Using extended reality (XR) for medical training and real-time clinical support during deep space missions.

Medical events can affect space crew health and compromise the success of deep space missions. To successfully manage such events, crew members must be sufficiently prepared to manage certain medical conditions for which they are not technically trained. Extended Reality (XR) can provide an immersive, realistic user experience that, when integrated with augmented clinical tools (ACT), can improve training outcomes and provide real-time guidance during non-routine tasks, diagnostic, and therapeutic procedures. The goal of this study was to develop a framework to guide XR platform development using astronaut medical training and guidance as the domain for illustration. We conducted a mixed-methods study-using video conference meetings (45 subject-matter experts), Delphi panel surveys, and a web-based card sorting application-to develop a standard taxonomy of essential XR capabilities. We augmented this by identifying additional models and taxonomies from related fields. Together, this "taxonomy of taxonomies," and the essential XR capabilities identified, serve as an initial framework to structure the development of XR-based medical training and guidance for use during deep space exploration missions. We provide a schematic approach, illustrated with a use case, for how this framework and materials generated through this study might be employed.

Nondepleting anti-CD40-based therapy prolongs allograft survival in nonhuman primates.

Costimulation blockade of the CD40/CD154 pathway has been effective at preventing allograft rejection in numerous transplantation models. This strategy has largely depended on mAbs directed against CD154, limiting the potential for translation due to its association with thromboembolic events. Though targeting CD40 as an alternative to CD154 has been successful at preventing allograft rejection in preclinical models, there have been no reports on the effects of CD40-specific agents in human transplant recipients. This delay in clinical translation may in part be explained by the presence of cellular depletion with many CD40-specific mAbs. As such, the optimal biologic properties of CD40-directed immunotherapy remain to be determined. In this report, we have characterized 3A8, a human CD40-specific mAb and evaluated its efficacy in a rhesus macaque model of islet cell transplantation. Despite partially agonistic properties and the inability to block CD40 binding of soluble CD154 (sCD154) in vitro, 3A8-based therapy markedly prolonged islet allograft survival without depleting B cells. Our results indicate that the allograft-protective effects of CD40-directed costimulation blockade do not require sCD154 blockade, complete antagonism or cellular depletion, and serve to support and guide the continued development of CD40-specific agents for clinical translation.

Influenza vaccination can induce new-onset anticardiolipins but not ß2-glycoprotein-I antibodies among patients with systemic lupus erythematosus.

BACKGROUND: Antiphospholipid syndrome is characterized by autoantibodies against cardiolipins (aCL), lupus anticoagulant, and independent ß2-glycoprotein (ß2GPI). Controversy exists as to whether vaccination triggers the development of antiphospholipid antibodies (aPL) in patients with systemic lupus erythematosus (SLE). METHODS: Patients with SLE (101) and matched controls (101) were enrolled from 2005-2009 and received seasonal influenza vaccinations. Sera were tested by ELISA for aCL at baseline, 2, 6, and 12 weeks after vaccination. Vaccine responses were ranked according to an overall anti-influenza antibody response index. Individuals with positive aCL were further tested for ß2GPI antibodies. RESULTS: Patients with SLE and healthy controls can develop new-onset aCL post vaccination, although at rates which do not differ between patients and controls (12/101 cases and 7/101 controls, OR 1.81, p = 0.34). New-onset moderate aCL are slightly enriched in African American SLE patients (5/36 cases; p = 0.094). The optical density measurements for aCL reactivity in patients were significantly higher than baseline at 2 weeks (p < 0.05), 6 weeks (p < 0.05), and 12 weeks (p < 0.05) post vaccination. No new ß2GPI antibodies were detected among patients with new aCL reactivity. Vaccine response was not different between patients with and without new-onset aCL reactivity (p = 0.43). CONCLUSIONS: This study shows transient increases in aCL, but not anti-ß2GPI responses, after influenza vaccination.

Male territoriality and 'sex confusion' in recently adapted lizards at White Sands.

