Peritoneal flap hernioplasty for repair of incisional hernias after orthotopic liver transplantation.

BACKGROUND: Repair of incisional hernias following orthotopic liver transplantation (OLT) is a surgical challenge due to concurrent midline and transverse abdominal wall defects in the context of lifelong immunosuppression. The peritoneal flap hernioplasty addresses this problem by using flaps of the hernial sac to bridge the fascial gap and isolate the mesh from both the intraperitoneal contents and the subcutaneous space, exploiting the retro-rectus space medially and the avascular plane between the internal and external oblique muscles laterally. We report our short and long-term results of 26 consecutive liver transplant cases with incisional hernias undergoing repair with the peritoneal flap technique. METHODS: Post-OLT patients undergoing elective peritoneal flap hernioplasty for incisional hernias from Jan 1, 2010-Nov 1, 2017 were identified from the Lothian Surgical Audit system (LSA), a prospectively-maintained computer database of all surgical procedures in the Edinburgh region of south-east Scotland. Patient demographics and clinical data were obtained from the hospital case-notes. Follow-up data were obtained in Feb 2020. RESULTS: A total of 517 liver transplantations were performed during the inclusion period. Twenty-six of these (18 males, 69%) developed an incisional hernia and underwent a peritoneal flap repair. Median mesh size (Optilene Elastic, 48 g/m2, BBraun) was 900 cm2 (range 225-1500 cm2). The median time to repair following OLT was 33 months (range 12-70 months). Median follow-up was 54 months (range 24-115 months) and median postoperative stay was 5 days (range 3-11 days). Altogether, three patients (12%) presented with postoperative complications: 1 with hematoma (4%) and two with chronic pain (8%). No episodes of infection or symptomatic seroma were recorded. No recurrence was recorded within the follow-up period. CONCLUSION: Repair of incisional hernias in patients following liver transplantation with the Peritoneal Flap Hernioplasty is a safe procedure associated with few complications and a very low recurrence rate. We propose this technique for the reconstruction of incisional hernias following liver transplantation.

Fundoplication is superior to medical therapy for Barrett's esophagus disease regression and progression: a systematic review and meta-analysis.

BACKGROUND: Fundoplication and medical management are current mainstays for management of Barrett's esophagus (BE), however our understanding of differences in outcomes between these two treatments is limited. The aim of this study was to perform a systematic review and meta-analysis to evaluate the efficacy of these interventions on BE disease regression and progression. METHODS AND PROCEDURES: A comprehensive search in MEDLINE, EMBASE, Scopus, Web of Science, and Cochrane Library databases was performed on February 22, 2021. Inclusion criteria were studies with both medical and surgical management comparators, BE diagnosis prior to treatment, patients aged ≥ 18 years, and studies with greater than five patients. Primary outcomes of interest included evaluating changes in histopathologic BE regression and disease progression between interventions. Meta-analysis was performed using a Mantel-Haenszel random-effects model (RevMan 5.4.1). RESULTS: A total of 7231 studies were retrieved after initial search with nine studies (1 randomized trial, 7 prospective cohorts, 1 retrospective cohort) meeting final inclusion criteria. Of included studies, 890 (65%) patients received medical management while 470 (35%) received surgical management. Medical management included proton pump inhibitors (n = 807, 91%; 6 studies), H2-receptor blockers (n = 40, 4% patients; 3 studies), and combination therapy (n = 43, 5%; 1 study). Nissen fundoplication was the most commonly performed type of fundoplication (n = 265, 93%). Median length of follow-up ranged from 1.5-7 years. Meta-analysis revealed that fundoplication was associated with improved histopathologic regression of metaplasia/low-grade dysplasia (OR 4.38; 95% CI 2.28-8.42; p < 0.00001) and disease progression to dysplasia/adenocarcinoma (OR 0.34; 95% CI 0.12-0.96; p = 0.04) compared to medical therapy. CONCLUSION: Fundoplication is superior to medical therapy with regards to improved odds of histopathologic BE disease regression and disease progression. Additional randomized trials which directly compare medical management and surgical intervention are required to delineate the optimal delivery and timing of these interventions.

LPS receptor subunits have antagonistic roles in epithelial apoptosis and colonic carcinogenesis.

