Stereotactic Body Radiotherapy for Large Unresectable Hepatocellular Carcinomas - A Single Institution Phase II Study.

AIMS: To evaluate the safety and efficacy of liver stereotactic body radiotherapy (SBRT) in the treatment of unresectable hepatocellular carcinomas (HCC) measuring >5 cm. MATERIALS AND METHODS: Between November 2013 and February 2016, 13 patients with unresectable HCC (>5 cm), ineligible for other local treatments, with a Child-Pugh score (CPS) ≤ B7, were enrolled into a single-institution phase II study. SBRT was delivered by volumetric-modulated arc radiotherapy. Radiological response was reported using modified Response Evaluation Criteria in Solid Tumours criteria and toxicities graded by Common Terminology Criteria for Adverse Events v4 criteria. RESULTS: Sixteen hepatomas (median size 7.5 cm, range 5.1-9.7 cm) were treated in 13 patients. The baseline CPS was A5/6 in nine patients (69%) and B7 in four patients (31%). Five patients (38%) received previous liver-directed treatment. The median prescribed dose was 45 Gy (range 40-45 Gy) in five fractions. The median follow-up was 17.7 months. The 1-year local control rate was 92%. The median overall survival was 17.7 months and the 1-year overall survival was 62%. The median time to local progression was not reached. Five patients (39%) had an increase in CPS by two or more points at 3 months. Overall, there were 10 grade 3 acute toxicities occurring in seven patients, of which six were haematological. Quality of life remained clinically stable or improved at 3 months in 61.5% and 53.8% of patients based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 Global Health Score and Functional Assessment of Cancer Therapy - Hepatobiliary version 4 score, respectively. CONCLUSIONS: In our cohort, SBRT to unresectable large HCC tumours provided excellent local control with acceptable toxicities. Regional recurrence remained the major cause of failure. Further studies are warranted to examine the role for SBRT in combination with other modalities to maximise disease control in the liver.

Employment outcomes for recent Canadian radiation oncology graduates.

Introduction: Radiation oncology (ro) is one of several specialties identified by the Royal College of Physicians and Surgeons of Canada with employment difficulties for graduating trainees. The purpose of the present study was to determine the employment status and location of recent Canadian ro trainees within 2 years after graduation, to monitor workforce recruitment trends over time, and to capture the opinions of program directors about employment difficulty for graduates and resident morale. Visa trainee graduates were excluded. Methods: Results of the survey administered to ro program directors in 2016 and again in 2018, both with 100% response rates, are presented here. Results: In both surveys, approximately 57% of ro graduates had attained staff or locum employment in Canada or abroad within 2 years from graduation (p = 0.92). However, graduates with Canadian staff employment increased by 46% to 32 in 2018 from 22 in 2016, while the proportion of graduates with staff positions abroad decreased to 6% from 27% (p = 0.04). Most trainees without staff positions were employed as fellows. The proportion of program directors reporting employment difficulties for graduates in the Canadian labour market declined to 38% from 85% (p = 0.04), and the morale of residents in training programs remained high. Conclusions: Employment challenges for newly certified Canadian-trained radiation oncologists continue. However, compared with the situation 2 years ago, trends in the Canadian ro job market suggest a modest improvement, with more staff employment in Canada and lower emigration rates for jobs abroad.

Stereotactic Body Radiotherapy for Small Unresectable Hepatocellular Carcinomas.

AIMS: Stereotactic body radiotherapy (SBRT) is an option for the treatment of hepatocellular carcinoma (HCC) in patients ineligible for standard local therapies. This study reports on the safety and efficacy of SBRT in small HCC tumours (≤5 cm) in the province of British Columbia. MATERIALS AND METHODS: Between March 2011 and July 2015, 31 patients with Child-Pugh Class A or B, with small HCCs measuring ≤5 cm were treated with SBRT at our institution. Primary end points were local control, progression-free survival, overall survival and toxicity. RESULTS: Thirty-four hepatomas (median size 3.3 cm, range 1.3-5.0 cm) were treated. The median follow-up was 18.3 months. Twenty-six patients (84%) had received previous liver-directed treatments. Most patients (88%) were treated with 45 Gy in three or five fractions. Six patients (19%) had worsened Child-Pugh score by two or more points during follow-up; overall 32% of patients experienced ≥ grade 3 + toxicities. One-year local control and overall survival were 94 and 84%, respectively. One-year progression-free survival was 49%; 81% of patients with disease progression received further HCC therapy. On univariate analysis, small tumour size predicted for improved overall survival (P = 0.01) whereas prescription biological equivalent dose (BED10) ≥100Gy10 approached significance (P = 0.06). CONCLUSION: SBRT provides high local control to small inoperable HCC. SBRT can be delivered safely even after previous liver-directed therapies and further liver therapies can follow treatment with SBRT. Although overall 32% of patients experienced ≥ grade 3 + toxicities, and 19% had a deterioration in Child-Pugh score of two or more points, these changes were mainly transient with minimal clinical impact. Despite excellent local control, disease progression outside of the irradiated site remains prominent. Further studies are warranted to examine combined therapy approaches to maximise disease control.

