Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Delayed immune-related adverse events with anti-PD-1-based immunotherapy in melanoma.

BACKGROUND: Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy [anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4)], but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy. PATIENTS AND METHODS: Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined. RESULTS: One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%). CONCLUSIONS: Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma.

Background: Combined cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1) blockade induces high rates of immune-related adverse events (irAEs). The safety of resuming anti-PD-1 in patients who discontinue combination therapy due to irAEs is not known. Patients and methods: We assessed patients who experienced clinically significant irAEs from combined CTLA-4 and PD-1 blockade leading to treatment discontinuation at four academic centers. We assessed the safety of resuming anti-PD-1 in terms of recurrent and distinct irAEs. Results: Eighty patients discontinued combination therapy due to irAEs, including colitis (41%), hepatitis (36%), and pneumonitis (4%). Of these, 96% received corticosteroids and 21% received additional immunosuppression (e.g. infliximab). All were rechallenged with anti-PD-1, and 14 (18%) had recurrent irAEs at a median of 14 days after therapy resumption (six grade 1-2, seven grade 3-4, and one grade 5 Steven-Johnson Syndrome). Colitis was less likely to recur than other irAEs (6% versus 28%, P = 0.01). Clinically significant but distinct toxicities occurred in an additional 17 (21%) patients (11 grade 1-2 and 6 grade 3-4). Duration of steroid taper, severity of initial irAEs and use of additional immunosuppressants did not predict for toxicity on rechallenge, although patients remaining on steroid therapy at anti-PD-1 resumption had higher rates of toxicities (55% versus 31%, P = 0.03). Conclusions: Patients who discontinued CTLA-4/PD-1 blockade for severe irAEs had relatively high rates of recurrent or distinct toxicities with anti-PD-1 resumption. However, many patients, particularly with combination-induced colitis, tolerated anti-PD-1 rechallenge well, and this approach can be considered in selected patients.

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.

Ultragiant urban aerosol particles.

Measurements taken 300 meters above ground level show surprisingly high concentrations of ultragiant aerosol particles both upwind and downwind of the St. Louis, Missouri, urban area. Assuming an average particle density of 2.0 grams per cubic centimeter, concentrations of particles with diameters between 5 and 55 micrometers sampled on 11 different days averaged 31 micrograms per cubic meter upwind and 55 micrograms per cubic meter downwind of the city.

Microbial diversity and biomarker analysis of modern freshwater microbialites from Laguna Bacalar, Mexico.

Laguna Bacalar is a sulfate-rich freshwater lake on the Yucatan Peninsula that hosts large microbialites. High sulfate concentrations distinguish Laguna Bacalar from other freshwater microbialite sites such as Pavilion Lake and Alchichica, Mexico, as well as from other aqueous features on the Yucatan Peninsula. While cyanobacterial populations have been described here previously, this study offers a more complete characterization of the microbial populations and corresponding biogeochemical cycling using a three-pronged geobiological approach of microscopy, high-throughput DNA sequencing, and lipid biomarker analyses. We identify and compare diverse microbial communities of Alphaproteobacteria, Deltaproteobacteria, and Gammaproteobacteria that vary with location along a bank-to-bank transect across the lake, within microbialites, and within a neighboring mangrove root agglomeration. In particular, sulfate-reducing bacteria are extremely common and diverse, constituting 7%-19% of phylogenetic diversity within the microbialites, and are hypothesized to significantly influence carbonate precipitation. In contrast, Cyanobacteria account for less than 1% of phylogenetic diversity. The distribution of lipid biomarkers reflects these changes in microbial ecology, providing meaningful biosignatures for the microbes in this system. Polysaturated short-chain fatty acids characteristic of cyanobacteria account for <3% of total abundance in Laguna Bacalar microbialites. By contrast, even short-chain and monounsaturated short-chain fatty acids attributable to both Cyanobacteria and many other organisms including types of Alphaproteobacteria and Gammaproteobacteria constitute 43%-69% and 17%-25%, respectively, of total abundance in microbialites. While cyanobacteria are the largest and most visible microbes within these microbialites and dominate the mangrove root agglomeration, it is clear that their smaller, metabolically diverse associates are responsible for significant biogeochemical cycling in this microbialite system.