The evolution of intersexual interactions, like mate choice, during ecological speciation has received widespread attention. However, changes in intrasexual interactions, like male territoriality, during ecological divergence are largely unexamined. We conducted field experiments with adaptively diverged populations of the eastern fence lizard (Sceloporus undulatus) to determine whether territorial males behaved differently towards ecologically similar vs. dissimilar intruders. We performed trials with light-coloured males from White Sands, New Mexico and dark-coloured males from the surrounding desert. We found that intruders from White Sands elicited more aggression than intruders from dark-soil habitat. We also documented a case of 'sex confusion' where white-sand males courted dark-soil intruders. We found population differences in signalling patch size that can explain both aggression bias and sex misidentification. We argue that direct selection (for population recognition or optimal signal transmission) and indirect selection (by-products of ecological adaptation) should influence both intersexual and intrasexual interactions during ecological speciation.

An evaluation of commercial DNA extraction kits for the isolation of bacterial spore DNA from soil.

AIMS: To evaluate six commercial DNA extraction kits for their ability to isolate PCR-quality DNA from Bacillus spores in various soil samples. METHODS AND RESULTS: Three soils were inoculated with various amounts of Bacillus cereus spores to simulate an outbreak or intentional release of the threat agent Bacillus anthracis. DNA was isolated from soil samples using six commercial DNA extraction kits. Extraction and purification efficiencies were assessed using a duplex real-time PCR assay that included an internal positive control. The FastDNA(®) SPIN kit for Soil showed the highest DNA extraction yield, while the E.Z.N.A.(®) Soil DNA and PowerSoil(®) DNA Isolation kits showed the highest efficiencies in removing PCR inhibitors from loam soil extracts. CONCLUSIONS: The results of this study suggest that commercially available extraction kits can be used to extract PCR-quality DNA from bacterial spores in soil. The selection of an appropriate extraction kit should depend on the characteristics of the soil sample and the intended downstream application. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study aid in the selection of an appropriate DNA extraction kit for a given soil sample. Its application could expedite sample processing for real-time PCR detection of a pathogen in soil.

Incorporation of 5-bromo-2'-deoxyuridine into colorectal liver metastases and liver in patients receiving a 7-day hepatic arterial infusion.

Preclinical and clinical data suggest that the combination of hepatic arterial bromodeoxyuridine (BrdUrd), a thymidine analogue radiation sensitizer, and high-dose three-dimensional conformal radiation therapy offer a high potential for improving the local control of intrahepatic cancers. A key step in the design of a successful protocol is to determine in patients the conditions for BrdUrd administration that would be expected to produce selective radiosensitization of the tumor. Therefore, we designed a clinical trial to assess BrdUrd incorporation into the DNA of hepatic colorectal metastases and normal liver after a 7-day continuous BrdUrd infusion at a dose rate of 25 mg/kg/day (the maximal tolerated dose for a 14-day infusion) for patients undergoing laparotomy for either resection of liver metastases or hepatic arterial catheter and pump placement. Thirteen patients were entered into this study. We found that the average replacement of thymidine by BrdUrd in the tumor and normal liver were 11.6 +/- 1.2% and 1.1 +/- 0.2%, respectively. This extent of incorporation would be expected to produce a single fraction radiation enhancement of 1.5 in the tumor without detectable sensitization of the normal liver. Immunohistochemical staining for BrdUrd revealed heterogeneity of incorporation with a range of approximately 60-80% of the cells labeled in different regions of the specimens. These findings suggest that hepatic arterial BrdUrd given at this dose and schedule has a high likelihood of producing clinically significant radiosensitization for patients with hepatic metastases from colorectal cancer. Furthermore, the demonstrated selectivity of tumor perfusion that can be obtained with hepatic arterial infusion combined with the high proliferative rate of colorectal metastases (versus normal liver) suggests that these patients may be good candidates for tumor-directed gene transfer therapy by using regionally delivered retroviral vectors.

Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy.