High-grade glioma management and response assessment-recent advances and current challenges.

The management of high-grade gliomas (hggs) is complex and ever-evolving. The standard of care for the treatment of hggs consists of surgery, chemotherapy, and radiotherapy. However, treatment options are influenced by multiple factors such as patient age and performance status, extent of tumour resection, biomarker profile, and tumour histology and grade. Follow-up cranial magnetic resonance imaging (mri) to differentiate treatment response from treatment effect can be challenging and affects clinical decision-making. An assortment of advanced radiologic techniques-including perfusion imaging with dynamic susceptibility contrast mri, dynamic contrast-enhanced mri, diffusion-weighted imaging, proton spectroscopy, mri subtraction imaging, and amino acid radiotracer imaging-can now incorporate novel physiologic data, providing new methods to help characterize tumour progression, pseudoprogression, and pseudoresponse. In the present review, we provide an overview of current treatment options for hgg and summarize recent advances and challenges in imaging technology.

Monte Carlo calculation of dose distributions in oligometastatic patients planned for spine stereotactic ablative radiotherapy.

Dosimetric consequences of plans optimized using the analytical anisotropic algorithm (AAA) implemented in the Varian Eclipse treatment planning system for spine stereotactic body radiotherapy were evaluated by re-calculating with BEAMnrc/DOSXYZnrc Monte Carlo. Six patients with spinal vertebral metastases were planned using volumetric modulated arc therapy. The planning goal was to cover at least 80% of the planning target volume with a prescribed dose of 35 Gy in five fractions. Tissue heterogeneity-corrected AAA dose distributions for the planning target volume and spinal canal planning organ-at-risk volume were compared against those obtained from Monte Carlo. The results showed that the AAA overestimated planning target volume coverage with the prescribed dose by up to 13.5% (mean 8.3% +/- 3.2%) when compared to Monte Carlo simulations. Maximum dose to spinal canal planning organ-at-risk volume calculated with Monte Carlo was consistently smaller than calculated with the treatment planning system and remained under spinal cord dose tolerance. Differences in dose distribution appear to be related to the dosimetric effects of accounting for body composition in Monte Carlo simulations. In contrast, the treatment planning system assumes that all tissues are water-equivalent in their composition and only differ in their electron density.

4D VMAT, gated VMAT, and 3D VMAT for stereotactic body radiation therapy in lung.

Four-dimensional volumetric modulated arc therapy (4D VMAT) is a treatment strategy for lung cancers that aims to exploit relative target and tissue motion to improve organ at risk (OAR) sparing. The algorithm incorporates the entire patient respiratory cycle using 4D CT data into the optimization process. Resulting treatment plans synchronize the delivery of each beam aperture to a specific phase of target motion. Stereotactic body radiation therapy treatment plans for 4D VMAT, gated VMAT, and 3D VMAT were generated on three patients with non-small cell lung cancer. Tumour motion ranged from 1.4-3.4 cm. The dose and fractionation scheme was 48 Gy in four fractions. A B-spline transformation model registered the 4D CT images. 4D dose volume histograms (4D DVH) were calculated from total dose accumulated at the maximum exhalation. For the majority of OARs, gated VMAT achieved the most radiation sparing but treatment times were 77-148% longer than 3D VMAT. 4D VMAT plan qualities were comparable to gated VMAT, but treatment times were only 11-25% longer than 3D VMAT. 4D VMAT's improvement of healthy tissue sparing can allow for further dose escalation. Future study could potentially adapt 4D VMAT to irregular patient breathing patterns.

Sci-Thur PM: YIS - 03: Comparing 4D-VMAT, Gated-VMAT and 3D-VMAT in SBRT treatment of lung cancer.