Colorectal carcinoma (CRC) is characterized by unlimited proliferation and suppression of apoptosis, selective advantages for tumor survival, and chemoresistance. Lipopolysaccharide (LPS) signaling is involved in both epithelial homeostasis and tumorigenesis, but the relative roles had by LPS receptor subunits CD14 and Toll-like receptor 4 (TLR4) are poorly understood. Our study showed that normal human colonocytes were CD14(+)TLR4(-), whereas cancerous tissues were CD14(+)TLR4(+), by immunofluorescent staining. Using a chemical-induced CRC model, increased epithelial apoptosis and decreased tumor multiplicity and sizes were observed in TLR4-mutant mice compared with wild-type (WT) mice with CD14(+)TLR4(+) colonocytes. WT mice intracolonically administered a TLR4 antagonist displayed tumor reduction associated with enhanced apoptosis in cancerous tissues. Mucosa-associated LPS content was elevated in response to CRC induction. Epithelial apoptosis induced by LPS hypersensitivity in TLR4-mutant mice was prevented by intracolonic administration of neutralizing anti-CD14. Moreover, LPS-induced apoptosis was observed in primary colonic organoid cultures derived from TLR4 mutant but not WT murine crypts. Gene silencing of TLR4 increased cell apoptosis in WT organoids, whereas knockdown of CD14 ablated cell death in TLR4-mutant organoids. In vitro studies showed that LPS challenge caused apoptosis in Caco-2 cells (CD14(+)TLR4(-)) in a CD14-, phosphatidylcholine-specific phospholipase C-, sphingomyelinase-, and protein kinase C-ζ-dependent manner. Conversely, expression of functional but not mutant TLR4 (Asp299Gly, Thr399Ile, and Pro714His) rescued cells from LPS/CD14-induced apoptosis. In summary, CD14-mediated lipid signaling induced epithelial apoptosis, whereas TLR4 antagonistically promoted cell survival and cancer development. Our findings indicate that dysfunction in the CD14/TLR4 antagonism may contribute to normal epithelial transition to carcinogenesis, and provide novel strategies for intervention against colorectal cancer.

Epilepsy surgery in children under 3 years.

PURPOSE: Resective epilepsy surgery in early childhood has become an important treatment option for selected infants and children with epilepsy. We describe experience and clinical outcomes of children under 3 years undergoing epilepsy surgery at Great Ormond Street Hospital (GOSH). METHODS: All children under 36 months of age who had resective surgery for the purpose of treating epilepsy within the GOSH epilepsy surgery programme were ascertained using a departmental database. Aetiology, post-operative seizure frequency, pre and post-operative cognitive function, long-term complications and re-operation rates were analysed by retrospective examination of clinical records. RESULTS: Forty-two children were included in our cohort with a median age at surgery of 20 months (range 3-36 months). Surgical procedures comprised 25 functional hemispherectomies, two anatomical hemispherectomies, four multilobar resections, seven lobar resections and four focal resections. 7/42 (17%, 95% CI 8-31%) children underwent re-operation. 20/42 (48%, 95% CI 33-62%) children achieved seizure freedom. 18/42 (43%, 95% CI 29-58) demonstrated an improvement in seizure frequency and no children had an increase in seizure frequency. Post-operative complications included subsequent shunt procedure in 5/25 (20%, 95% CI 9-39%) children undergoing hemispherectomy. There were no mortalities. In 23 children pre- and post-operative DQ or IQ was determinable allowing longitudinal comparison. Five children had a decrease in DQ/IQ >15 and two children had an increase DQ/IQ >15. DISCUSSION: Epilepsy surgery in children under 3 years of age offers suitable candidates a good chance of significantly improved seizure outcome which compares with rates in older cohorts.

Heterotopic pancreas: typical and atypical imaging findings.

Heterotopic pancreas is a common condition often encountered during laporotomy or autopsy. Prospective radiographic diagnosis is challenging because of the variable imaging appearances. The purpose of this review is to present the typical and atypical appearances of heterotopic pancreas on imaging studies. Familiarity with the spectrum of radiological findings in conjunction with biochemical markers is helpful to improve diagnostic accuracy.

Temporal profile of fluorodeoxyglucose uptake in malignant lesions and normal organs over extended time periods in patients with lung carcinoma: implications for its utilization in assessing malignant lesions.

