Search

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

Summary Background Further optimisation of present standard chemoradiation is needed in patients with locally advanced rectal cancer. Veliparib, an oral poly(ADP-ribose) polymerase inhibitor, has been shown to enhance the antitumour activity of chemotherapy and radiotherapy in preclinical models. We aimed to establish the maximum tolerated dose and establish the recommended phase 2 dose of veliparib combined with neoadjuvant capecitabine and radiotherapy. Methods This phase 1b, open-label, multicentre, dose-escalation study was done at six hospitals (one in Australia and five in the USA). Patients were eligible if they were aged 18 years or more and were newly diagnosed with stage II to III locally advanced, resectable adenocarcinoma of the rectum with a distal tumour border of less than 12 cm from anal verge. Patients were ineligible if they had received anticancer therapy or surgery (except colostomy or ileostomy) 28 days or less before the first dose of study drug, previous pelvic radiotherapy, or previous treatment with poly (ADP-ribose) polymerase inhibitors. Enrolled patients received capecitabine (825 mg/m 2 orally twice daily) with radiotherapy (50·4 Gy in 1·8 Gy fractions daily, approximately 5 days consecutively per week for about 5·5 weeks). Veliparib (20–400 mg orally twice daily) was administered daily starting on day 2 of week 1 and continuing until 2 days after radiotherapy completion. Patients underwent total mesorectal excision 5–10 weeks after radiotherapy completion. The primary objectives were to establish the maximum tolerated dose and recommended phase 2 dose of veliparib plus capecitabine and radiotherapy, with an exposure-adjusted continual reassessment methodology. Efficacy and safety analyses were done per protocol. The reported study has completed accrual and all analyses are final. This trial is registered with ClinicalTrials.gov, number NCT01589419. Findings Between June 12, 2012, and Jan 13, 2015, 32 patients received veliparib (22 in the dose-escalation group; ten in the safety expansion group); 31 were assessable for efficacy ( Interpretation Veliparib plus capecitabine and radiotherapy had an acceptable safety profile and showed a dose-proportional pharmacokinetic profile with no effect on the pharmacokinetics of capecitabine. Preliminary antitumour activity warrants further evaluation. Funding AbbVie Inc.

Purpose Oxaliplatin neurotoxicity has a spectrum of manifestations from an often reversible acute neurotoxicity to a more irreversible “stocking and glove” chronic neuropathy that is associated with high morbidity. Quantitative sensory testing (QST) is a noninvasive psychometric testing method that can potentially be used in the clinic setting to measure subclinical neurologic changes early on to identify patients that will experience chronic oxaliplatin-induced peripheral neuropathy at 1 year. Patients and Methods Thirty patients with gastrointestinal malignancies who were receiving oxaliplatin were recruited. QST and patient-reported outcomes were assessed at baseline; during infusion cycles 1, 2, 4, and 6; and at 1 year. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0, chronic neuropathy scores were assessed at the 1-year time point. The variables at each time point were evaluated for prediction of 1-year chronic neuropathy scores. Results We found that patients with preexisting subclinical neuropathy were more likely to experience grades 2 and 3 chronic neuropathy than were those who did not have this condition (heat detection threshold, Spearman correlation coefficient (r s ) = 0.39; P = .037; pellet retrieval time, r s = 0.47; P = .024). Patients in whom thermal and cutaneous sensory deficits developed with cycle 1 infusion were also more likely to experience grades 2 and 3 neuropathy at 1 year (cold detection threshold, r s = 0.50; P = .007; heat detection threshold, r s = 0.39; P = .042; cutaneous detection threshold, r s = 0.42; P = .043). Conclusion QST provides a noninvasive, commercially available, and feasible clinical test to select patients, even before oxaliplatin treatment, who are likely to experience moderate to severe chronic peripheral neuropathy.