Iron-mineral accretion from acid mine drainage and its application in passive treatment.

This study demonstrates substantial removal of iron (Fe) from acid mine drainage (pH ≈3) in a passive vertical flow reactor (VFR) with an equivalent footprint of 154 m(2) per L/s mine water and residence times of >23 h. Average Fe removal rate was 67% with a high of 85% over the 10-month trial. The fraction of Fe passing a 0.22 µm filter (referred to here as Fe-filt) was seen to be removed in the VFR even when Fe(II) was absent, indicating that the contribution of microbial Fe(II) oxidation and precipitation was not the dominant removal mechanism in the VFR. Removal rates of Fe-filt in the VFR were up to 70% in residence times as low as 8 h compared with laboratory experiments where much smaller changes in Fe-filt were observed over 60 h. Centrifugation indicated that 80-90% of the influent Fe had particle sizes <35 nm. Together with analyses and geochemical modelling, this suggests that the Fe-filt fraction exists as either truly aqueous (but oversaturated) Fe(III) or nanoparticulate Fe(III) and that this metastability persists. When the water was contacted with VFR sludge, the Fe-filt fraction was destabilized, leading to an appreciably higher removal of this fraction. Heterogeneous precipitation and/or aggregation of nanoparticulate Fe(III) precipitates are considered predominant removal mechanisms. Microbial analyses of the mine water revealed the abundance of extracellular polymeric substance-generating Fe-oxidizing bacterium 'Ferrovum myxofaciens', which may aid the removal of iron and explain the unusual appearance and physical properties of the sludge.

Phase II trial of high-dose melphalan and autologous bone marrow transplantation for metastatic colon carcinoma.

Colon carcinoma, the second leading cause of cancer-related deaths in the United States, is resistant to chemotherapy in a large majority of cases. Single-agent and combination chemotherapy have failed to prolong survival. New approaches are clearly needed. In experimental models, a steep dose-response curve for colorectal cancer has been demonstrated using various agents. The hematopoietic toxicity of high-dose therapy with these drugs can be circumvented by autologous bone marrow transplantation. We investigated the use of high-dose melphalan with autologous bone marrow rescue in 20 patients with metastatic colon carcinoma. Each patient received melphalan, 180 mg/m2 intravenously (IV), followed eight hours later by bone marrow infusion. Median duration of granulocytopenia (less than 500 neutrophils/microL) was twelve days (range, 5 to 35 days), while transfusion-dependent thrombocytopenia (less than 20,000 platelets/microL) had a median duration of eight days (range, 3 to 23 days). Time to bone marrow engraftment was not affected by prior 5-fluorouracil therapy. Nausea and vomiting occurred in 14 patients but was generally short lived. Mild stomatitis, esophagitis, and diarrhea were common. Severe gastrointestinal (GI) side effects did not occur. One treatment-related death occurred secondary to intramural tumor necrosis, which resulted in massive lower GI bleeding. Complete responses were observed in three patients (15%) and partial responses in six patients (30%), for an overall response rate of 45%. Median survival was 198 days in this group of patients with extensive disease. High-dose melphalan therapy for metastatic colon carcinoma, when used with autologous bone marrow transplantation, appears to achieve a high response rate with tolerable toxicity. Further investigation is needed to define the role of this therapy in the care of advanced colon carcinoma.

High-dose melphalan with autotransplantation for refractory multiple myeloma: results of a Southwest Oncology Group phase II trial.