AIM: In this study, the fluorodeoxyglucose (FDG) uptake was prospectively investigated in tumors as well as the normal organs over 8 h in patients with non small cell lung carcinoma (NSCLC). The intent of this study was to collect positron emission tomography (PET) data with regard to the time course of FDG uptake in the primary and metastatic sites and the normal tissues over extended time periods (up to 8 h) after intravenous FDG injection in patients. METHODS: Three patients (2 males, 1 female; mean age: 64 years; age range: 57-76 years) with the diagnosis of NSCLC underwent a series of whole body FDG-PET at several time points, beginning at 5 min and extending up to 8 h after the intravenous administration of FDG. We calculated the standardized uptake values (SUVmax) in the malignant lesions and all organs. SUVmax was calculated over contiguous slices and the highest value was considered for the analysis. Similar locations were used for the placement of regions of interest in subsequent images. Time activity curves (TACs) were generated utilizing these SUV values for each of these sites. The ratios of the SUVmax of the malignant lesions to those of normal organs (viz. lung and liver) at specific time points were also calculated and the TACs for these ratios were generated. The blood and plasma decay curves of (18)F activity over time were generated based on the counts obtained from blood sample analysis. The ratios of 18F activity of blood to plasma were also calculated and the TACs of this ratio were generated. RESULTS: The observed mean SUVmax at different time points (5 min, 1 h, 2 h, 4 h, 6 h and 8 h) in the organs and the lesions were as follows: 1) heart: 2.9, 2, 1.9, 1.6, 1.3, 1.5; 2) kidney: 3.3, 3.5, 2.6, 2.1, 2, 2; 3) liver: 3.9, 2.2, 1.9, 1.6, 1.5, 1.8; 4) lung: 0.6, 0.5, 0.4, 0.4, 0.4, 0.4, 0.4; 5) large bowel: 2.1, 1.4, 1.8, 1.4, 2, 2.2; 6) small bowel: 2.6, 1.6, 1.4, 1.2, 1.3, 1.5; 7) lung neoplasm: 3.7, 5.1, 6.1, 6.8, 6.9, 6.8; 8) mediastinal lesion 1: 6.8, 8.8, 13, 12.7, 13.8, 12.5; 9) mediastinal lesion 2: 5.5, 8.6, 10.7, 13.2, 11.7, 12.1; 10) adrenal metastasis (starting at 1 h): 3.3, 3.7, 4.7, 4.7, 4.7; 11) right iliac metastasis: 2.6, 2.6, 3.1, 3.5, 3.4. For the right iliac metastasis, we had SUVmax up to 6 h. The SUVmax ratios of malignant lesions to those of normal lung and liver and their TACs demonstrate initial rise followed by a delayed plateau. Increasing (18)F count ratios of blood to plasma with time was observed in 2 patients where these data were available. CONCLUSIONS: The results from this preliminary study indicate that while the tumor sites show increased uptake of FDG during the course of 8 h, surrounding normal tissues demonstrate declining or stable values with time. This would indicate increasing contrast between the lesion and the background and, therefore, possibly improved sensitivity of the test. While the high SUV at 5 min can be explained by the blood pool activity in the organs and the malignant lesions, the SUVmax values at the later times decreases or remains the same in normal organs. The observation on the different slopes of the curves among the various malignant lesions can be partly explained by the well known ''seed and soil'' theory in cancer biology. The finding of continued increases in the blood to plasma count ratios of (18)F activity is also noteworthy and most likely reflects GLUT-1 mediated glucose transport into red blood cells.

FDG-PET/MRI coregistration improves detection of cortical dysplasia in patients with epilepsy.

OBJECTIVE: Patients with cortical dysplasia (CD) are difficult to treat because the MRI abnormality may be undetectable. This study determined whether fluorodeoxyglucose (FDG)-PET/MRI coregistration enhanced the recognition of CD in epilepsy surgery patients. METHODS: Patients from 2004-2007 in whom FDG-PET/MRI coregistration was a component of the presurgical evaluation were compared with patients from 2000-2003 without this technique. For the 2004-2007 cohort, neuroimaging and clinical variables were compared between patients with mild Palmini type I and severe Palmini type II CD. RESULTS: Compared with the 2000-2003 cohort, from 2004-2007 more CD patients were detected, most had type I CD, and fewer cases required intracranial electrodes. From 2004-2007, 85% of type I CD cases had normal non-University of California, Los Angeles (UCLA) MRI scans. UCLA MRI identified CD in 78% of patients, and 37% of type I CD cases had normal UCLA scans. EEG and neuroimaging findings were concordant in 52% of type I CD patients, compared with 89% of type II CD patients. FDG-PET scans were positive in 71% of CD cases, and type I CD patients had less hypometabolism compared with type II CD patients. Postoperative seizure freedom occurred in 82% of patients, without differences between type I and type II CD cases. CONCLUSIONS: Incorporating fluorodeoxyglucose-PET/MRI coregistration into the multimodality presurgical evaluation enhanced the noninvasive identification and successful surgical treatment of patients with cortical dysplasia (CD), especially for the 33% of patients with nonconcordant findings and those with normal MRI scans from mild type I CD.