Purpose Radiosensitizing chemotherapy improves the outcomes in comparison with radiation alone for gastrointestinal cancers. The delivery of radiation therapy with yttrium90 ( 90 Y) radioembolization, in combination with the radiosensitizing chemotherapeutic agent capecitabine, provides the opportunity to enhance the effects of radiation on hepatic malignancies. This phase 1 study sought to determine the maximum tolerated dose (MTD) of 90 Y plus capecitabine in patients with cholangiocarcinoma or liver metastases confined to the liver. Methods and Materials Patients were given initial treatment at full-dose capecitabine during days 1 to 14 of a 21-day cycle. At days 1 to 7 of the second cycle, whole-liver 90 Y was given at the test dose, after which time capecitabine was continued. Dose-limiting toxicity (DLT) was determined 6 weeks after 90 Y infusion. If a DLT was not observed, the 90 Y dose was escalated. The planned dose cohorts were 110, 130, 150, and 170 Gy. The primary endpoint was to determine the MTD of 90 Y with full-dose capecitabine. Results Sixteen patients were treated according to the study protocol. Two patients experienced DLTs. Nine patients required capecitabine dose reduction as a result of toxicities attributable to capecitabine alone. The criteria for establishing 90 Y MTD were not met, indicating an MTD of >170 Gy. Conclusion The MTD of 90 Y delivered in conjunction with capecitabine in the setting of intrahepatic cholangiocarcinoma or metastatic disease confined to the liver exceeds 170 Gy. This is the highest 90 Y dose reported to date and has important implications on combined therapy with the radiosensitizing oral chemotherapeutic capecitabine. Further studies are under way.

Purpose To present data on safety, antitumoral response, and survival following yttrium-90 ( 90 Y) radioembolization for patients with unresectable intrahepatic cholangiocarcinoma (ICC). Materials and Methods The present study expands on the cohort of 24 patients with ICC described in a pilot study, and includes 46 patients treated with 90 Y radioembolization at a single institution during an 8-year period. Via retrospective review of a prospectively collected database, patients were stratified by performance status, tumor distribution (solitary or multifocal), tumor morphology (infiltrative or peripheral), and presence/absence of portal vein thrombosis. Primary endpoints included biochemical and clinical toxicities, and secondary endpoints included imaging response (World Health Organization [WHO] and European Association for the Study of Liver Disease [EASL] criteria) and survival. Uni-/multivariate analyses were performed. Results Ninety-two treatments were performed, with a mean of two per patient. Fatigue and transient abdominal pain occurred in 25 patients (54%) and 13 patients (28%), respectively. Treatment-related gastroduodenal ulcer developed in one patient (2%). WHO imaging findings included partial response (n = 11; 25%), stable disease (n = 33; 73%), and progressive disease (n = 1; 2%). EASL imaging findings included partial/complete response (n = 33; 73%) and stable disease (n = 12; 27%). Survival varied based on presence of multifocal (5.7 mo vs 14.6 mo), infiltrative (6.1 mo vs 15.6 mo), and bilobar disease (10.9 mo vs 11.7 mo). Disease was converted to resectable status in five patients, who successfully underwent curative (ie, R0) resection. Conclusions Radioembolization with 90 Y is safe and demonstrates antitumoral response and survival benefit in select patients with ICC. Results are most pronounced in patients with solitary tumors, for whom conversion to curative resection is possible.

BackgroundBased upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC).Patients and methodsPatients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD.ResultsTwenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients.ConclusionThe MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Purpose To present long-term outcomes on the safety and efficacy of Yttrium-90 radioembolization in the treatment of unresectable hepatic neuroendocrine metastases refractory to standard-of-care therapy. Methods and Materials This study was approved by our institutional review board and was compliant with the Health Insurance Portability and Accountability Act. Forty patients with hepatic neuroendocrine metastases were treated with 90 Y radioembolization at a single center. Toxicity was assessed using National Cancer Institute Common Terminology Criteria v3.0. Response to therapy was assessed by World Health Organization (WHO) guidelines for size and European Association for the Study of the Liver disease (EASL) guidelines for necrosis. Time to response and overall survival were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed. Results The median dose was 113 Gy (29–299 Gy). Clinical toxicities included fatigue (63%), nausea/vomiting (40%), abdominal pain (18%), fever (8%), diarrhea and weight loss (5%); Grade 3 and 4 bilirubin toxicities were experienced by 2 patients and 1 patient, respectively. Different responses were noted by WHO (complete response, 1.2%; partial response, 62.7%) and EASL (complete response, 20.5%; partial response, 43.4%). Median time to response was 4 and 4.9 months by lesion and patient, respectively. The 1-, 2-, and 3-year overall survival rates were 72.5%, 62.5%, and 45%, respectively. Eastern Cooperative Oncology Group (ECOG) performance score 0 ( p p = 0.0019), albumin ≥3.5 g/dL ( p = 0.017), and bilirubin ≤1.2 mg/dL ( p = 0.002) prognosticated survival on univariate analysis; only ECOG performance score 0 and bilirubin ≤1.2 mg/dL prognosticated better survival outcome on multivariate analysis ( p = 0.0001 and p = 0.02). Conclusion Yttrium-90 therapy for hepatic neuroendocrine metastases leads to satisfactory tumor response and patient survival with low toxicity, in line with published national guidelines recommending radioembolization as a potential option for unresectable hepatic neuroendocrine metastases.