PURPOSE: To evaluate the treatment plan qualities of 4D-VMAT, gated-VMAT and 3D-VMAT in the treatment of non-small cell lung cancer (NSCLC) in stereotactic body radiation therapy (SBRT). METHODS: 4D-VMAT is a motion compensation strategy that aims to exploit relative target and OAR motion to increase OAR sparing over 3D-VMAT without the long treatment times associated with gated-VMAT. The 4D-VMAT algorithm incorporates the entire patient respiratory cycle and 4D-CT in the optimization process. Resulting treatment plans synchronize the delivery of each MLC aperture to a specific phase of the target motion. Using software developed in Matlab™, SBRT treatment plans for 4D-VMAT, gated-VMAT and 3D-VMAT were generated on 3 patients with NSCLC. Tumour motion ranged from 1.4-3.4 cm. The fractionation scheme was 48Gy in 4 fractions with the GTV receiving 100% of the prescribed dose. For gated-VMAT, the treatment window constrained residual tumour motion to 3 mm or less corresponding to duty cycles of 40-60%. In 3D-VMAT, the ITV was generated by merging the GTV from all phases. A b-spline transformation model was used to register the 4D-CT images and DVHs were calculated from total dose accumulated on the max expiration phase. RESULTS AND CONCLUSION: For the majority of OARs, gated-VMAT provided the greatest radiation sparing but significantly extended treatment times (25-35 gantry interruptions/arc). For 3D-VMAT, only 2 patients had clinically acceptable plans that met all the strict dose limits. OAR sparing in 4D-VMAT was comparable to gated-VMAT but with significantly improved delivery efficiency.

SU-E-T-637: 4D-VMAT Vs. Gated VMAT in Lung Cancer SBRT.

PURPOSE: To assess plan quality and treatment efficiency of 4D-VMAT and gated-VMAT in the treatment of non-small cell lung cancer using SBRT. METHODS: Treatment planning software was developed in Matlab to simulate both 4D-VMAT and gated-VMAT on patients with stage I lung cancer and at least 1 cm of tumour motion. Gated-VMAT delivers radiation to the tumour during only a portion of the respiratory cycle and hence requires frequent start and stop motions of the gantry. In the 4D-VMAT algorithm, target and organ motion from the entire respiratory cycle is incorporated during optimization. Gantry moves continuously but delivery of each MLC aperture is synchronized to specific phases of target motion. All 4D-CT scan consisted of 10 phases and were acquired with the patients breathing freely. The SBRT fractionation scheme was 48 Gy in 4 fractions with at least 95% of the PTV receiving 100% of the prescription dose. For gated-VMAT, the PTV was derived from the ITV of the relevant respiratory phases plus a 5mm margin. In the 4D VMAT algorithm, the GTV was defined on a single phase and the PTV created with a 5mm margin. PTVs for the other respiratory phases were determined through 4D-image registration and deformation using a bspline transformation model. For both treatment deliveries, dose was accumulated on the maximum exhale phase and DVHs generated. RESULTS: Findings show gated-VMAT and 4D-VMAT deliveries resulted in maximum doses to most OARs far below SBRT protocol constraints. The 4D-VMAT beam on time is on average 8 min. Gated-VMAT will have similar beam on time but treatment time can more than double after accounting for 25 to 35 beam interruptions per arc. CONCLUSIONS: Gated-VMAT and 4D-VMAT were able to produce dosimetrically acceptable lung SBRT plans. The advantage of 4D-VMAT is the greater efficiency in treatment delivery.

Recent molecular advances in studies of the concentrative Na+-dependent nucleoside transporter (CNT) family: identification and characterization of novel human and mouse proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib).

The human concentrative (Na+-linked) plasma membrane transport proteins hCNT1 and hCNT2, found primarily in specialized epithelia, are selective for pyrimidine nucleosides (system cit) and purine nucleosides (system cif), respectively. Both have orthologs in other mammalian species and belong to a gene family (CNT) that also includes members in lower vertebrates, insects, nematodes, pathogenic yeast and bacteria. The CNT transporter family also includes a newly identified human and mouse CNT3 transporter isoform. This paper reviews the studies of CNT transport proteins that led to the identification of hCNT3 and mCNT3, and gives an overview of the structural and functional properties of these latest CNT family members. hCNT3 and mCNT3 have primary structures that place them in a CNT subfamily separate from CNT1/2, transport a wide range of physiological pyrimidine and purine nucleosides and antineoplastic and antiviral nucleoside drugs (system cib), and exhibit a Na+:uridine coupling ratio of at least 2:1 (cf 1:1 for hCNT1/2). Cells and tissues containing hCNT3 transcripts include mammary gland, differentiated HL-60 cells, pancreas, bone marrow, trachea, liver, prostrate and regions of intestine, brain and heart. In HL-60 cells, hCNT3 is transcriptionally regulated by phorbol myristate (PMA). The hCNT3 gene, which contains an upstream PMA response element, mapped to 9q22.2 (cf chromosome 15 for hCNT1 and hCNT2).

Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib).

The human concentrative (Na(+)-linked) plasma membrane transport proteins hCNT1 and hCNT2 are selective for pyrimidine nucleosides (system cit) and purine nucleosides (system cif), respectively. Both have homologs in other mammalian species and belong to a gene family (CNT) that also includes hfCNT, a newly identified broad specificity pyrimidine and purine Na(+)-nucleoside symporter (system cib) from the ancient marine vertebrate, the Pacific hagfish (Eptatretus stouti). We now report the cDNA cloning and characterization of cib homologs of hfCNT from human mammary gland, differentiated human myeloid HL-60 cells, and mouse liver. The 691- and 703-residue human and mouse proteins, designated hCNT3 and mCNT3, respectively, were 79% identical in amino acid sequence and contained 13 putative transmembrane helices. hCNT3 was 48, 47, and 57% identical to hCNT1, hCNT2, and hfCNT, respectively. When produced in Xenopus oocytes, both proteins exhibited Na(+)-dependent cib-type functional activities. hCNT3 was electrogenic, and a sigmoidal dependence of uridine influx on Na(+) concentration indicated a Na(+):uridine coupling ratio of at least 2:1 for both hCNT3 and mCNT3 (cf 1:1 for hCNT1/2). Phorbol myristate acetate-induced differentiation of HL-60 cells led to the parallel appearance of cib-type activity and hCNT3 mRNA. Tissues containing hCNT3 transcripts included pancreas, bone marrow, trachea, mammary gland, liver, prostate, and regions of intestine, brain, and heart. The hCNT3 gene mapped to chromosome 9q22.2 and included an upstream phorbol myristate acetate response element.

Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na(+) nucleoside cotransporters hCNT1 and hCNT2.

hCNT1 and hCNT2 mediate concentrative (Na(+)-linked) cellular uptake of nucleosides and nucleoside drugs by human cells and tissues. The two proteins (650 and 658 residues, 71 kDa) are 72% identical in sequence and contain 13 putative transmembrane helices (TMs). When produced in Xenopus oocytes, recombinant hCNT1 is selective for pyrimidine nucleosides (system cit), whereas hCNT2 is selective for purine nucleosides (system cif). Both transport uridine. We have used (i) chimeric constructs between hCNT1 and hCNT2, (ii) sequence comparisons with a newly identified broad specificity concentrative nucleoside transporter (system cib) from Eptatretus stouti, the Pacific hagfish (hfCNT), and (iii) site-directed mutagenesis of hCNT1 to identify two sets of adjacent residues in TMs 7 and 8 of hCNT1 (Ser(319)/Gln(320) and Ser(353)/Leu(354)) that, when converted to the corresponding residues in hCNT2 (Gly(313)/Met(314) and Thr(347)/Val(348)), changed the specificity of the transporter from cit to cif. Mutation of Ser(319) in TM 7 of hCNT1 to Gly enabled transport of purine nucleosides, whereas concurrent mutation of Gln(320) to Met (which had no effect on its own) augmented this transport. The additional mutation of Ser(353) to Thr in TM 8 converted hCNT1/S319G/Q320M, from cib to cif, but with relatively low adenosine transport activity. Additional mutation of Leu(354) to Val (which had no effect on its own) increased the adenosine transport capability of hCNT1/S319G/Q320M/S353T, producing a full cif-type transporter phenotype. On its own, the S353T mutation converted hCNT1 into a transporter with novel uridine-selective transport properties. Helix modeling of hCNT1 placed Ser(319) (TM 7) and Ser(353) (TM 8) within the putative substrate translocation channel, whereas Gln(320) (TM 7) and Leu(354) (TM 8) may exert their effects through altered helix packing.

Complications of diabetes: acute and chronic.

