Preliminary observations on biochemical relapse-free survival rates after short-course intensity-modulated radiotherapy (70 Gy at 2.5 Gy/fraction) for localized prostate cancer

PURPOSE: To compare the preliminary biochemical relapse-free survival rates between short-course intensity-modulated radiotherapy (SCIM-RT) delivering 70 Gy in 28 fractions and three-dimensional conformal radiotherapy (3D-CRT) delivering 78 Gy in 39 fractions. METHODS AND MATERIALS: Between January 1998 and December 1999, 166 patients were treated with SCIM-RT and 116 with 3D-CRT. The SCIM-RT cases were treated to 70 Gy (2.5 Gy/fraction) using 5 intensity-modulated fields using a dynamic multileaf collimator. The BAT transabdominal ultrasound system was used for localization of the prostate gland in all SCIM-RT cases. The 116 3D-CRT cases were treated to 78.0 Gy (2.0 Gy/fraction). The study sample therefore comprised 282 cases; 70 Gy in 28 fractions is equivalent to 78 Gy in 39 fractions for late-reacting tissues, according to the linear-quadratic model. The median follow-up for all cases was 25 months (range 3-42). The median follow-up was 21 months for the SCIM-RT cases (range 3-31) and 32 months for the 3D-CRT cases (range 3-42). The follow-up period was shorter for the SCIM-RT cases, because SCIM-RT was started only in October 1998. Biochemical relapse was defined as 3 consecutive rising prostate-specific antigen levels after reaching a nadir. The analysis was then repeated with a more stringent definition of biochemical control: reaching and maintaining a prostate-specific antigen level of < or =0.5 ng/mL. Radiation Therapy Oncology Group toxicity scores were used to assess complications. RESULTS: For the 282 patients, the biochemical relapse-free survival rate at 30 months was 91% (95% confidence interval 88-95%). The biochemical relapse-free survival rate at 30 months for 3D-CRT vs. SCIM-RT was 88% (95% confidence interval 82-94%) vs. 94% (95% confidence interval 91-98%), respectively. The difference was not statistically significant between the two treatment arms (p = 0.084). The multivariate time-to-failure analysis using the Cox proportional hazards model for clinical parameters showed the pretreatment prostate-specific antigen level (p <0.001) and biopsy Gleason score (p <0.001) to be the only independent predictors of biochemical relapse. Clinical T stage (p = 0.66), age (p = 0.15), race (p = 0.25), and neoadjuvant androgen deprivation (p = 0.66) were not independent predictors of biochemical failure. SCIM-RT showed only a trend toward a better outcome on multivariate analysis (p = 0.058). Late rectal toxicity was limited; the actuarial combined Grade 2 and 3 late rectal toxicity rate at 30 months was 5% for SCIM-RT vs. 12% for 3D-CRT (p = 0.24). Grade 3 late rectal toxicity (rectal bleeding requiring cauterization) occurred in a total of 10 patients. The actuarial Grade 3 late rectal toxicity rate at 30 months was 2% for the SCIM-RT cases and 8% for the 3D-CRT cases (p = 0.059). Late urinary toxicity was rare in both groups. CONCLUSION: With the currently available follow-up period (< or =30 months), the hypofractionated intensity-modulated radiotherapy schedule of 70.0 Gy delivered at 2.5 Gy/fraction had a comparable biochemical relapse profile with the prior 3D-CRT schedule delivering 78.0 at 2.0 Gy/fraction. The late rectal toxicity profile has been extremely favorable. If longer follow-up confirms the favorable biochemical failure and low late toxicity rates, SCIM-RT will be an alternative and more convenient way of providing dose escalation in the treatment of localized prostate cancer.     