Background & Aims We sought to study receiver-operating characteristics (ROC) of the European Association for the Study of the Liver (EASL), Response Evaluation Criteria in Solid Tumors (RECIST), and World Health Organization (WHO) guidelines for assessing response following locoregional therapies individually and in various combinations. Methods Eighty-one patients with hepatocellular carcinoma underwent liver explantation following locoregional therapies. Response was assessed using EASL, RECIST, and WHO. Kappa statistics were used to determine inter-method agreement. Uni/multivariate logistic regression analyses were performed to determine the variables predicting complete pathologic necrosis. Numerical values were assigned to the response classes: complete response=0, partial response=1, stable disease=2, and progressive disease=3. Various mathematical combinations of EASL and WHO were tested to calculate scores and their ROCs were studied using pathological examination of the explant as the gold standard. Results Median times (95% CI) to the WHO, RECIST, and EASL responses were 5.3 (4–11.5), 5.6 (4–11.5), and 1.3months (1.2–1.5), respectively. Kappa coefficients for WHO/RECIST, WHO/EASL, and RECIST/EASL were 0.78, 0.28, and 0.31, respectively. EASL response demonstrated significant odds ratios for predicting complete pathologic necrosis on uni/multivariate analyses. Calculated areas under the ROC curves were: RECIST: 0.63, WHO: 0.68, EASL: 0.82, EASL+WHO: 0.82, EASL×WHO: 0.85, EASL+(2×WHO): 0.79 and (2×EASL)+WHO: 0.85. An EASL×WHO Score of ⩽1 had 90.2% sensitivity for predicting complete pathologic necrosis. Conclusions The product of WHO and EASL demonstrated better ROC than the individual guidelines for assessment of tumor response. EASL×WHO scoring system provides a simple and clinically applicable method of response assessment following locoregional therapies for hepatocellular carcinoma.

Purpose To describe a technique of segmental radioembolization for the treatment of patients with unresectable hepatocellular carcinoma (HCC). Radiation segmentectomy was defined as radioembolization of two or fewer hepatic segments. We sought to ( 1 ) calculate dose when activity is delivered segmentally assuming uniform and nonuniform distribution and, ( 2 ) determine safety and efficacy of this novel technique. Methods and Materials A total of 84 patients with HCC who were treated with 90 Y radioembolization using a segmental approach were included in this analysis. The dose delivered to the segment was calculated assuming uniform and nonuniform microsphere distribution within the treatment volume. To calculate dose assuming nonuniform distribution, a tumor hypervascularity ratio was assigned. Posttreatment response (using size and necrosis guidelines), toxicity, time to progression, and survival were determined. Results The median treatment volume was 110 cm 3 . The median radiation-naive liver volume was 1403 cm 3 . The median dose delivered to the segment(s) assuming uniform distribution was 521 Gy. Taking into account tumor hypervascularity (nonuniform distribution), the median dose delivered to the tumor and normal infused hepatic volume was 1214 Gy and 210 Gy, respectively. Response by size and necrosis guidelines was seen in 59% and 81% of patients. Grade 3/4 biochemical toxicities were observed in 8 patients (9%). Median time to progression was 13.6 months (95% confidence interval, 9.3–18.7 months); median survival was 26.9 months (95% confidence interval, 20.5–30.2 months). Conclusions Radiation segmentectomy is a safe and efficacious method of selectively delivering high dose to the tumor with minimal exposure of normal parenchyma.

