Citations

Pulmonary nocardiosis is a severe and uncommon opportunistic infection caused by Nocardia species. We present a patient with cryptogenic organizing pneumonia who was receiving long-term immunosuppressive therapy, whose treatment course was complicated by cutaneous and pulmonary nocardiosis. Tissue cultures confirmed Nocardia brasiliensis. Nocardiosis should be a diagnostic consideration for patients treated with long-term immunosuppression who have worsening pulmonary symptoms and relapsing pustular skin lesions.

Abstract Background Multimodal analgesia is standard practice for total knee arthroplasty; however, the role of regional techniques in improved perioperative outcomes remains unknown. The authors hypothesized that peripheral nerve blockade would result in lower pain scores and opioid consumption than two competing periarticular injection solutions. Methods This three-arm, nonblinded trial randomized 165 adults undergoing unilateral primary total knee arthroplasty to receive (1) femoral catheter plus sciatic nerve blocks, (2) ropivacaine-based periarticular injection, or (3) liposomal bupivacaine-based periarticular injection. Primary outcome was maximal pain during postoperative day 1 (0 to 10, numerical pain rating scale) in intention-to-treat analysis. Additional outcomes included pain scores and opioid consumption for postoperative days 0 to 2 and 3 months. Results One hundred fifty-seven study patients received peripheral nerve block (n = 50), ropivacaine (n = 55), or liposomal bupivacaine (n = 52) and reported median maximal pain scores on postoperative day 1 of 3, 4, and 4.5 and on postoperative day 0 of 1, 4, and 5, respectively (average pain scores for postoperative day 0: 0.6, 1.7, and 2.4 and postoperative day 1: 2.5, 3.5, and 3.7). Postoperative day 1 median maximal pain scores were significantly lower for peripheral nerve blockade compared to liposomal bupivacaine-based periarticular injection ( P = 0.016; Hodges–Lehmann median difference [95% CI] = −1 [−2 to 0]). After postanesthesia care unit discharge, postoperative day 0 median maximal and average pain scores were significantly lower for peripheral nerve block compared to both periarticular injections (ropivacaine: maximal −2 [−3 to −1]; P < 0.001; average −0.8 [−1.3 to −0.2]; P = 0.003; and liposomal bupivacaine: maximal −3 [−4 to −2]; P < 0.001; average −1.4 [−2.0 to −0.8]; P < 0.001). Conclusions Ropivacaine-based periarticular injections provide pain control comparable on postoperative days 1 and 2 to a femoral catheter and single-injection sciatic nerve block. This study did not demonstrate an advantage of liposomal bupivacaine over ropivacaine in periarticular injections for total knee arthroplasty.

498 Background: Surgery for RCC patients with IVC thrombus above the hepatic veins is complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with adverse surgical outcomes. The objective of this study is to determine the preoperative predictors of major complications and 90 day mortality after surgery in RCC patients with IVC thrombus above the hepatic veins. Methods: Records were reviewed of all RCC patients with IVC tumor thrombus above hepatic veins who had surgery from 1/2000 to 12/2012 at Mayo Clinic, MD Anderson, UT Southwestern and the University of Wisconsin. Major complications were recorded were defined as 3A or greater according to the Clavien- Dindo system within 90 days of surgery. Univariate and multivariate (MV) analyses were used to evaluate associations of preoperative clinical, pathological or laboratory variables with risk of major complications or 90-day mortality. Results: A total of 162 patients were identified for study (thrombus level 3,4 in 69 and 93 patients, respectively, according to Neves classification). Cardiopulmonary bypass was used in 60/162 (37.5%), while 40 (24.7%) patients underwent pre-operative angioembolization. Major complications were reported in 55 (34.0%) patients, with the most common being respiratory (12.4%), hematologic (9.2%) and cardiac (8.6%). On MV analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with an increased risk of major complications. Mortality was reported in 17 (10.5%) patients within 90 days after surgery. On MV analysis, ECOG performance status and low serum albumin were independently associated with increased risk of 90 day mortality. Conclusions: Contemporary perioperative mortality and major complication rates for RCC patients with upper level thrombus are 10 and 34%, respectively. ECOG PS >1 and low serum albumin are associated with an increased risk of perioperative mortality, and should be considered when selecting patients for neoadjuvant systemic therapy trials.