Decompressive craniectomy for hemispheric infarction: predictive factors for six month rehabilitation outcome.

BACKGROUND: Decompressive craniectomy after hemispheric infarction has been shown to reduce mortality and functional outcome in selected patients. However, the optimal timing for surgery and patient most likely to benefit from this procedures was not known. We aimed to determine possible factors predictive of outcome following decompressive craniectomy for ischemic infarction from review of oneurological outcome in our patients at six months. METHODS: We retrospectively reviewed 21 patients who underwent decompressive craniectomy for hemispheric infarction over a three year period in a regional neurosurgical center in Hong Kong. All patients were recruited subsequently for active in-patient rehabilitation, when suitable. FINDINGS: The median age was 53 and the male to female ration was 1:3. Four patients (19%) achieved independent activity of daily living at six months after rehabilitation. Neither early surgery, within 24-48 hours after admission, nor side of infarction correlated with six month neurological outcome. All four patients with favourable neurological outcome at six month demonstrated favourable clinical improvement even at one month. CONCLUSIONS: Early decompressive hemicraniectomy is not predictive of neurological outcome, determined by Glasgow outcome score, at six months (P = 1.00, NS).

Predicting survival in patients with hepatocellular carcinoma: a UK perspective.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a cancer of rising incidence in the UK. The aim of this study was to compare the Okuda, Cancer of the Liver Italian Program (CLIP), and Barcelona Clinic Liver Cancer (BCLC) classifications as predictors of survival in UK patients with HCC. METHODS: Data were analysed from a prospective database maintained in a specialist hepatobiliary unit from 1998 to 2003. Each system was assessed for its discriminatory power, monotonicity of gradient, and independent contribution to prediction of mortality status based on a multivariate model. RESULTS: One hundred and two patients (77 males, 25 females) were identified with a median age of 65 (range, 14-87) years. The overall median survival time was 13 months and the one- and five-year survival rates were 52.9% (95% CI: 43.2%, 62.6%) and 35.3% (95% CI: 26.0%, 44.6%), respectively. All three classification systems had the capacity to differentiate between patient survival times across different stages. The Okuda system was superior in overall discriminatory power and in strength of monotonicity. The BCLC system, however, made the highest independent contribution of all three systems in predicting survival in the Cox regression model. CONCLUSIONS: All three classification systems were effective in predicting survival for patients with HCC in a UK population.

The endogenous immune response modulates the course of IgA-immune complex mediated nephropathy.

In animal models of IgA nephropathy, the inevitable endogenous immune response to passively administered antigens alone or in complex with specific IgA mask the exact role each might play in pathogenesis. To delineate the role the immune response might play, we have developed a passive model with exclusive IgA-immune complex-mediated nephropathy in B-cell-deficient (BCD) mice. Glomerular IgA immune deposits were induced by administration of purified IgA antiphosphorylcholine and the specific pneumococcal C-polysaccharide (PnC) antigen daily for 2 weeks into BCD and wild-type (WT) mice. In BCD mice IgA+PnC deposits induced severe glomerular injury and renal dysfunction. In contrast, WT mice developed intense glomerular IgG and IgM and C3 co-deposits of the IgA+PnC with significantly less renal injury. Cytofluorometric analysis revealed that PnC induced in BCD, but not in WT, a rapid and dramatic increase in number of activated CD3(+)/CD69(+) T-cell population. The nuclear factor-kappa B (NF-kappaB) transcription factor was activated early and progressively increased in response to glomerular IgA+PnC deposits. These results suggest that nephritogenic IgA+PnC immune deposits induce glomerular and renal dysfunction through activation of the NF-kappaB. This inflammatory pathway is modulated by the endogenous cellular and antibody response to the antigen affecting the course of IgA nephropathy progression.

The origins of the thenar and hypothenar muscles.