Purpose There are currently at least six major competing criteria used to determine response to yttrium-90 and other liver-directed therapies, including: (i) Response Evaluation Criteria in Solid Tumors (RECIST); (ii) World Health Organization (WHO), (iii) volumetric, (iv) two-dimensional (2D) European Association for the Study of the Liver (EASL), and (v) three-dimensional (3D) EASL criteria; and (vi) functional diffusion-weighted (DW) magnetic resonance (MR) imaging. This study evaluated agreement among these competing tumor response classification schemes based on quantitative measurements of tumor size, necrosis, and changes in water mobility. Materials and Methods In this retrospective study, 20 patients with hepatocellular carcinoma (HCC) underwent 90 Y radioembolization. The patients' tumor burden before and 3–6 months after treatment was assessed with MR imaging. The percent change in size of tumors was used to classify patients into response categories. κ and agreement statistics were used to compare concordance among the different criteria. Results Conventional size criteria (RECIST, WHO, and volumetric) all had a substantial level of agreement (κ = 0.76–0.78) when classifying patients into response categories. However, the conventional size criteria in relation to 2D or 3D EASL had only slight to moderate concurrence, with κ statistics as low as 0.06. Two-dimensional EASL criteria and functional DW MR imaging resulted in the highest response rates, 55% ( n = 11) and 75% ( n = 15), respectively, whereas conventional size criteria produced lower response rates. Conclusions Classification of HCC response to 90 Y radioembolization is related to which of the competing criteria are used. It is recommended that anatomic imaging criteria be used as the primary method to determine response and functional imaging criteria be used as a complementary secondary method.

The past decade has seen significant advancement in the locoregional management of liver tumors; novel and promising therapies such as transarterial chemoembolization, radioembolization, and radiofrequency ablation are now available. The development of new techniques and devices has led to the improved safety and efficacy profiles of external-beam radiation. Radioembolization with yttrium-90 ((90)Y) microspheres has emerged as a safe and efficacious treatment modality for liver malignancies. The purpose of this article is to present a comprehensive evidence-based review of the complications and adverse events that may be associated with radioembolization with (90)Y microspheres. Strategies to mitigate these adverse events are also discussed.

Purpose Angiographic endpoints for chemoembolization of hepatocellular carcinoma (HCC) are subjective, and optimal endpoints remain unknown. Transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging, when performed in a combined MR/interventional radiology (MR-IR) suite, offers an objective method to quantify intraprocedural tumor perfusion changes, but was previously limited to two spatial dimensions. This study prospectively tested the hypothesis that a new volumetric acquisition over time, four-dimensional TRIP MR imaging, can measure HCC perfusion changes during chemoembolization. Materials and Methods Seven men (mean age, 53 years; range, 42–65 y) with eight tumors (mean size, 2.5 × 2.4 cm 2 ; diameter range, 1.5–5.2 cm) underwent chemoembolization in an MR-IR suite between February and December 2007, with intraprocedural tumor perfusion reductions monitored with four-dimensional TRIP MR imaging. Microcatheter chemoembolization was performed with a 1:1 mixture of chemotherapy agent and emulsifying contrast agent, followed by the administration of gelatin microspheres. Pre- and post-chemoembolization time–intensity curves were generated for each tumor. Semiquantitative measures of tumor perfusion, including area under the curve (AUC), peak signal intensity (SI), time to peak SI, and maximum upslope (MUS), were calculated, and mean differences before and after chemoembolization were compared with paired t tests. Results Four-dimensional TRIP MR imaging–monitored chemoembolization was successful in all cases. Calculated AUCs before and after chemoembolization (439 vs 221, P = .004, 50% reduction), peak SI (32 vs 19, P = .012, 41% reduction), and MUS (11 vs 3, P = .028, 73% reduction) showed significant reductions after chemoembolization. Time to peak SI did not significantly change (23 sec vs 36 sec, P = .235, 57% increase). Conclusions Four-dimensional TRIP MR imaging can successfully measure semiquantitative changes in HCC perfusion during MR-IR–monitored chemoembolization. Future studies may correlate changes in these objective functional parameters with tumor response.