274 Background: The objectives of the formative research were to identify key themes of patient-centered cancer care and determine the best method to collect data to develop the CAHPS Survey for Cancer Care Prototype. This survey seeks to measure aspects of care most important to patients and allow comparisons of those aspects across treatment centers and treatment modalities. Methods: We developed a library of 1,781 items from CAHPS and cancer care surveys. We conducted 14 focus groups with patients (including 2 conducted in Spanish) who had received cancer care in the past 12 months, and 2 focus groups involving family members of cancer patients. We met with 10 experts representing patients and survivors, or who had expertise in quality improvement, oncology, shared decision-making and patient safety to obtain feedback on the development of the survey, potential markets for the instrument, and to assist with overall strategy. Finally, we conducted separate interviews with 5 stakeholder groups representing oncology associations to obtain feedback on focal provider, attribution and sampling. Results: While the focus group results validated findings from the item library, new concepts also emerged, such as the need for having a plan of care. Patients most readily identified with a team of providers, rather than a single provider. The two most important domains to patients were (1) how well the cancer care team communicates with patients and (2) whether the cancer care team keeps patients informed about cancer treatment. Patients were also interested in care coordination, access to information, providers who are up-to-date, and shared decision-making. Stakeholder interviews noted that survey results would be most valuable if presented by treatment modality: medical, radiation, and surgical oncology. Conclusions: These findings suggest that cancer care is best for the patient when providers are knowledgeable and straightforward with medical information, yet can demonstrate empathy and compassion.

523 Background: This study was done to assess the toxicity and efficacy of IMRT for anal cancer in a multi-institutional setting. Methods: Records of 152 total patients (pts) were reviewed retrospectively. Data on disease control and toxicity were collected as well as pt and treatment characteristics. Acute (<6 months) and late (>=6 months) severe toxicity (grade >=3) were recorded at each institution. Four were excluded for either presence of metastatic disease (2) or stage TX (2). There was data for late toxicity on 120 pts. Results: T stage was T1 in 28, T2 in 79, T3 in 29 and T4 in 12 pts. N stage was N0 in 77, N1 in 40, N2 in 19 and N3 in 12 pts. The median age was 56 yrs and median follow-up was 26.8 months. Cumulative IMRT dose was 51.25 Gy (median) (range: 4.32-61.2 Gy) in a median of 28 fractions (2-34). Chemotherapy was given in all but 2 pts and the most common regimen was 5- fluorouracil plus mitomycin-C. The median total elapsed treatment time was 40 days. Local control at 3 yrs was 87% and was significantly worse for patients with T3-4 disease (79% vs 90% at 3 years; p=0.04). There was no correlation between dose and local control. Regional control, distant control and overall survival were 97%, 91%, and 87% at 3 yrs, respectively. Nodal status was associated with regional and distal control as well as overall survival (p<0.01 for each). The most common acute severe toxicity was hematologic (41%). Severe acute GI, skin or other toxicity was 11%, 20% and 1% respectively. There were two grade 5 toxicities (hematologic and GI). Severe late toxicity was limited to skin (1%) and GI (3%). Conclusions: IMRT resulted in excellent local control in this multi-institutional cohort of pts. Although T stage did predict for worse local control, most pts with T3-4 disease were controlled with IMRT. Nodal status predicts for regional and distal control as well as overall survival. Severe toxicity was acceptable with this technique.