This paper presents an anatomical study of the origins of the thenar and hypothenar muscles and postulates the causes of weakness and pillar pain following carpal tunnel release.

'Tongue-and-groove' effect in intensity modulated radiotherapy with static multileaf collimator fields.

The 'tongue-and-groove problem' in step-and-shoot delivery of intensity modulated radiotherapy is investigated. A 'tongue-and-groove' index (TGI) is introduced to quantify the 'tongue-and-groove' effect in step-and-shoot delivery. Four different types of leaf sequencing methods are compared. The sliding window method and the reducing level method use the same number of field segments to deliver the same intensity map, but the TGI is much less for the reducing level method. The leaf synchronization method of Van Santvoort and Heijmen fails in step-and-shoot delivery, but a new method inspired by the method of Van Santvoort and Heijmen is shown to eliminate 'tongue-and-groove' underdosage completely.

A method of calculating a lung clinical target volume DVH for IMRT with intrafractional motion.

The motion of lung tumors from respiration has been reported in the literature to be as large as 1-2 cm. This motion requires an additional margin between the Clinical Target Volume (CTV) and the Planning Target Volume (PTV). In Intensity Modulated Radiotherapy (IMRT), while such a margin is necessary, the margin may not be sufficient to avoid unintended high and low dose regions to the interior on moving CTV. Gated treatment has been proposed to improve normal tissues sparing as well as to ensure accurate dose coverage of the tumor volume. The following questions have not been addressed in the literature: (a) what is the dose error to a target volume without a gated IMRT treatment? (b) What is an acceptable gating window for such a treatment. In this study, we address these questions by proposing a novel technique for calculating the three-dimensional (3-D) dose error that would result if a lung IMRT plan were delivered without a gated linac beam. The method is also generalized for gated treatment with an arbitrary triggering window. IMRT plans for three patients with lung tumors were studied. The treatment plans were generated with HELIOS for delivery with 6 MV on a CL2100 Varian linear accelerator with a 26 pair MLC. A CTV to PTV margin of 1 cm was used. An IMRT planning system searches for an optimized fluence map phi(x,y) for each port, which is then converted into a dynamic MLC file (DMLC). The DMLC file contains information about MLC subfield shapes and the fractional Monitor Units (MUs) to be delivered for each subfield. With a lung tumor, a CTV that executes a quasiperiodic motion z(t) does not receive phi(x,y), but rather an Effective Incident Fluence EIF(x,y). We numerically evaluate the EIF(x,y) from a given DMLC file by a coordinate transformation to the Target's Eye View (TEV). In the TEV coordinate system, the CTV itself is stationary, and the MLC is seen to execute a motion -z(t) that is superimposed on the DMLC motion. The resulting EIF(x,y) is input back into the dose calculation engine to estimate the 3-D dose to a moving CTV. In this study, we model respiratory motion as a sinusoidal function with an amplitude of 10 mm in the superior-inferior direction, a period of 5 s, and an initial phase of zero.

Intensity-modulated radiotherapy for a prostate patient with a metal prosthesis.

When treating prostate patients having a metallic prosthesis with radiation, a 3D conformal radiotherapy (3DCRT) treatment plan is commonly created using only those fields that avoid the prosthesis in the beam's-eye view (BEV). With a limited number of portals, the resulting plan may compromise the dose sparing of the rectum and bladder. In this work, we investigate the feasibility of using intensity-modulated radiotherapy (IMRT) to treat prostate patients having a metallic prosthesis. Three patients, each with a single metallic prosthesis, who were previously treated at the University of Chicago Medical Center for prostate cancer, were selected for this study. Clinical target volumes (CTV = prostate + seminal vesicles), bladder, and rectum volumes were identified on CT slices. Planning target volumes (PTV) were generated in 3D by a 1-cm expansion of the CTVs. For these comparative studies, treatment plans were generated from CT data using 3DCRT and IMRT treatment planning systems. The IMRT plans used 9 equally-spaced 6-MV coplanar fields, with each field avoiding the prosthesis. The 3DCRT plans used 5 coplanar 18-MV fields, with each field avoiding the prosthesis. A 1-cm margin around the PTV was used for the blocks. Each of the 9-field IMRT plans spared the bladder and rectum better than the corresponding 3DCRT plan. In the IMRT, plans, a bladder volume receiving 80% or greater dose decreased by 20-77 cc, and a volume rectal volume receiving 80% or greater dose decreased by 24-40 cc. One negative feature of the IMRT plans was the homogeneity across the target, which ranged from 95% to 115%.