PURPOSE: To develop more effective regional therapy for patients with unresectable primary hepatobiliary cancer using concurrent conformal radiation therapy and intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd). PATIENTS AND METHODS: Twenty-six patients with unresectable, nonmetastatic primary hepatobiliary cancer were treated with concurrent IAH FdUrd (0.2 mg/kg/d) and conformal hepatic radiation therapy (1.5 to 1.65 Gy per fraction twice per day). The total dose of radiation administered to the tumor depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for toxicity, hepatobiliary relapse, and survival; 17 patients were assessable for response (eight had cholangiocarcinoma not assessable by computed tomographic [CT] scan and one progressed distantly during treatment). The median potential follow-up duration was 27 months. RESULTS: Whole-liver radiation was administered to six patients with diffuse hepatocellular carcinoma (HCC). Eleven patients with localized HCC and nine with cholangiocarcinoma received focal radiation to a dose of 48 to 72.6 Gy. An objective response for assessable patients was observed in 11 of 11 patients treated with focal radiation, but only one of six patients treated with whole-liver radiation. Whole-liver radiation accounted for five of seven patients with > or = grade 3 toxicity and four of six local treatment failures. Two patients had nonfatal radiation hepatitis. The median survival duration for patients with localized hepatobiliary cancer was 19 months, while patients with diffuse HCC had a median survival duration of 4 months. The rate of actuarial freedom from hepatobiliary progression in patients with localized disease was 72% at 24 months. CONCLUSION: These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer.

Bromodeoxyuridine alternating with radiation for advanced uterine cervix cancer: a phase I and drug incorporation study.

PURPOSE: Preclinical studies show a significant increase in the ratio of the radiosensitizer bromodeoxyuridine (BUdR) in tumors versus the intestinal mucosa during the drug elimination period, compared with the ratio during drug infusion. We constructed a phase I study in patients with locally advanced cervix cancer, using alternating cycles of BUdR and radiation therapy (RT). PATIENTS AND METHODS: Eighteen patients with stage IIB to IVA cervix cancer participated. A treatment cycle consisted of a 4-day BUdR infusion followed by a week of pelvic RT, 15 Gy twice daily in 1.5-Gy fractions. After three cycles, additional BUdR was infused, followed by brachytherapy. The fraction of thymidine replaced by BUdR and the fraction of cells incorporating BUdR were determined in rectal mucosa and tumor biopsies at the end of the first BUdR infusion (day 5), at the middle of the first RT week (day 10), and at the time of brachytherapy. RESULTS: Dose-limiting toxicity was observed in one of 16 patients receiving 1,000 mg/m2/d x 4 days and in both patients receiving 1,333 mg/m2/d x 4 days each cycle. After a median follow-up of 39 months, 12 patients (66%) were free of pelvic disease and nine (50%) were alive and disease free. The ratio of tumor to rectum BUdR incorporation averaged 1.5 to 1.8 and did not differ significantly between day 5 and day 10. A trend toward reduced ratio was observed at brachytherapy. Drug-containing cells in rectal biopsies migrated from the crypts to the mucosal surface. CONCLUSION: In this schedule, 1,000 mg/m2/d is the maximum-tolerated dose of BUdR. BUdR incorporation levels in tumors were consistent with clinically significant radiosensitization. The migration of BUdR-containing rectal mucosa cells from the crypts to the surface at the time of RT suggests that this regimen may offer a relative sparing of the mucosa from radiosensitization.

Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer.

PURPOSE: The primary objective of this phase I trial was to determine the maximum-tolerated dose of radiation that could be delivered to the primary tumor concurrent with full-dose gemcitabine in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous infusion at a dose of 1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration of radiation constant at 3 weeks. A second cycle of gemcitabine alone was intended after a 1-week rest. RESULTS: Two of six assessable patients experienced dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two additional patients at this dose level experienced late gastrointestinal toxicity that required surgical management. CONCLUSION: The final dose investigated (42 Gy) is not recommended for further study considering the occurrence of both acute and late toxicity. However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a radiation dose of 36 Gy in 2.4-Gy fractions, is recommended on the basis of tolerance, patterns of failure, and survival data.

Shielding of the D loop of ribosome-bound tRNA by elongation factor G.

The topography of the complex of elongation factor G with post-translocative ribosomes has been studied in the Escherichia coli system using fluorescence spectroscopy. We find that a fluorophore attached to the D loop of tRNA is shielded from solvent access by the presence of the factor, and this effect is dependent on factor-promoted GTP hydrolysis. The shielding result suggests that (1) the factor could bind to the tRNA during translocation and (2) the tRNA binding site may be close to that of the factor. The alternative explanation, that the factor affects the conformation of the tRNA bound at a distant site, seems less likely.

