Stereotactic Body Radiotherapy for Oligoprogression in Castration-Resistant Prostate Cancer: Early Toxicity Analysis of the TRAP Trial.

AIMS: To assess toxicity and patient quality of life after stereotactic body radiotherapy (SBRT) to oligoprogressive disease (OPD) in patients with metastatic castrate-resistant prostate cancer (CRPC) on androgen receptor targeted agents (ARTA). MATERIAL AND METHODS: This phase II trial enrolled patients with metastatic CRPC with ≤ 2 oligoprogressive lesions in bone, lymph node, lung, or prostate. All patients were receiving systemic treatment with abiraterone or enzalutamide at the time of oligoprogression. All patients received SBRT to the OPD site(s) and continued the current ARTA. Patients received 30 Gy in 5 fractions (alternate days) to the OPD site. The primary endpoint of the trial is to assess if SBRT to OPD sites results in progression free survival of >6 months. The primary endpoint for this toxicity analysis is the rate of grade 3 or higher adverse events at any timepoint up to 6 months after SBRT. Secondary endpoints included comparing pre- and post-SBRT patient-related outcomes reported using visual analogue scale scores and EQ-5D health questionnaire. RESULTS: Forty enrolled patients had at least 6 months of follow-up at the time of analysis. Grade 3 or higher toxicity from any cause recorded using common terminology criteria for adverse events and radiation therapy oncology group was found in 8/40 (20%) of patients, but only 1/40 (2.5%) was deemed possibly related to SBRT. There was no significant difference in mean EQ5D visual analogue scale score from baseline to each timepoint after SBRT (p = 0.449). CONCLUSION: In this prospective phase II clinical trial for OPD whilst on ARTA in the CRPC setting, we report low grade ≥ 3 toxicity after SBRT. There is no discernible change in patient-reported quality of life due to SBRT treatment. The final results of progression-free survival and toxicity of SBRT treatment will be reported once further follow-up is complete.

The Dandelion Dilemma Revisited for Oligoprogression: Treat the Whole Lawn or Weed Selectively?

Oligoprogressive disease is a relatively new clinical concept describing progression at only a few sites of metastasis in patients with otherwise controlled widespread disease. In the era of well-tolerated targeted treatments, resistance inevitably occurs and overcoming this is a challenge. Local ablative therapy for oligoprogressive disease may allow the continuation of systemic treatments by overcoming the few sub-clones that have developed resistance. Stereotactic body radiotherapy is now frequently used in treating oligometastatic disease using ablative doses with minimally invasive techniques and acceptable toxicity. We discuss the current retrospective clinical evidence base supporting the use of local ablative therapy for oligoprogression in metastatic patients on targeted treatments within multiple tumour sites. As there is currently a lack of published prospective data available, the best management for these patients remains unclear. We discuss current trials in recruitment and the potential advancements in treating this group of patients with stereotactic radiotherapy.

Evaluating Retention of Skin Cancer Education in Kidney Transplant Recipients Reveals a Window of Opportunity for Re-education.

BACKGROUND: Skin cancer is the most common malignancy after solid organ transplant and can lead to significant morbidity. The likelihood of developing squamous cell carcinomas and melanomas is 100 and 2.4 times more likely, respectively, in kidney transplant recipients when compared with the general population. There are few data regarding the assessment and influence of solid organ transplant recipient (SOTR) knowledge of skin cancer and its effect on short- and long-term awareness and behavior. METHODS: The purpose of this study was to assess the baseline knowledge of SOTR immediately after transplantation, and then to reassess their knowledge following a 5-minute educational video. We also wanted to determine whether lifestyle modifications had been implemented 4 to 8 months after the intervention. RESULTS: Forty patients were enrolled within 2 months of transplantation. Eighty-seven percent of patients were renal transplant recipients, and 75% of patients were available for long-term follow-up. There was a significant increase in knowledge in the immediate postintervention period, which was sustained at 4- to 8-month follow-up, as assessed by patient questionnaire. Patients appeared to be applying this knowledge by participating in lifestyle risk modification and positive sun-protective behavior. CONCLUSIONS: Our study suggests that incorporating additional skin cancer education into the early transplant timeline (perhaps in the first one or two outpatient follow-up visits) with an easy to administer educational video and question and answer form increases patient knowledge and influences positive sun-protective behavior.

Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing.

In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes. We show that the extent of spatial heterogeneity is positively associated with the size of biopsied focal lesions consistent with regional outgrowth of advanced clones. The results support a model for multiple myeloma progression with clonal sweeps in the early phase and regional evolution in advanced disease. We suggest that multi-region investigations are critical to understanding intra-patient heterogeneity and the evolutionary processes in multiple myeloma.In multiple myeloma, malignant cells expand within bone marrow. Here, the authors use multi-region sequencing in patient samples to analyse spatial clonal architecture and heterogeneity, providing novel insight into multiple myeloma progression and evolution.

Prokaryotic DNA polymerase I: evolution, structure, and "base flipping" mechanism for nucleotide selection.

Accurate transmission of DNA material from one generation to the next is crucial for prolonged cell survival. Following the discovery of DNA polymerse I in Escherichia coli, the DNA polymerase I class of enzymes has served as the prototype for studies on structural and biochemical mechanisms of DNA replication. Recently, a series of genomic, mutagenesis and structural investigations have provided key insights into how Pol I class of enzymes function and evolve. X-ray crystal structures of at least three Pol I class of enzymes have been solved in the presence of DNA and dNTP, thus allowing a detailed description of a productive replication complex. Rapid-quench stop-flow studies have helped define individual steps during nucleotide incorporation and conformational changes that are rate limiting during catalysis. Studies in our laboratory have generated large libraries of active mutant enzymes (8000) containing a variety of substitutions within the active site, some of which exhibit altered biochemical properties. Extensive genomic information of Pol I has recently become available, as over 50 polA genes from different prokaryotic species have been sequenced. In light of these advancements, we review here the structure-function relationships of Pol I, and we highlight those interactions that are responsible for the high fidelity of DNA synthesis. We present a mechanism for "flipping" of the complementary template base to enhance interactions with the incoming nucleotide substrate during DNA synthesis.

Esophageal contribution to chest pain in patients with coronary artery disease.

We conducted a prospective study to determine the role of the esophagus in causing chest pain in patients with established CAD on optimum therapy. Thirty-two men with documented CAD who complained of frequent and usually daily retrosternal chest pain were evaluated. Following a standard esophageal manometry and acid perfusion test, simultaneous two-channel ambulatory Holter monitor and esophageal pH record tests were performed for 24 hours. Fifty-three episodes of chest pain were documented in 20 patients; 11 patients were free of pain. Of the 20 patients who complained of chest pains, 17 (85 percent) demonstrated at least one episode of PPR, defined as a drop in distal esophageal pH to less than 4 within ten minutes before or after the onset chest pain. Episodes of asymptomatic GER were common. The correlation of PPR with chest pain was 70 percent (37/53 episodes) and of ischemic ECG changes with chest pain 13 percent (7/53); in the remaining, there was no correlation with either. Two patients demonstrated simultaneous PPR and ischemic ECG changes. Seventeen esophageal motility abnormalities were observed in 14 patients (45 percent). It is our conclusion that esophageal disorders contribute to chest pain in patients with documented CAD. In this group, GER plays a greater role than in those with normal coronary arteries. In addition, esophageal motility disorders are common in these patients. Esophageal testing can be undertaken safely in these patients.

Evaluation of an unused 1952 Ridley intraocular lens.