The acute and chronic complications of diabetes account for the morbidity and mortality associated with this disease. Acute complications include diabetic ketoacidosis, hyperosmolar hyperglycemic nonketotic coma, and hypoglycemia. Chronic hyperglycemia is central to the pathophysiology of chronic complications such as cardiovascular and peripheral vascular disease, retinopathy, nephropathy, and neuropathy. Pathophysiology and assessment of, and interventions for these complications are discussed.

Anterior temporal lobectomy and medically refractory temporal lobe epilepsy of childhood.

The evaluation and outcome of 22 patients who had onset of complex partial seizures (CPS) of temporal lobe origin in childhood and subsequently underwent anterior temporal lobectomy are described. All patients showed improved seizure control; 81.8% had a reduction greater than or equal to 95% in seizure frequency. However, many patients had difficulty adjusting to a seizure-free life. Psychosocial, behavioral, and educational problems occurred more frequently in patients whose surgery was delayed until adult life. We conclude that attempts should be made early in the course of CPS of childhood to determine whether the seizures are truly intractable to medical management so that surgical intervention can be expedited.

Predictors of stroke outcome using objective measurement scales.

We set out to determine if rehabilitation variables predicted the motor and functional outcomes of stroke patients. Using the Modified Motor Assessment Scale (motor status) and the Barthel Index (functional status), we tested 50 stroke patients less than or equal to 3 days, 1 week, and 1 month after their stroke and at discharge from the hospital. Both measures are reliable and valid. We used the Spearman correlation coefficient (r) and stepwise regression analysis to analyze the data. Balanced sitting and bladder control scores at 1 week correlated significantly with motor score at discharge (r = 0.83), Barthel Index score at discharge (r = 0.82), and walking score at discharge (r = 0.80). The combined arm score at 1 month correlated significantly with the combined arm score at discharge (r = 0.94). Regression equations using the scores at 1 month produced the highest r2 values (range 0.76-0.95) in predicting the Barthel Index, motor, walking, and arm recovery scores at discharge. The correlation coefficients and the regression equations have uses in both research and clinical settings. We suggest that these objective predictors of recovery be used as adjuncts in prioritizing and directing the rehabilitation management of patients with stroke.

Electrophysiological connections between the hippocampus and entorhinal cortex in patients with complex partial seizures.

The electrophysiological properties of the neural pathways between the hippocampus and the entorhinal cortex were studied intraoperatively in 31 patients undergoing anterior temporal lobectomy for medically intractable complex partial seizures. The hippocampus, removed en bloc, was studied histologically and the pathology was correlated with the electrophysiological findings. In 29 of the patients, entorhinal stimulation evoked a characteristic positive-negative potential in the hippocampus. The entorhinal-evoked hippocampal response closely resembled, or was identical to, the spontaneously occurring hippocampal interictal spike discharge. In patients with Ammon's horn sclerosis in whom there was a major loss of neurons in the hippocampal subfields CA1, CA3, and CA4, the evoked responses were of simple morphology and long latency (mean 21.9 msec to the peak of the first potential). In patients with a ganglioglioma in whom the hippocampus was histologically normal, the evoked responses were of greater complexity and shorter latency (mean 11.8 msec). Stimulation at a single entorhinal site evoked similar waveforms at different hippocampal recording sites. Conversely, stimulation at different entorhinal sites evoked similar responses at a single hippocampal recording site. Stimulation of the hippocampus evoked a potential in the entorhinal cortex and, in some instances, in the amygdala, insula, and lateral temporal cortex. These connections may produce a positive feedback loop that favors seizure generation.

Reliability of the Modified Motor Assessment Scale and the Barthel Index.

Many physical therapists use descriptive and functional assessments of motor recovery for patients with stroke. The purpose of this study was to establish the reliability of two such assessments. The Modified Motor Assessment Scale (MMAS) assesses motor recovery; the Barthel Index assesses functional independence. Interrater and intrarater reliability were determined for the total scores and individual item ratings using videotaped MMAS and Barthel Index assessments of seven patients with stroke. Therapists viewed and rated the videotaped assessments on two occasions separated by one month. The intrarater reliability results were higher than the interrater reliability results for total scores, and both results were acceptable statistically. Interrater and intrarater reliability of the individual item ratings were also determined. The MMAS and Barthel Index are reliable assessments of motor recovery and function for patients with stroke. Physical therapists are encouraged to use the two scales to document changes in the motor recovery and functional independence of patients with stroke.