To test the hypothesis that transcatheter arterial embolization (TAE) induces expression of hypoxia-inducible factor-1alpha (HIF-1alpha) within the same rabbit VX2 liver tumor.Seven VX2 tumors were grown in the livers of five New Zealand white rabbits. Ultrasonography-guided biopsy was performed before and 10 minutes after TAE in all tumors. Pre- and post-TAE tumor biopsy specimens along with post-TAE whole liver tumor sections were stained with HIF-1alpha antibody and analyzed for percentage of HIF-1alpha-positive nuclei by using a spectral unmixing system mounted on a high-powered microscope. Statistical data comparisons were performed with the Wilcoxon signed-rank test (alpha = 0.05).TAE of liver tumors resulted in a statistically significant increase in the mean percentage of HIF-1alpha expression. The mean percentage of HIF-1alpha-positive stained nuclei increased from 23% +/- 3.5 in pre-TAE biopsy specimens to 41% +/- 8.7 in post-TAE biopsy specimens (P.02). The increase was even more significant when the mean percentage of HIF-1alpha-positive stained nuclei from the same pre-TAE biopsy specimens was compared with sections from post-TAE whole tumor specimens (60% +/- 8.9, P.02).The results of this study revealed that hypoxia caused by TAE of VX2 liver tumors activates HIF-1alpha, a transcription factor that in turn regulates other pro-angiogenic factors.

Purpose Yttrium-90 ( 90 Y) radioembolization has emerged as a promising and safe therapeutic modality for patients with hepatocellular carcinoma (HCC) or metastatic liver cancer. The present report describes biliary sequelae following intraarterial 90 Y therapy in patients with HCC or liver metastases. Materials and Methods All patients were treated with 90 Y therapy according to standard lobar treatment protocol. Pre- and posttreatment imaging, liver function tests, and serum total bilirubin measurements were performed. Three to 6 months after treatment, biliary sequelae were evaluated with computed tomography and magnetic resonance imaging, and any liver-related laboratory adverse events were noted. Results A total of 327 patients (HCC, n = 190; liver metastases, n = 137) received 569 infusions of 90 Y. At follow-up imaging, 33 patients (10.1%; liver metastases, n = 26; HCC, n = 7) had 40 imaging findings related to the biliary tree, including biliary necrosis ( n = 17), biloma ( n = 3), cholecystitis ( n = 2), gallbladder wall enhancement ( n = 6), gallbladder wall rent ( n = 3), abscess ( n = 1), and stricture ( n = 8). A total of 31 patients exhibited grade 3/4 bilirubin toxicities (13 [6.8%] with HCC, 18 [13.1%] with liver metastases). Unplanned interventions prompted by biliary sequelae were necessary in six of 327 patients (1.8%). Conclusions 90 Y therapy in patients with HCC or metastatic disease to the liver is associated with an acceptable rate of biliary toxicities. Further studies assessing long-term biliary sequelae are warranted.

Purpose To test the hypothesis that transcatheter arterial embolization (TAE) of VX2 rabbit liver tumors increases the expression of hypoxia-inducible factor-1α (HIF-1α), a transcription factor that regulates the expression of pro-angiogenic genes. Materials and Methods VX2 tumors were implanted in the livers of eight New Zealand white rabbits. Once tumor growth was seen at T2-weighted turbo spin-echo magnetic resonance (MR) imaging, four of the eight rabbits underwent TAE with 45–150-μm polyvinyl alcohol particles. The remaining four rabbits served as non-TAE controls. The TAE end point was stasis of antegrade blood flow. All rabbits were sacrificed for tumor harvest 2 hours after TAE. Tumor tissue and corresponding normal liver tissue in each rabbit liver were stained with anti-human HIF-1α monoclonal antibody and reviewed with light microscopy. Percentages of stained viable tumor and normal liver cells were compared by using the Mann-Whitney U test (α = 0.05). Results In eight rabbits with 24 discrete liver tumors, the mean percentage (±standard deviation) of positive HIF-1α–stained cells in the TAE group was greater than that in the control group (19% ± 7.0 vs 12% ± 8.0, respectively) ( P = .05). Normal liver tissue in both the TAE and control groups showed no HIF-1α staining. Conclusion Although HIF-1α is not expressed in normal rabbit liver parenchyma—even after TAE—HIF-1α expression is present in implanted VX2 rabbit liver tumors and significantly increased in lesions that have undergone embolization.