PURPOSE: To evaluate high-dose melphalan followed by autologous stem-cell transplantation in patients with refractory multiple myeloma. PATIENTS AND METHODS: Multiple myeloma patients with alkylating agent or vincristine/doxorubicin/dexamethasone-refractory disease were eligible for the phase II multi-institutional Southwest Oncology Group trial S8993. Patients up to age 70 years were enrolled between April 15, 1991, and May 1, 1996. Patients without prior stem-cell collection were primed with high-dose cyclophosphamide (HD-CTX; 6 g/m(2)) and granulocyte-macrophage colony-stimulating factor. After stem-cell procurement, patients received melphalan 200 mg/m(2) with autologous transplantation. Upon recovery from melphalan, patients were to receive interferon alfa-2b until relapse. RESULTS: Seventy-two patients were enrolled onto S8993; five were ineligible and one received no therapy. Of the 66 assessable patients, 56 patients underwent the transplant procedure; 54 were assessable for response and 56 for toxicity. The response to HD-CTX (n = 37) included three complete remissions (CRs; 8%) and five partial remissions (PR; 14%); response to melphalan (n = 54) included 16 CRs (30%) and 19 PRs (35%), for an overall CR and >/= PR (n = 66; intent-to-treat) of 27% and 58%, respectively. Toxicities included six treatment-related deaths: two during HD-CTX and four during transplantation. The median progression-free survival (PFS) and overall survival (OS) durations on an intent-to-treat basis from transplant registration was 11 months and 19 months (95% confidence interval, 14 to 29 months), respectively. The 3-year actuarial PFS and OS rates were 25% and 31%, respectively. CONCLUSION: High-dose therapy with melphalan 200 mg/m(2) is feasible with high response rates (58% overall) and an OS of 19 months in patients with refractory multiple myeloma.

Prolongation of survival for high-grade malignant gliomas with adjuvant high-dose BCNU and autologous bone marrow transplantation.

Employment of postoperative brain irradiation in the initial management of high-grade malignant glial tumors has now become standard. The addition of conventional chemotherapy to irradiation has not significantly improved median survival beyond 1 year. We treated 25 consecutive patients (13 pilot patients and 12 protocol patients) with histologically confirmed unresectable grade 3 or 4 malignant gliomas with high-dose BCNU (carmustine) followed by autologous bone marrow transplantation and whole brain irradiation. Within 3 weeks of initial surgery, each patient had autologous bone marrow stored (median 2 X 10(8) nucleated cells/kg), and then received BCNU 1,050 mg/m2 intravenously (IV). Peripheral granulocytes recovered (greater than 500/microL) at a median of 19 days (range, 10 to 37 days), and platelets recovered (greater than 20,000/microL) at a median of 18 days (range, 13 to 40 days), following bone marrow infusion. Patients received 60 Gy whole brain irradiation when granulocytes were greater than 1,500/microL. Toxicity was well tolerated. Nausea occurred in 19 patients (76%); however, only eight patients (32%) experienced vomiting (mild in three, moderate in five). Eleven patients (44%) did not require empiric antibiotics, six of whom never developed an absolute granulocyte count less than 500/microL. Three patients with a poor performance status died early (one seizure with vomiting and asphyxiation; one, klebsiella urinary tract infection (UTI) with bacteremia; one, candidal pneumonia), and one additional patient who was performing well died of pulmonary hemorrhage. The 13 pilot patients have now been followed for a median of 23 months, with a significant survival advantage compared with the 52 consecutive historical control patients who received similar surgery and radiotherapy without high-dose BCNU (P = .037). The overall study group of 25 patients also has a significant survival advantage when compared with the same historical control group, with a projected median survival of 26 months (P = .007). This new approach using early postoperative intensive therapy consisting of high-dose BCNU, autologous bone marrow transplantation, and whole brain irradiation appears to significantly improve survival.

Angiotensin-converting enzyme inhibitor therapy affects left ventricular mass in patients with ejection fraction > 40% after acute myocardial infarction.