Mechanism of ribosomal translocation. tRNA binds transiently to an exit site before leaving the ribosome during translocation.

Escherichia coli ribosomes have a site (E) to which deacylated tRNA binds transiently before leaving the ribosome during translocation. The affinity of the site is Mg2+ dependent and low at physiological Mg2+ concentrations. Correct codon-anticodon interaction is unnecessary in this site. With these features, the E site cannot reduce frameshift errors through additional mRNA anchorage. Occupancy of the A site does not influence the tRNA binding in the E site, although a conformational change of elongation factor G, brought about by GTP hydrolysis, is necessary for efficient tRNA release. The tRNA can dissociate unhindered from the E site when the elongation factor is bound to the ribosome by fusidic acid. During elongation, the thermodynamically stable state is not attained, since E site occupation inhibits translocation. However, the E site can aid elongation by providing an intermediate state for tRNA dissociation, dispersing the process into more than one step.

Pre-steady-state kinetics of ribosomal translocation.

The two partial reactions of elongation factor G dependent translocation, the release of deacylated tRNA from the P site and the displacement of peptidyl tRNA from the A to the P site, have been studied with the stopped-flow technique. The experiments were performed with poly(U)-programmed ribosomes from Escherichia coli carrying deacylated tRNAPhe in the P site and N-AcPhe-tRNAPhe in the A site in the presence of GTP. The kinetics of the reaction were followed by monitoring either the intensity or the polarization of the fluorescence of both wybutine and proflavine located in the anticodon loop or of proflavine located in the D loop of yeast tRNAPhe or N-AcPhe-tRNAPhe. Both displacement and release fluorescence changes could be described by three exponentials, exhibiting apparent first-order rate-constants (20 degrees C) of 2 to 5 s-1 (15 s-1, 35 degrees C), 0.1 to 0.3 s-1, and 0.01 to 0.02 s-1, measured with a saturating concentration of elongation factor G (1 microM). The activation energy for the fast process of both reactions was found to be 70 kJ/mol (17 kcal/mol), while the intermediate process exhibits an activation energy of 30 kJ/mol (7 kcal/mol). The fast step is assigned to the displacement of the N-AcPhe-tRNAPhe from the A to the P site, and to the release of the tRNAPhe from the P site. The reactions take place simultaneously to form an intermediate post-translocation complex. The latter, in the intermediate step, rearranges to form a post-translocation complex carrying the deacylated tRNAPhe in an exit site and N-AcPhe-tRNAPhe in the P site, both in their equilibrium states. In parallel, or subsequently, the deacylated tRNAPhe spontaneously dissociates from the ribosome, thus completing the translocation process. The slow process has not been assigned.

Topological arrangement of two transfer RNAs on the ribosome. Fluorescence energy transfer measurements between A and P site-bound tRNAphe.

The relative arrangement of two tRNAPhe molecules bound to the A and P sites of poly(U)-programmed Escherichia coli ribosomes was determined from the spatial separation of various parts of the two molecules. Intermolecular distances were calculated from the fluorescence energy transfer between fluorophores in the anticodon and D loops of yeast tRNAPhe. The energy donors were the natural fluorescent base wybutine in the anticodon loop or proflavine in both anticodon (position 37) and D loops (positions 16 and 17). The corresponding energy acceptors were proflavine or ethidium, respectively, at the same positions. Four distances were measured: anticodon loop-anticodon loop, 24(+/- 4) A; anticodon loop (A site)-D loop (P site), 46(+/- 12) A: anticodon loop (P site)-D loop (A site), 38(+/- 10) A: D loop-D loop, 35(+/- 9) A. Assuming that both tRNAs adopt the conformation present in the crystal and that the CCA ends are close to each other, the results are consistent with the two anticodons being bound to contiguous codons and suggest an asymmetric arrangement in which the planes of the two L-shaped molecules enclose an angle of 60 degrees +/- 30 degrees.