QSAR with electrotopological state atom index: human factor Xa inhibitor N2-aroylanthranilamides

Recently, N2-aroylanthranilamides have been reported as novel series of possible anticoagulant drug candidates and the two aryl rings (A and B) have been suggested to interact with S1 and S4 regions, respectively, of human factor Xa (hfXa). In the present effort, quantitative structure-activity relationship (QSAR) of the hfXa binding affinity of 32 N2-aroylanthranilamides have been attempted, in continuation of our previous report on the QSAR analysis of the data set using linear free energy related (LFER) model, with electrotopological state atom (ETSA) index (Kier and Hall, 1991, Adv. Drug Design., 22, 1-38), to explore the atoms/regions of the compounds that modulate the activity comparatively to the greater extent. The univariate and bivariate relations involving the ETSA values of different common atoms of the compounds show importance of the atom nos. 12, 3 and 17 (arbitrary numbering): B ring carbon bearing meta R2 substituents, C ring carbon bearing R4 substituent, and carbonyl oxygen of A ring amide linkage. The importance of atom 12 is suggested to be due to detrimental effects of meta R2 substituents (B ring) on the hfXa binding affinity, which may be owing to interference in the attainment of the proper orientation of the phenyl ring in the S4 site. Atom 3 signifies the impact of R4 substituents (central C ring) on the binding affinity. Again, atom 17 (carbonyl oxygen of A ring amide linkage) has been suggested to form hydrogen bonding with the NH group of the other amide linkage, producing a pseudo ring and thus stabilizing the structure. The relations were improved further using indicator and physicochemical variables and the present results are in good agreement with the previous findings of the Hansch analysis.     

Salivary gland cancers: current treatments, molecular characteristics and new therapies

Salivary gland cancers are relatively rare and quite diverse. Current therapy relies on local ablation. There are few large clinical trials or randomized trials to guide treatment, especially for metastatic disease. This article reviews the epidemiology, staging, molecular characteristics, and treatment evidence for the most common types of salivary cancers and suggests potential future diagnostic and treatment directions. Progress in understanding the molecular and cell biology of salivary gland cancers may lead to the development of targeted therapies in these rare tumors. Multidisciplinary and multi-institutional collaborative studies are needed to help improve survival in salivary gland cancers.     

The utility of secretin-enhanced MRCP in diagnosing congenital anomalies

Purpose

To assess the additional value of secretin-enhanced MRCP (SMRCP) over conventional MRCP in diagnosing divisum.

Methods

Retrospective HIPAA-compliant and IRB-approved review found 140 patients with SMRCP and ERCP correlation within 6 months of each other. All studies were anonymized and the SMRCP images (SMRCP image set) were separated from 2D and 3D MRCP and axial and coronal T2-weighted images (conventional MRI image set). Each image set on each patient was assigned different and randomized case numbers. Two reviewers (R1 and R2) independently reviewed the image sets for divisum vs. no divisum, complete divisum vs. incomplete divisum, and the certainty of diagnosis (1 = definitely certain, 2 = moderately certain, and 3 = unsure). ERCP findings were taken as gold standard.

Results

There was no difference in age and gender between the divisum (n = 97, with 13 incomplete divisum) and no divisum (n = 43) groups. In diagnosing divisum anatomy, the sensitivity was higher for SMRCP compared to conventional MRI for R1 (84.5 vs. 72.2, p = 0.02) but not R2 (89.7 vs. 84.4, p = 0.25). The specificity was higher in SMRCP image set compared to conventional MRI (R1: 88.1 vs. 76.2, p = 0.01; R2: 81.4 vs. 65.1, p < 0.001). The mean area under ROC curve was higher for SMRCP image set (R1: 0.86 vs. 0.74, p = 0.01; R2: 0.87 vs. 0.74, p = 0.01). The certainty of diagnosis was higher in SMRCP image set compared to conventional MRI (p = 0.02 for both reviewers). SMRCP was not found to be superior in distinguishing incomplete from complete divisum. The main reasons for erroneous SMRCP diagnosis were the presence of an ansa loop in the main duct and ductal strictures due to chronic pancreatitis.

Conclusion

Even though the reviewers had more sequences (axial and coronal) to evaluate in the non-secretin image set, there was some improvement in diagnosing divisum with SMRCP.     

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.