Blood oxygenation level-dependent (BOLD) magnetic resonance (MR) imaging is a noninvasive method to assess changes in oxygen delivery to tissues. It was hypothesized that BOLD MR imaging can detect changes in rabbit VX2 liver tumor oxygenation after hepatic artery embolization with polyvinyl alcohol particles. In four discrete VX2 liver tumors, a statistically significant mean reduction in apparent transverse relaxation time was shown, from 55 milliseconds before embolization to 41 milliseconds after embolization (P.01). This reduction corresponded to a decrease in hepatic tumor oxygenation. The use of BOLD MR imaging to monitor changes in hepatic tumor oxygenation after embolization is feasible. These functional MR imaging measurements of hypoxia may be targeted as an endpoint for therapy in future studies.

Yttrium 90 radioembolization is a transcatheter therapy for unresectable hepatocellular carcinoma (HCC) that delivers internal radiation to tumors. In contrast to the usual method of lobar regional delivery, catheter-directed computed tomographic (CT) angiography was investigated as a potentially useful technique to evaluate the administration of segmental 90Y tumor radiation doses superselectively without significantly altering liver function or Child-Pugh classification.Fourteen patients underwent 90Y therapy for unresectable HCC. After standard angiographic placement of a 3-F microcatheter in a segmental hepatic artery supplying the tumor, each patient underwent CT angiography with use of segmental hepatic artery injection of iodinated contrast agent to confirm segmental perfusion and delineate segmental liver volume. 90Y was later injected into the same segmental artery. Target dose was calculated according to infused 90Y activity and targeted hepatic volume with standard lobar volume (before CT angiography) versus segmental liver volume (after CT angiography). The Wilcoxon signed-rank test (alpha = 0.05) was used to compare the estimated 90Y dose before CT angiography with the actual 90Y dose after CT angiography, as well as changes in serum bilirubin level and Child-Pugh classification as a result of treatment.The mean estimated tumor dose before CT angiography (SD) was 100 Gy +/- 43 (range, 35-169 Gy). The mean actual tumor dose after CT angiography was 348 Gy +/- 204 (range, 105-857 Gy), which was significantly greater (P.001). The mean bilirubin level before treatment was 1.0 mg/dL +/- 0.97 (range, 0.2-4.0 mg/dL), whereas the mean bilirubin level after treatment was 1.3 mg/dL +/- 0.85 (range, 0.5-3.8 mg/dL). This difference, although statistically significant (P = .03), was not clinically important. Thirteen of 14 patients had no change in Child-Pugh class.CT angiography can be used to delineate the blood supply and volume to a targeted hepatic segment, allowing superselective 90Y radioembolization. This approach significantly increases effective 90Y tumor radiation dose without clinically altering liver function or Child-Pugh class.

Caspases are a conserved family of proteases that play a critical role in the execution of apoptosis by cleaving key cellular proteins at Asp residues and modifying their function. Using an expression cloning strategy we recently developed, we isolated human RAD21/SCC1/MCD1 as a novel caspase substrate. RAD21 is a component of the cohesin complex that holds sister chromatids together during mitosis and repairs double-strand DNA breaks. Interestingly, RAD21 is cleaved by a caspase-like Esp1/separase at the onset of anaphase to trigger sister chromatid separation. Here, we demonstrate that human RAD21 is preferentially cleaved at Asp(279) by caspases-3 and -7 in vitro to generate two major proteolytic products of approximately 65 and 48 kDa. Moreover, we show that RAD21 is specifically proteolyzed by caspases into a similarly sized 65-kDa carboxyl-terminal product in cells undergoing apoptosis in response to diverse stimuli. We also demonstrate that caspase proteolysis of RAD21 precedes apoptotic chromatin condensation and has important functional consequences, viz. the partial removal of RAD21 from chromatin and the production of a proapoptotic carboxyl-terminal cleavage product that amplifies the cell death signal. Taken together, these findings point to an entirely novel function of RAD21 in the execution of apoptosis.