OBJECTIVES: We tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitor therapy decreases left ventricular (LV) mass in patients with a left ventricular ejection fraction (LVEF) > 40% and no evidence of heart failure after their first acute Q wave myocardial infarction (MI). BACKGROUND: Recently, ACE inhibitor therapy has been shown to have an early mortality benefit in unselected patients with acute MI, including patients without heart failure and a LVEF > 35%. However, the effects on LV mass and volume in this patient population have not been studied. METHODS: Thirty-five patients with a LVEF > 40% after their first acute Q wave MI were randomized to titrated oral ramipril (n = 20) or conventional therapy (control, n = 15). Magnetic resonance imaging (MRI) performed an average of 7 days and 3 months after MI provided LV volumes and mass from summated serial short-axis slices. RESULTS: Left ventricular end-diastolic volume index did not change in ramipril-treated patients (62 +/- 16 [SD] to 66 +/- 17 ml/m2) or in control patients (62 +/- 16 to 68 +/- 17 ml/m2), and stroke volume index increased significantly in both groups. However, LV mass index decreased in ramipril-treated patients (82 +/- 18 to 73 +/- 19 g/m2, p = 0.0002) but not in the control patients (77 +/- 15 to 79 +/- 23 g/m2). Systolic arterial pressure did not change in either group at 3-month follow-up. CONCLUSIONS: In patients with a LVEF > 40% after acute MI, ramipril decreased LV mass, and blood pressure and LV function were unchanged after 3 months of therapy. Whether the decrease in mass represents a sustained effect that is associated with a decrease in morbid events requires further investigation.

Gadolinium-enhanced magnetic resonance venography of the portal venous system prior to transjugular intrahepatic portosystemic shunts and liver transplantation. Original investigation.

RATIONALE AND OBJECTIVES: The accuracy of gadolinium-enhanced magnetic resonance venography (GdMRV) in identifying visceral venous abnormalities was assessed in patients before they underwent transjugular intrahepatic portosystemic shunt (TIPS) or orthotopic liver transplantation (OLT). METHODS: Twenty-seven patients with portal hypertension underwent GdMRV and transcatheter venography prior to OLT or TIPS. The gadolinium dose was 0.5 mL/kg (0.25 mmol/kg), administered by rapid hand injection. Coronal 3D spoiled gradient-echo GdMRV was performed in a single breath-hold. Four blinded reviewers retrospectively evaluated coronal maximum intensity projection (MIP) images, while two reviewers evaluated the MIPs and multiplanar reconstructions. Abnormalities that could affect transjugular intrahepatic portosystemic shunt or transplantation were noted and compared with the results of corresponding catheter venograms read by a separate blinded reviewer. RESULTS: Abnormalities were identified by GdMRV with a sensitivity and specificity of 83% and 97% for the right hepatic vein, 86% and 100% for the main portal vein (MPV), 42% and 99% for the right portal vein, 54% and 94% for the left portal vein, 61% and 96% for the superior mesenteric vein, and 74% and 91% for the splenic vein. Varices and shunts were correctly identified with a sensitivity of 96%. Multiplanar reconstruction increased MPV sensitivity to 100%. CONCLUSION: Vascular abnormalities that affect TIPS and OLT can be identified by GdMRV. Multiplanar reconstruction increased the accuracy to 100% for the MPV.

Carmustine, Ara C, cyclophosphamide and etoposide with autologous bone marrow transplantation in relapsed or refractory lymphoma: a dose-finding study.

The purpose of this study was to define the dose-limiting non-hematologic toxicity of carmustine, Ara C, cyclophosphamide and etoposide (BACE). Between October 1986 and March 1990, 37 patients with relapsed or refractory lymphoma received escalating doses of combination chemotherapy followed by autologous bone marrow transplant (ABMT). Twenty patients with Hodgkin's disease (HD) and 17 patients with intermediate or high grade non-Hodgkin's lymphoma (NHL) initially received conventional-dose therapy with either a 7 week course of modified MACOP-B or a single dose of cyclophosphamide (CY) at 2 g/m2 depending on prior therapy and response. Regardless of response, patients then received escalating doses of BACE, toxicity permitting. Ten patients obtained complete responses (CR) and 12 patients were partial responders (PR), CR+PR (75%) with modified MACOP-B and 7 (64%) patients obtained PR with CY. The maximum-tolerated dose (MTD) for BACE was determined to be carmustine 700 mg/m2, Ara C 1500 mg/m2, CY 150 mg/kg and etoposide 1500 mg/m2. When Ara C was escalated from 1500 mg/m2 to 3000 mg/m2 holding the other drugs at the prior doses, the next two patients died secondary to diffuse alveolar damage. Overall and event-free survivals are identical with 14 of 37 patients (38%) alive with a median follow-up of 61 months (range 38-79 months). Ten patients were treated at the MTD, none of whom died a toxic death and 3 (30%) are alive with a median follow-up of 42 months (range 38-52 months). We defined the MTD and BACE showing pulmonary toxicity to be the dose-limiting non-hematologic toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Nutrition and feeding in infants with bronchopulmonary dysplasia after initial hospital discharge: risk factors for growth failure.

