parkinson’s disease.DesignRandomized single-blind pilot study.SubjectsTwenty-two patients with mild Parkinson’s disease (Hoehn & Yahr scale; H&Y 1–2).MethodsPatients were randomly assigned to an experimental group for robotic balance training and to a control group for conventional balance training. Each patient received 20 treatments (45 min/session, 5 times/week). Blinded evaluations were conducted before and after the treatment and 1 month post-treatment. Primary outcome measures were Mini BESTest, and Berg Balance Scale; secondary outcome measures were 10-Meter Walk Test, Five Times Sit to Stand Test, and Parkinson’s Disease Questionnaire 39.ResultsPrimary outcome measures in patients in both the experimental and control groups improved significantly after the balance treatment. Similar results were found for all the secondary outcome measures. The experimental group performed significantly better than the control group at both post-intervention and follow-up evaluation in the primary outcomes (p < 0.05). No significant differences between groups were found in secondary outcomes.ConclusionRobot-assisted balance training may be a promising tool to improve postural stability in patients with mild Parkinson’s disease.LAY ABSTRACTMore than 10 million people worldwide are living with Parkinson’s disease. Parkinson’s disease is a slowly progressive neurodegenerative disorder that leads to balance problems. Balance is a major concern in patients with Parkinson’s disease, and shows poor response to pharmacological treatment. It is known that exercise and physiotherapy can help. The best approach is to start exercising at the early stages of the disease with personalized rehabilitation treatment. This study explored the effectiveness of a new robotic platform treatment on balance compared with the conventional approach. Both trainings were found to improve balance, walking and quality of life. However, robotic balance training could have a major impact. The robotic device enables the training to be intense, fun, task-oriented, challenging and personalized, enhancing motor learning and neuroplasticity. This advance in rehabilitation technology could help to meet the challenges presented by Parkinson’s disease.Key words: robotic-assisted balance training, postural instability, neurorehabilitation, Parkinson’s disease

Postural instability (PI), or impaired balance, is one of the cardinal motor symptoms that characterizes Parkinson’s disease (PD). It is the inability to maintain equilibrium under both static and dynamic conditions, affecting balance control mainly in 4 domains: (i) balance during quiet stance, (ii) reactive postural adjustments to external perturbations, (iii) anticipatory postural adjustments, and (iv) dynamic balance (1).PI is prominent in the advanced stage of PD, as reflected by the Hoehn & Yahr scale, where this problem appeared clinically only in the third stage. Nevertheless, PI is also present in the early stages of PD, before any clinically visible balance disturbance has appeared (2).Early identification of instability and effective timely intervention is mandatory to limit the increasing burden of PI in the lives of patients with PD. In fact, PI leads to loss of mobility, falls, disability, and reduced quality of life (QoL). Among these, falls have a major economic burden, considerable morbidity, and high psychological impact. Limited responsiveness to dopaminergic therapy and deep brain stimulation implicates the need for alternative strategies to address balance disorder and prevent falls (3, 4). It is clear that exercise and physiotherapy play a beneficial role (5) and different studies have identified the beneficial effect on balance of a series of non-pharmacological approaches, such us treadmill training (6), robot-assisted gait training (7), tai chi (8), virtual reality (9), and movement strategy training (10). However, which rehabilitation strategies are useful in practice in reducing balance problems and falls is a matter of debate. Patients with PD may benefit from a personalized exercise programme and a multidisciplinary approach (11) designed to help avoid falls and maintain mobility.Recent technological advances in delivery of therapy (e.g. virtual reality and other gamification elements) have led to increasing interest in the field of neurorehabilitation in PD (12). A robotic device, hunova® (Movendo Technology, Genoa, Italy), has been developed recently to apply sensorimotor rehabilitation of the lower limbs and trunk in static and dynamic conditions. This robotic platform was introduced for post-stroke functional re-education, treatment of degenerative diseases of the central nervous system and lesions of the peripheral nervous system.The robotic program enables personalized treatment with a challenging progression from simple to difficult tasks, attentional strategies, augmented visual and audio feedbacks, in a stimulating environment. Therefore, this study hypothesized that the robotic platform training (experimental robotic training group) would be more effective in improving postural control and in decreasing falls risk than conventional training (conventional training group).To our knowledge, there are no published studies exploring the effects of this new technology in patients with PD. Therefore, the aim of this pilot study was to investigate the efficacy and feasibility of a 4-week hunova®-assisted training programme in patients with mild PD on postural control. The primary aim was to evaluate whether the robotic balance training is effective in improving postural stability. The secondary aim was to assess whether robotic balance training can also have a positive impact on risk of falls, walking ability, and QoL.     

Acute lymphoblastic leukaemia occurring as second malignancy: report of the GIMEMA Archive of Adult Acute Leukaemia

Between July 1992 and June 1996, 901 new cases of adult acute lymphoblastic leukaemia were recorded in the GIMEMA Archive of Adult Acute Leukaemia; 21 of them (2.3%) had a previous primary malignancy (PM). We found that secondary acute lymphoblastic leukaemia cases (sALL) presented with older age, a high incidence of pre-pre-B immunophenotype and a significantly higher prevalence of cancer among relatives compared to de novo ALL. The leukaemogenic activity of the cytotoxic drugs employed for the treatment of PM may have played a potential role in only a proportion of patients, opening the possibility that some sALL patients may have developed two or more malignancies due to individual predisposing factors.