Mechanism of ribosomal translocation. Translocation limits the rate of Escherichia coli elongation factor G-promoted GTP hydrolysis.

The pre-steady-state kinetics of GTP hydrolysis catalysed by elongation factor G and ribosomes from Escherichia coli has been investigated by the method of quenched-flow. The GTPase activities either uncoupled from or coupled to the ribosomal translocation process were characterized under various experimental conditions. A burst of GTP hydrolysis, with a kapp value greater than 30 s-1 (20 degrees C) was observed with poly(U)-programmed vacant ribosomes, either in the presence or absence of fusidic acid. The burst was followed by a slow GTP turnover reaction, which disappears in the presence of fusidic acid. E. coli tRNAPhe, but not N-acetylphenylalanyl-tRNAPhe (N-AcPhe-tRNAPhe), stimulates the GTPase when bound in the P site. If the A site of poly(U)-programmed ribosomes, carrying tRNAPhe in the P site, is occupied by N-AcPhe-tRNAPhe, the burst of Pi discharge is replaced by a slow GTP hydrolysis. Since, under these conditions, N-AcPhe-tRNAPhe is translocated from the A to the P site, this GTP hydrolysis very probably represents a GTPase coupled to the translocation reaction.

Left ventricular O2 requirements of pressure and volume loading in the normal canine heart and inaccuracy of pressure-derived indices of O2 demand.

The purpose of this study was to: 1) re-evaluate the left ventricular O2 requirements (MVO2) of pressure and volume-loading; and b) assess the accuracy of pressure-derived indices of left ventricular (LV) O2 demand under pressure-loading and volume-loading conditions. Using a right heart bypass preparation (heart rate 150 beats . min-1), mean arterial pressure (7.3 to 22.9 kPa) and cardiac output (0.8 to 6.0 litre . min-1) were varied independently. Adequate left ventricular O2 supply was demonstrated by normal transmural distribution of blood flow, normal myocardial lactate metabolism, and intact reactive hyperaemic responses. For equivalent increases in cardiac external work (from 2 to 4 joules . min-1) pressure-loading and volume-loading resulted in similar increases in O2 uptake (59% and 49%, respectively, P = 0.21). MVO2 was consistently greater for volume-loading than for pressure-loading at any SPTI, pressure-rate product, and triple product. The prediction of O2 demands by these indices under these loading conditions collectively was unreliable (r = 30 to 0.42). O2 requirements of the left ventricle with both pressure-loading and volume-loading were highly correlated (r = 0.82 to 0.99) with meridional wall stress. We conclude that: 1) volume-loading conditions have a greater O2 requirement than appreciated previously; 2) pressure loads and volume loads require similar O2 uptake in the normal canine heart for similar external work; 3) currently used pressure-derived indices are unreliable predictors of LV O2 demand when loading conditions are varied; and 4) O2 requirements are more uniformly related to meridional wall stress.

A possible role for vitamins C and E in cataract prevention.

Biochemical evidence suggests that oxidative stress caused by accumulation of free radicals is involved in the pathogenesis of senile cataracts. If so, appropriate amounts of the antioxidant vitamins C and E might be expected to prevent or retard the process. Such activity has been observed in several in vitro and in vivo studies of experimentally-induced cataracts. A recent epidemiologic study found that cataract patients tended to have lower serum levels of vitamins C, E, or carotenoids than did control subjects. The present investigation, which compared the self-reported consumption of supplementary vitamins by 175 cataract patients with that of 175 individually matched, cataract-free subjects, revealed that the latter group used significantly more supplementary vitamins C and E (P = 0.01 and 0.004, respectively). Because the results suggested a reduction in the risk of cataracts of at least 50%, a randomized, controlled trial of vitamin supplementation in cataract prevention may be warranted.

A phase I trial of intravenous bromodeoxyuridine and radiation therapy for pancreatic cancer.