442 Background: For patients with advanced or locally recurrent (LR) renal cell carcinoma (RCC), the role of intra-operative radiation therapy (IORT) remains controversial. We analyzed outcomes in a multi-institutional cohort of patients with RCC who received IORT. Methods: Between 1985 and 2010, 98 patients were treated with IORT for advanced or LR RCC at 9 institutions. We collected demographic, clinical, treatment, and outcomes data for all patients. Overall (OS), disease specific (DSS), and disease-free survival (DFS) was estimated using the Kaplan-Meier method. A multivariate Cox hazards regression was used to test significance. Results: IORT was delivered at nephrectomy for advanced disease (28%) or during resection of LR RCC in the renal fossa (72%). 69% of patients were male and mean age at RCC diagnosis was 57. At initial nephrectomy, primary T-stage was 17% T1, 12% T2, 55% T3, and 16% T4. Prior to IORT, 87% had visibly complete surgical resection of tumor. Mean IORT dose delivered was 14.7Gy (range 9-20Gy). Average post-op hospitalization was 10.7 days. Median follow-up after IORT was 1.6 years. OS at 1 and 5 years after IORT was 69% and 37% for advanced patients and 94% and 55% for LR patients, respectively. DFS at 1 and 5 years was 72% and 39% for advanced patients and 96% and 52% for LR patients, respectively. DSS at 1 and 5 years was 72% and 41% for advanced patients and 96% and 60% for LR patients, respectively. For the entire cohort, higher IORT dose (HR 1.3, p < 0.001), positive initial node status (HR 2.9-3.6, p < 0.01), and presence of sarcomatoid features (HR 3.7-6.9, p < 0.05) had a significant association with decreased OS, DFS and DSS. Patients who received adjuvant systemic therapy after IORT showed decreased DSS (HR 2.4, p = 0.03). When analyzing LR tumors alone, positive margin (HR 2.6, p = 0.01) was associated with decreased OS. Conclusions: We report on the largest known cohort of patients with RCC managed with IORT and we have identified factors associated with survival. Outcomes in our cohort with LR RCC treated with local resection and IORT compare favorably to similar groups treated with resection alone suggesting improved DSS may be possible with IORT.

249 Background: Evaluating tumor specific pathologic and genetic profiles in mCRPC stage is difficult due to the limited availability of mCRPC tissue. We describe findings from a prospective cohort study performed to obtain concomitant histopathology and genetic information in mCRPC. Methods: Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial (3 months apart) metastatic (met) site needle core biopsies (NCB1/2). Bone lesions were biopsied using 11-13G core needles and 18G core biopsy devices were used for non-osseous masses. Up to 4 cores were obtained at each biopsy with the 1st core (S1) sent for DNA sequencing, the 2nd (S2) for RNA sequencing, and the 3rd/4th (X3, X4) submitted for xenograft implantation. From each, 1-2 mm segments were separated and formalin-fixed for histopathologic examination (HPE). Results: A total of 54 patients, enrolled between June 2013 and July 2014, underwent 94 NCB (54 NCB1, 40 NCB2), rendering a total of 259 samples (94 S1; 75 S2; 59 X3 and 31 X4) of which 85 (32%) were positive (pos) for tumor by HPE. Positivity for tumor in S1, S2, X3, and X4 cores was 42%, 33%, 22%, and 19%, respectively. At least one core pos for met tumor was observed in 62% NCB1 and 52% NCB2 (overall 52/94; 56%). Met sites biopsied include bone (71), lymph nodes (18), liver (3), penile (1) and pelvic (1) soft tissues. HPE revealed met adenocarcinoma in 44/52, and poorly differentiated carcinoma in 8/52. Gleason grade applied to the met ranged from 3+4 to 5+5. 45/85 pos samples (53%) had > 50% tumor cellularity. Pos NCB in bone lesions was observed in 23/71 (32%), compared to 17/23 (73%) of non-bone sites (p=.0004). 85 S1 samples yielded DNA material, of which 66 (77%) had ≥10% tumoral DNA. 24 cases with negative HPE had ≥10% tumoral DNA; 7 cases with pos HPE had <10 tumoral DNA. In all, 76/94 (81%) NCB yielded tumor material either by HPE or DNA analysis. Conclusions: NCB of mCRPC is feasible and provides adequate tissue for pursuing HPE and sequencing studies. HPE of extracted material correlates with DNA sequencing data and provides complementary information on tumor features. Bone lesions yield significantly less tumoral material than non-osseous sites.