OBJECTIVES To investigate the change in creatinine clearance (CrCl) over time following upper abdominal radiation utilizing a dose-volume histogram (DVH) multivariate analysis. METHODS The study population included 125 patients with gastrointestinal malignancy treated with abdominal radiation therapy at our institution between 1994 and 2006, with available creatinine and DVH information. Kidney dose-volume data collected included mean kidney dose, volume of kidney irradiated, V5, V10, and V20 of total kidney volume, and number of mL of kidney greater than and less than 20 Gy. RESULTS With a median follow-up of 2.4 years, and a mean kidney dose of 16.2 Gy, a significant correlation between decrease in CrCl and irradiated kidney volume observed was noted for all DVH parameters. The strongest correlations were found when using V5, V10, and number of mL of kidney treated to greater than 20 Gy. There was no significant change in number of antihypertensive medications taken by patients over time, and no relationship between outcome variables and pre-existing comorbidities. CONCLUSIONS This is the first study that we are aware of comparing DVH data with measurement of renal toxicity. We show significant correlations between dose and volume irradiated and decline in renal function. This will be clinically useful when determining a treatment plan for patients with borderline preradiation CrCl and provides evidence that minimizing radiation to the kidney could have important clinical ramifications.

It is not clear whether survival times of patients with hepatocellular carcinoma (HCC) are associated with their response to therapy. We analyzed the association between tumor response and survival times of patients with HCC who were treated with locoregional therapies (LRTs) (chemoembolization and radioembolization).Patients received LRTs over a 9-year period (n = 463). Patients with metastases, portal venous thrombosis, or who had received transplants were excluded; 159 patients with Child-Pugh B7 or lower were analyzed. Response (based on European Association for the Study of the Liver [EASL] and World Health Organization [WHO] criteria) was associated with survival times using the landmark, risk-of-death, and Mantel-Byar methodologies. In a subanalysis, survival times of responders were compared with those of patients with stable disease and progressive disease.Based on 6-month data, in landmark analysis, responders survived longer than nonresponders (based on EASL but not WHO criteria: P = .002 and .0694). The risk of death was also lower for responders (based on EASL but not WHO criteria: P = .0463 and .707). Landmark analysis of 12-month data showed that responders survived longer than nonresponders (P.0001 and .004, based on EASL and WHO criteria, respectively). The risk of death was lower for responders (P = .0132 and .010, based on EASL and WHO criteria, respectively). By the Mantel-Byar method, responders had longer survival than nonresponders, based on EASL criteria (P.0001; P = .596 with WHO criteria). In the subanalysis, responders lived longer than patients with stable disease or progressive disease.Radiographic response to LRTs predicts survival time. EASL criteria for response more consistently predicted survival times than WHO criteria. The goal of LRT should be to achieve a radiologic response, rather than to stabilize disease.

Background & Aims Chemoembolization is one of several standards of care treatment for hepatocellular carcinoma (HCC). Radioembolization with Yttrium-90 microspheres is a novel, transarterial approach to radiation therapy. We performed a comparative effectiveness analysis of these therapies in patients with HCC. Methods We collected data from 463 patients who were treated with transarterial locoregional therapies (chemoembolization or radioembolization) over a 9-year period. We excluded patients who were not appropriate for comparison and analyzed data from 245 (122 who received chemoembolization and 123 who received radioembolization). Patients were followed for signs of toxicity; all underwent imaging analysis at baseline and follow-up time points. Overall survival was the primary outcome measure. Secondary outcomes included safety, response rate, and time-to-progression. Uni- and multivariate analyses were performed. Results Abdominal pain and increased transaminase activity were more frequent following chemoembolization ( P .05). There was a trend that patients treated with radioembolization had a higher response rate than with chemoembolization (49% vs 36%, respectively, P = .104). Although time-to-progression was longer following radioembolization than chemoembolization (13.3 months vs 8.4 months, respectively, P = .046), median survival times were not statistically different (20.5 months vs 17.4 months, respectively, P = .232). Among patients with intermediate-stage disease, survival was similar between groups that received chemoembolization (17.5 months) and radioembolization (17.2 months, P = .42). Conclusions Patients with HCC treated by chemoembolization or radioembolization with Yttrium-90 microspheres had similar survival times. Radioembolization resulted in longer time-to-progression and less toxicity than chemoembolization. Post hoc analyses of sample size indicated that a randomized study with > 1000 patients would be required to establish equivalence of survival times between patients treated with these two therapies.