PURPOSE: Improved radiosensitization may lead to improved results of treatment for pancreatic cancer. This Phase I trial was designed to determine the maximum tolerable dose of intravenous bromodeoxyuridine (BrdUrd) when given in an alternating weekly fashion with radiation therapy for patients with pancreatic cancer. METHODS AND MATERIALS: Patients with resected or locally unresectable pancreatic cancer were eligible if distant metastases were not present. A continuous intravenous infusion of BrdUrd was given on weeks 1, 3, 5, and 7. Twice a day radiation therapy (1.5 Gy per fraction) was given on weeks 2, 4, 6, and 8 to the pancreas/pancreatic bed (total dose 60 Gy) and draining regional lymph nodes (total dose 45 Gy). The starting dose of BrdUrd was 800 mg/m2/day with a planned escalation to 1000 mg/m2/day if at least six out of eight patients were without Grade > or = 3 toxicity. Patients were assessed weekly for toxicity, and were followed every 3 months after treatment for complications and survival. RESULTS: Fifteen patients with resected (six) or unresectable (nine) pancreatic cancer were enrolled. One patient failed to complete therapy due to tumor progression. One of 11 patients treated with 800 mg/m2/day had a Grade 3 toxicity, while Grade 3 or 4 toxicity was found in all 3 patients receiving 1000 mg/m2/day. The dose-limiting toxicities were hematologic. The acute gastrointestinal toxicity was minimal. Two patients, including one with unresectable disease, were without evidence of disease during exploration for complications (ulcer, small bowel obstruction). CONCLUSIONS: The recommended dose of BrdUrd for Phase II study is 800 mg/m2/day. The gastrointestinal mucosa did not appear to be sensitized by this method of BrdUrd administration. The presence of a pathologic complete response is encouraging. Further improvements in radiosensitization are possible and may lead to improved local control.

The position and volume of the small bowel during adjuvant radiation therapy for rectal cancer.

PURPOSE: The rate of small bowel toxicity from adjuvant pelvic radiation therapy (RT) for rectal cancer has been reported to be lower for patients treated preoperatively (Preop). This was probably due to a lesser volume of irradiated small bowel; however, studies of postoperative treatment reported that patients with an abdominoperineal resection (APR), who likely have the largest volume of small bowel in the pelvis, had less acute and chronic toxicity than those with a low anterior resection (LAR). In this study, three-dimensional treatment planning techniques were used to characterize the position and volume of small bowel in the pelvis and compare these to repeat studies obtained during the typical 5-week course of treatment to attempt to explain the above observations. METHODS AND MATERIALS: Treatment planning CT scans were obtained in 30 patients with rectal cancer (10 Preop, 10 LAR, 10 APR), including 12 patients with weekly CT scans during RT (65 scans). The position of the small bowel was measured by the distance to the nearest small bowel from the bones of the posterior pelvis and by the volume of small bowel within four anatomically defined regions of the pelvis. The motion of the small bowel was expressed as the standard deviation of the small bowel position measured with both the distance and the volume in the 12 patients with repeat studies. RESULTS: Contrast-containing small bowel was found an average 2.9 cm more anterior than small bowel without contrast below the sacral promontory. The position of the small bowel in Preop patients was significantly more anterior (p < or = 0.01) with less volume (p < or = 0.04) in the pelvis than postoperatively treated patients. The small bowel was also more anterior for patients with an LAR vs. APR (p < or = 0.03) but with similar volume in all pelvic regions. Small bowel motion, expressed as the standard deviation of the distance from the bones of the posterior pelvis to the closest small bowel, was 2.9 cm, 1.4 cm, and 0.2 cm for the Preop, LAR, and APR group, respectively. The LAR group had a considerable degree of motion in the posterior pelvis. Increased bladder volume was associated with reduced small bowel volumes, although this benefit decreased during treatment. CONCLUSION: Because treatment planning CT scans can detect small bowel that does not contain contrast, they may be more accurate than the traditional small bowel series. The Preop patients had significantly less pelvic small bowel supporting the clinical observation of better tolerance to therapy. The higher small bowel toxicity reported for LAR vs. APR patients may be explained by the greater variability of both the position and volume of the small bowel in the posterior pelvis for LAR patients. This finding suggests that a single planning study may not be accurate for the block design used for boost treatment of LAR patients. Bladder-filling techniques were useful for Preop and LAR but not APR patients, and decreased in benefit over time. This study suggested that treatment planning CT scans were more useful than a small bowel series and that more than one treatment planning CT may be obtained in any patient receiving > 45 Gy for rectal cancer. However, further research will be necessary to determine the optimal timing and total number of repeat studies.