353 Background: One mechanism leading to castrate-resistant prostate cancer (CRPC) is upregulation of CYP17. Abiraterone acetate (AA) inhibits CYP17 and continuous AA administration (CAAA) is one the most common and effective CRPC treatments. Mathematical models can be potentially powerful clinical tools for optimizing treatment strategies and eliminating guess work. Here, we introduce a new model which builds on our previous work (Morken JD, Packer A, Everett RA, Nagy JD, Kuang Y. Mechanisms of resistance to intermittent androgen deprivation therapy identified in prostate cancer patients by novel computational method. Cancer Res 2014;74:2673-83.) and may be capable of predicting how patients will respond to CAAA and intermittent AA administration (IAAA). We are currently proposing a personalized IAAA protocol on the basis of these results. Methods: In this ongoing retrospective study, we use PSA data from patients whom underwent CAAA to validate the accuracy of our model of tumor growth and evolution. The PSA output is driven by dynamics of three cell populations—castration-sensitive (CS), castration-resistant abiraterone-sensitive (CSAS), and castration-sensitive abiraterone-resistant (CSAR) cells. We fit the model output to PSA data to find parameter values which minimize normalized mean squared error (NMSE). Once parameters are obtained, we ran simulations employing various IAAA protocols. Results: The model’s PSA dynamics are highly accurate. NMSE is very low across patients ranging from 0.0001-0.0085. Conclusions: Our results suggest that there exists an IAAA protocol for each patient that, at worst, yields the same time to tumor progression as CAAA, yet improves quality of life and reduces cost. In nearly 20% of patients, IAAA appears to delay tumor progression over CAAA. The model is accurate at predicting how patients will respond to CAAA and IAAA for patients whose PSA is regularly monitored. Near-future work aims to personalize IAAA protocol based on patient pre CRPC PSA dynamics and to identify a protocol which delays progression for most patients.

54 Background: After diagnosis and treatment, lung cancer survivors do not return to a health-related quality of life (QOL) and function comparable to pre-diagnosis levels as observed in other adult cancer survivors. We hypothesize that inadequate attention has been paid to addressing and improving QOL and function among lung cancer survivors. Our primary goal is to evaluate existing symptoms and QOL deficits among lung cancer survivors. Methods: We are evaluating patterns of QOL deficits (scored 5 or less on the scale from 0 [worst] to 10 [best]) in relation to time of lung cancer diagnosis, treatments, progression and/or recurrence, and health-related conditions. We are collecting and analyzing relevant health care utilization for selected QOL deficits, and identifying availability, accessibility, and effectiveness of evidence-based interventions. The expected outcomes will be new knowledge on patterns of QOL deficits, quality-adjusted life years in relation to the availability, accessibility, and adequacy of needed care and the effectiveness of interventions targeting improvement in QOL and symptoms. Results: In our initial analysis, among 3,707 lung cancer survivors who were diagnosed in 1999 to 2010, post-cancer treatment, and followed through 2011, 39% (1,442) reported deficits in overall QOL, 71% fatigue, 60% dyspnea, 41% being sedentary, 17% low spiritual well-being (SWB), and 10% currently smoking cigarettes. Among the 1,442 lung cancer survivors with a deficit in overall QOL, 97.5% reported severe fatigue or dyspnea, being sedentary or smoking, or having low SWB. In the remaining 36 of the 1,442, 24 had pain, cough, poor appetite, or other symptoms; only 12 (<1%) did not report deficit in any of the measured QOL domains. Analyses are ongoing. Conclusions: Based on evidence gained to date, we are developing and testing interventions targeting symptoms and QOL deficits. We expect to gain strong evidence for recommendations in redefining and delivering care and support that are necessary for improving the health and QOL of lung cancer survivors.

SummarySimtuzumab, a monoclonal antibody inhibitor of extracellular matrix enzyme lysyl oxidase‐like‐2, showed preclinical promise and was well tolerated in clinical studies. A phase 2, open‐label study of simtuzumab was conducted in patients with primary myelofibrosis (MF), post‐polycythaemia vera MF and post‐essential thrombocythaemia MF. Fifty‐four patients were randomized to receive simtuzumab alone (200 or 700 mg [n = 12 each group]) or simtuzumab (200 or 700 mg) with ruxolitinib (n = 15 each group) for 24 weeks. Simtuzumab alone or in combination with ruxolitinib showed no clinical benefit at 24 weeks. The mean serum simtuzumab trough concentrations appeared to increase dose‐proportionally between the 200‐mg and 700‐mg treatment groups. Therapy‐related serious adverse events were pyrexia, pain in extremity (both in 1 patient) and infusion reaction (in another patient). Bone marrow fibrosis (BMF) score was reduced at 24 weeks in 2 patients (16·7%) in the simtuzumab 700‐mg group, 1 (6·7%) in the simtuzumab 200‐mg + ruxolitinib group, and 2 (13·3%) in the simtuzumab 700‐mg + ruxolitinib group; similar numbers of patients had increased BMF. Simtuzumab alone or with ruxolitinib was well tolerated but did not produce clinical benefit nor consistently reduce BMF in patients with MF by 24 weeks.