PURPOSE: To evaluate an unused 1952 historic Ridley intraocular lens (IOL) brought to Bombay, India, in 1952 from an Oxford Ophthalmologic Conference in England and given to 1 of the authors during his residency. SETTING: Alcon Laboratories, Fort Worth, Texas, USA. METHODS: The Ridley IOL was evaluated at Alcon Laboratories, Inc., using the established procedures of its Intraocular R&D Laboratories. Various optical and physical aspects of the Ridley lens were evaluated including (1) dimensions, (2) weight, (3) power, (4) resolution efficiency and modulation transfer function (MTF), (5) surface sphericity by interferometry, (6) ultraviolet (UV)-visible transmission characteristic, (7) attenuated total reflectance (ATR)-Fourier transform infrared reflectance spectrum, and (8) cosmetics by visual inspection using light microscopy. RESULTS: This 8.5 mm diameter, 2.4 mm thick, 23 diopter biconvex IOL weighed 108 mg. The ATR spectrum, UV-visible transmission, and refractive index confirmed its poly-(methyl methacrylate) material. The 0.56 MTF value at 100 line pairs/mm, per the International Standards Organization--IOL Optics Standard, and 93% resolution efficiency in water, per the American National Standard Institute IOL Optics Standard, revealed the IOL's excellent optics. This was confirmed by 0.278 wave root mean square surface figure as measured by Zygo interferometer using a 633 nm wavelength. Visual inspection revealed rough edges with sharp corners and some surface scratches. Early clinical experience with Ridley IOLs in Bombay, India, is briefly given. CONCLUSION: The Ridley IOL had excellent optical quality, meeting the requirements of current IOL optics standards. The selection of its dimensions was guided by the human crystalline lens, and the Ridley IOL was half as bulky. Although its clinical results were mixed, successful cases inspired subsequent improvements, leading to modern, highly satisfactory IOLs. This IOL represented a revolutionary innovation in ophthalmology.

Dose equivalent response of a TLD badge--influence of body backscatter.

In personnel monitoring, operational quantities recommended by ICRU Publication No. 39 for photon radiation can be realized by calibrating dosimeters on a phantom and considering body backscatter photons by using established conversion factors. Personnel dosimeters used in this study are based on CaSO4:Dy Teflon thermoluminescence dosimeter discs (TLD) that have a highly photon energy-dependent response. Since body backscattered photons have lower energies than the incidence photons, methods for correcting for energy dependence of both the incident and body backscattered photons have to be developed. By using readouts of two TLD discs (one under a composite metal filter and the other without a metal filter) in an empirical relation valid at all energies, it is possible to correct for the effect of change in response from change in the photon energies. It was found that the new operational quantities recommended by ICRU could be estimated to within +/- 15% by a TLD badge design based on this method. Angular dependence limits for photons in accordance with the new international standards and a high beta dose-equivalent discrimination in the mixed fields of beta and low-energy x rays could also be achieved.

A rare case of segmental small bowel pneumatosis intestinalis: A case report.

INTRODUCTION: Pneumatosis intestinalis is a rare condition affecting 0.03% of the population. It has a myriad of aetiological causes and hence presentation can vary immensely. The management of symptomatic pneumatosis intestinalis in an acute and outpatient setting remains a challenge to both physicians and surgeons. CASE PRESENTATION: We present a case of a 79 year old who presented in a gastroenterology outpatients department with a history suggestive of intermittent small bowel obstruction associated with abdominal pain aggravated by eating and posture. He was found to have signs suggestive of Marfan's syndrome. Computed tomography demonstrated extensive pneumatosis intestinalis of the small bowel. Due to deterioration in symptoms, an exploratory laparotomy was performed demonstrating segmental small bowel pneumatosis intestinalis secondary to a hypermobile mesentery. CONCLUSION: This case highlights the importance of both surgical and gastroenterology expertise in successfully managing symptomatic pneumatosis intestinalis.

Development and Validation of a Simple Isocratic HPLC Method for Simultaneous Estimation of Phytosterols in Cissus quadrangularis.

Cissus quadrangularis L. is a promising remedy prescribed in the ancient Ayurvedic literature for bone fracture healing properties. As this activity has been extensively investigated and well established, a range of formulations containing C. quadrangularis has been marketed. This work reports the development and validation of a reliable RP-HPLC method for the analysis of phytosterols in the various extracts of the plant. The proposed method utilizes a Cosmosil C(8) column (250 ΄ 4.6 mm) with a compatible Phenomenex C(8) guard column with isocratic elution of acetonitrile and water (95:5 v/v) at 25°. An effluent flow rate of 2 ml/min and UV detection at 202 nm was used for the analysis of phytosterols. The described method was linear in the range of 1-500 µg/ml, with excellent correlation coefficients. The precision, robustness and ruggedness values were also within the prescribed limits (less than 2%). The recovery values were within the range, which indicates that the accuracy of the analysis was good and that the interference of the matrix with the recovery of phytosterols was low. The phytosterols were found to be stable in a stock solution for 48 h (% RSD was below 2%) and no interfering extra peaks were observed under controlled stress conditions. The proposed method is simple, specific, precise, accurate, and reproducible and thus can be used for routine analysis of C. quadrangularis phytosterols in quality control laboratories.