Phorbol esters modulate the Ras exchange factor RasGRP3.

RasGRP represents the prototype of a new class of guanine nucleotide exchange factors that activate small GTPases. The guanyl nucleotide-releasing protein (GRP) family members contain catalytic domains related to CDC25, the Ras exchange factor of Saccharomyces cerevisiae. They also contain a motif resembling a pair of calcium-binding EF-hands and a C1 domain similar to the diacylglycerol interaction domain of protein kinase C. The sequence of KIAA0846, identified in a human brain cDNA library, encodes a member of the GRP family that we refer to as RasGRP3. We show here that RasGRP3 bound phorbol esters with high affinity. This binding depended on anionic phospholipids, which is characteristic of phorbol ester binding to C1 domain proteins. In addition, phorbol esters also caused activation of the RasGRP3 exchange activity in intact cells, as determined by an increase in RasGTP and phosphorylation of the extracellular-regulated kinases. Finally, both phorbol 12-myristate 13-acetate and the diacylglycerol analogue 1,2-dioctanoyl-sn-glycerol induced redistribution of RasGRP3 to the plasma membrane and/or perinuclear area in HEK-293 cells, as demonstrated using a green fluorescent fusion protein. We conclude that RasGRP3 serves as a PKC-independent pathway to link the tumor-promoting phorbol esters with activation of Ras GTPases.

Method of identifying dynamic multileaf collimator irradiation that is highly sensitive to a systematic MLC calibration error.

In intensity modulated radiotherapy (IMRT), radiation is delivered in a multiple of multileaf collimator (MLC) subfields. A subfield with a small leaf-to-leaf opening is highly sensitive to a leaf-positional error. We introduce a method of identifying and rejecting IMRT plans that are highly sensitive to a systematic MLC gap error (sensitivity to possible random leaf-positional errors is not addressed here). There are two sources of a systematic MLC gap error: centerline mechanical offset (CMO) and, in the case of a rounded end MLC, radiation field offset (RFO). In IMRT planning system, using an incorrect value of RFO introduces a systematic error ARFO that results in all leaf-to-leaf gaps that are either too large or too small by (2*DeltaRFO), whereas assuming that CMO is zero introduces systematic error DeltaCMO that results in all gaps that are too large by DeltaCMO=CMO. We introduce a concept of the average leaf pair Opening (ALPO) that can be calculated from a dynamic MLC delivery file. We derive an analytic formula for a fractional average fluence error resulting from a systematic gap error of Deltax and show that it is inversely proportional to ALPO; explicitly it is equal to Deltax/(ALPO+ 2 * RFO+ epsilon), in which epsilon is generally of the order of 1 mm and Deltax =2 * Delta RFO + CMO. This analytic relationship is verified with independent numerical calculations.

A monitor unit verification calculation in intensity modulated radiotherapy as a dosimetry quality assurance.

In standard teletherapy, a treatment plan is generated with the aid of a treatment planning system, but it is common to perform an independent monitor unit verification calculation (MUVC). In exact analogy, we propose and demonstrate that a simple and accurate MUVC in intensity modulated radiotherapy (IMRT) is possible. We introduce the concept of modified Clarkson integration (MCI). In MCI, we exploit the rotational symmetry of scattering to simplify the dose calculation. For dose calculation along a central axis (CAX), we first replace the incident IMRT fluence by an azimuthally averaged fluence. Second, the Clarkson integration is carried over annular sectors instead of over pie sectors. We wrote a computer code, implementing the MCI technique, in order to perform a MUVC for IMRT purposes. We applied the code to IMRT plans generated by CORVUS. The input to the code consists of CORVUS plan data (e.g., DMLC files, jaw settings, MU for each IMRT field, depth to isocenter for each IMRT field), and the output is dose contribution by individual IMRTs field to the isocenter. The code uses measured beam data for Sc, Sp, TPR, (D/MU)ref and includes effects from multileaf collimator transmission, and radiation field offset. On a 266 MHz desktop computer, the code takes less than 15 to calculate a dose. The doses calculated with the MCI algorithm agreed within +/-3% with the doses calculated by CORVUS, which uses a 1 cm x 1 cm pencil beam in dose calculation. In the present version of MCI, skin contour variations and inhomogeneities were neglected.