Potential benefits of eliminating planning target volume expansions for patient breathing in the treatment of liver tumors.

PURPOSE: To investigate potential benefits derived from reduction or elimination of planning target volume (PTV) margins associated with patient breathing through examination of hepatic tumors treated with conformal therapy. METHODS AND MATERIALS: We reviewed the treatment plans of 50 patients who had previously received conformal partial organ liver irradiation for treatment of hepatic malignancies. PTVs for these plans included expansions (1-2 cm) for patient breathing. Data consisted of the three-dimensional dose distributions computed for the conformal plans generated for these volumes, and also for plans using identical beam arrangements but smaller block margins to treat planning target volumes that did not include the expansions for breathing. We calculated effective volumes (V(eff)) and normal tissue complication probabilities (NTCP) using dose-volume histograms for normal liver and analyzed changes in: V(eff), NTCP at the prescription dose, doses associated with selected NTCP levels, and tumor control probabilities (TCP) at these new dose levels. RESULTS: Elimination of the patient breathing components of the PTVs for these conformal treatments of liver tumors: (a) decreased the average V(eff) by 5%; (b) decreased the average predicted NTCP at the prescription (isocenter) dose used to treat the patients by 4.5%; (c) increased the average target volume (isocenter) dose associated with low (1-10%) predicted normal liver NTCP by 6-8 Gy, which corresponded to (d) a predicted average 6-7% increase in TCP for aggressive liver tumors. Plans with PTV expansions for breathing that occurred mostly within the liver showed greatest potential benefit. CONCLUSIONS: Elimination of the margin added to hepatic target volumes for patient ventilation could lead to clinically meaningful increases in dose without increasing the predicted frequency of complications.

Pelvic radiation therapy combined with hepatic artery chemotherapy for resected rectal carcinoma with liver metastases.

PURPOSE: Patients with hepatic metastases from rectal cancer treated with hepatic artery (HA) chemotherapy have a life expectancy great enough to be at risk for pelvic failure. Therefore, a treatment plan was developed for patients with resected rectal cancer and unresectable hepatic metastases, when the pathologic features of transmural invasion and perirectal lymph node metastases were present. Treatment consisted of concurrent pelvic radiation therapy (RT) and HA 5-fluorouracil (FUra), as systemic levels of FUra are achievable with HA administration, followed by HA fluorodeoxyuridine (FdUrd). METHODS AND MATERIALS: Fifteen patients were offered combined pelvic RT and HA FUra. Radiation was given to an initial dose of 45 Gy to the pelvis, followed by boost treatment for an additional 5.4-10.8 Gy. Concurrent HA chemotherapy was given using FUra or FUra/leucovorin administered in two cycles of 14 days for each cycle. If HA chemotherapy could not be done, then intravenous FUra was given during RT. Following completion of RT and HA FUra, patients were evaluated for treatment with HA FdUrd. RESULTS: Eleven patients received concurrent HA FUra or FUra/leucovorin and pelvic RT. Of these, six continued to receive HA FdUrd after completion of RT, as five patients were found to have progressive hepatic disease. Four patients could not have therapy as outlined, but did receive pelvic RT with concurrent intravenous FUra (two patients), FUra/leucovorin (one patient), or sequential HA FUra (one patient). There were four pelvic recurrences at 1, 4, 14, and 17 months after RT. One was the first site of progression, two occurred simultaneously with other failure, and one occurred after hepatic progression. The liver was the most frequent site of first progression (alone in seven patients; as a component of progression in four patients). Treatment was well tolerated with three Grade > or = 3 toxicities. The median survival was 14 months. CONCLUSIONS: These data support the hypothesis that patients with metastatic rectal cancer are also at risk for pelvic recurrence. The frequency of hepatic progression supports continued aggressive therapy directed to this site. As systemic and regional therapy of metastatic rectal cancer improves, we anticipate that more patients will be at risk for a pelvic recurrence, making it increasingly important to explore the role of pelvic radiation therapy despite the presence of metastatic disease.