Striatal leucine-rich repeat kinase 2 mRNA is increased in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned common marmosets (Callithrix jacchus) with L-3, 4-dihydroxyphenylalanine methyl ester-induced dyskinesia.

The level of leucine-rich repeat kinase 2 (Lrrk2) mRNA expression was measured by reverse transcription-polymerase chain reaction in anterior striatum from normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets (Callithrix jacchus) that had L-3,4-dihydroxyphenylalanine methyl ester (L-DOPA)-induced dyskinesia. The level of striatal Lrrk2 mRNA was increased in MPTP-treated common marmosets that had L-DOPA-induced dyskinesia compared with normal animals that did not receive l-DOPA. Marmosets that exhibited higher levels of dyskinesia had the greatest increase in striatal Lrrk2 mRNA. Lrrk2 mRNA expression was also measured in human striatum and substantia nigra from control subjects and patients dying with Parkinson's disease. In contrast to marmoset tissue, no alteration in Lrrk2 mRNA expression was found in parkinsonian human brain. However, the brain was from patients who had an overall low level of dyskinesia. The correlation between striatal Lrrk2 mRNA levels in MPTP-treated common marmoset striatum and L-DOPA-induced dyskinesia indicates that LRRK2 may have a role in the molecular alterations that cause L-DOPA-induced dyskinesia.

Targeted therapy for metastatic renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) has historically been refractory to cytotoxic and hormonal agents; only interleukin 2 and interferon alpha provide response in a minority of patients. We reviewed RCC biology and explored the ways in which this understanding led to development of novel, effective targeted therapies. Small molecule tyrosine kinase inhibitors, monoclonal antibodies and novel agents are all being studied, and phase II studies show promising activity of sunitinib, sorafenib and bevacizumab. The results of phase III studies will determine the role of these agents in metastatic RCC.

Risk factors for pneumonia after percutaneous endoscopic gastrostomy.

Percutaneous endoscopic gastrostomy (PEG) is currently a popular method of administering enteral feeding. Most of these patients are elderly, debilitated, and chronically ill. They are on a number of medications and have multiple diseases. With impaired consciousness and swallowing disability, these patients are prone to develop pneumonia. In order to identify possible risk factors, we followed 24 men who underwent PEG for the occurrence of pneumonia or until they died. We then analyzed the medical records of these patients for potential risk factors for pneumonia. The presence of esophagitis during PEG placement endoscopy and history of pneumonia prior to PEG were significant risk factors. Advanced age and cerebrovascular accident (CVA) tended to indicate a higher risk of pneumonia. Taking these risk factors into consideration may be beneficial in the management of such patients.

DNA polymerase active site is highly mutable: evolutionary consequences.

DNA polymerases contain active sites that are structurally superimposable and highly conserved in sequence. To assess the significance of this preservation and to determine the mutational burden that active sites can tolerate, we randomly mutated a stretch of 13 amino acids within the polymerase catalytic site (motif A) of Thermus aquaticus DNA polymerase I. After selection, by using genetic complementation, we obtained a library of approximately 8, 000 active mutant DNA polymerases, of which 350 were sequenced and analyzed. This is the largest collection of physiologically active polymerase mutants. We find that all residues of motif A, except one (Asp-610), are mutable while preserving wild-type activity. A wide variety of amino acid substitutions were obtained at sites that are evolutionarily maintained, and conservative substitutions predominate at regions that stabilize tertiary structures. Several mutants exhibit unique properties, including DNA polymerase activity higher than the wild-type enzyme or the ability to incorporate ribonucleotide analogs. Bacteria dependent on these mutated polymerases for survival are fit to replicate repetitively. The high mutability of the polymerase active site in vivo and the ability to evolve altered enzymes may be required for survival in environments that demand increased mutagenesis. The inherent substitutability of the polymerase active site must be addressed relative to the constancy of nucleotide sequence found in nature.