Enhanced antitumor immunity by fusion of CTLA-4 to a self tumor antigen.

The idiotypic determinant (Id) of the immunoglobulin expressed by a B-cell malignancy can serve as an effective tumor-specific antigen but is only weakly immunogenic. This study demonstrates that the immunogenicity of the tumor Id protein can be dramatically increased by directing it to antigen-presenting cells (APCs). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) present on activated T cells has a strong binding affinity to both B7-1 and B7-2 molecules, which are primarily expressed on APCs. After construction of a fusion protein consisting of Id and CTLA-4 (Id-CTLA4), mice immunized with the fusion protein induced high titers of Id-specific antibody and T-cell proliferative responses without adjuvants and were protected from lethal tumor challenge. The Id-CTLA4 fusion protein was so potent that even low doses (down to 0.1 microg) of the immunogen were able to elicit strong antibody responses. By using an Id-CTLA4 mutant protein, the ability to bind B7 molecules on APCs was shown to be required for the enhanced immunogenicity of Id-CTLA4. These findings demonstrate that fusing CTLA-4 to a potential tumor antigen represents an effective approach to prime antitumor immunities in vivo and may be applicable to the design of vaccines for a variety of other diseases. (Blood. 2000;96:3663-3670)

Induction of CD8 T cells by vaccination with recombinant adenovirus expressing human papillomavirus type 16 E5 gene reduces tumor growth.

The potential of the E5 protein as a tumor vaccine candidate has not been explored yet. In this study, we evaluate the human papillomavirus type 16 (HPV-16) E5 protein delivered by an adenovirus vector as a tumor vaccine for cervical lesions. The results demonstrate that a single intramuscular injection of a recombinant adenovirus carrying the HPV-16 E5 gene into syngeneic animals can reduce the growth of tumors which contain E5 gene expression. Moreover, the E5 vaccine-induced tumor protection occurs through CD8 T cells but not through CD4 T cells in in vitro assays. In addition, our studies using knockout mice with distinct T-cell deficiencies confirm that cytotoxic T-lymphocyte-induced tumor protection is CD8 dependent but CD4 independent. Hence, HPV-16 E5 can be regarded as a tumor rejection antigen.

Intensity modulated radiotherapy dose delivery error from radiation field offset inaccuracy.

In Intensity Modulated Radiotherapy (IMRT), irradiation is delivered in a number of small aperture subfields. The fluences shaped by these small apertures are highly sensitive to inaccuracies in multileaf collimator (MLC) calibration. The Radiation Field Offset (RFO) is the difference between a radiation and a light field at the Source to Axis Distance (SAD) for a MLC. An Intensity Modulated Radiotherapy (IMRT) system must incorporate a RFO by closing in all leaf openings. In IMRT, RFO inaccuracy will result in a dose error to the interior of a target volume. We analyze dosimetric consequences of incorporating a wrong RFO into the CORVUS, 1 cm x 1 cm, step and shoot, IMRT system. The following method was employed. First an IMRT plan is generated for a target volume in a phantom, which produces a set of dynamic MLC (DMLC) files with the correct RFO value. To simulate delivery with a wrong RFO value, we wrote a computer code that reads in the DMLC file with the correct RFO value and produces another DMLC with an incorrect RFO specified by a user. Finally the phantom was irradiated with the correct and the incorrect RFO valued DMLC files, and the doses were measured with an ionization chamber. The method was applied to 9 fields, 6 MV, IMRT plans. We measured Dose Error Sensitivity Factor (DESF) for each plan, which ranged from (0-8)% mm(-1). The DESF(x) is defined as a fractional dose error to a point (x) in a target volume per mm of the RFO error, i.e., DESF(x) is equivalent to ¿deltaD(x)/D(x)deltaRFO¿. Therefore, we concluded that for CORVUS, 6 MV, 1 cm x 1 cm, step and shoot IMRT, RFO must be determined within an accuracy of 0.5 mm if a fractional dose error to a target volume is to be less than 4%. We propose an analytic framework to understand the measured DESF's. From the analysis we conclude that a large DESF was associated with an DMLC file with small average leaf openings. For 1 cm x 1 cm, step and shoot IMRT, the largest possible DESF is predicted to be 20% mm(-1). In addition, we wrote computer code that can calculate a DESF of a DMLC file. The code was written in Mathematica 3.0. The code can be used to screen patient IMRT plans that are highly sensitive to a RFO error.