OBJECTIVE: To identify nutritional risk factors for growth failure in infants with bronchopulmonary dysplasia (BPD) after initial hospital discharge, and to describe growth in and feeding concerns about these infants after discharge to the community. DESIGN: A cohort of 40 infants with BPD was followed up for 7 monthly visits after initial hospital discharge. Data on potential risk factors were gathered prospectively. SUBJECTS/SETTING: Forty infants with BPD were recruited from all 4 tertiary-level neonatal intensive care units in the Puget Sound area of Washington. Exclusionary criteria included congenital or chromosomal anomalies, grade IV intraventricular hemorrhage, and drug or alcohol exposure in utero. MAIN OUTCOME MEASURES: Growth failure defined as weight less than the 5th percentile on National Center for Health Statistics growth curves at 2 or more points in time and a decrease in weight-for-age z score during the study period. STATISTICAL ANALYSES PERFORMED: Relative risk of growth failure with exposure to each risk factor was determined. The chi 2 test was used to measure association between growth and development, and change in z scores was used to examine growth patterns. RESULTS: Growth failure occurred in 8 of 40 infants. Twenty-nine of the infants experienced a drop in weight-for-age z score from the initial to the final study visit. Growth failure was associated with low socioeconomic status (relative risk = 4.0, 95% confidence interval = 1.3, 12.6), postdischarge days of illness (relative risk = 10.5, 95% confidence interval = 1.4, 77.4) and "suspect" development (chi 2 = 7.12, P = .014). APPLICATIONS: Infants with BPD may benefit from comprehensive postdischarge nutrition and feeding therapy that includes ensuring adequate energy intake, parental support and education, and feeding evaluation and therapy.

Gadolinium-enhanced magnetic resonance angiography of renal transplants.

Our purpose was to investigate three-dimensional (3D) gadolinium-enhanced magnetic resonance angiography (Gd-MRA) in the evaluation of renal transplant arteries. Eleven MR angiography examinations were performed in nine renal transplant patients. Gd-MRA, three-dimensional phase contrast (3D-PC) post-gadolinium, and two-dimensional time-of-flight (2D-TOF) MR angiography were performed and independently reviewed by three vascular radiologists who, for each MR angiography sequence, separately graded occlusive disease in the ipsilateral iliac artery, the transplant artery anastomosis, and the transplant artery itself. The Gd-MRA and 3D-PC data were reviewed as maximum intensity projections (MIP) reconstructed in standard planes, and the 2D-TOF data were interpreted from source images. In addition, a single vascular radiologist prospectively interpreted the Gd-MRA and 3D-PC data together, hereinafter Gd/PC, from MIP reconstructions for each case. In all of these patients either surgical (n = 3) or angiographic studies (n = 8) were performed within 21 days following the MR examination, which served as a reference standard to determine sensitivity and specificity. The sensitivity/specificity for the detection of significant stenosis were as follows: Gd-MRA, 67/88; 3D-PC, 60.3/76.6; 2D-TOF, 47/81; and Gd/PC, 100/100. The kappa statistic (kappa) for interobserver agreement for the grading of stenoses by 2D-TOF, Gd-PC, and Gd-MRA was 0.48, 0.60, and 0.74, respectively. The percentage of all vascular segments seen well enough to grade (cumulative for all three observers) was 94%, 85%, and 79% for Gd-MRA, 3D-PC, and 2D-TOF, respectively. The combination of Gd-MRA and 3D-PC is a promising approach to the evaluation of transplant renal arteries.

Circumferential mucosectomy with stapled proctopexy is a safe, effective outpatient alternative for the treatment of symptomatic prolapsing hemorrhoids in the elderly.

BACKGROUND: Circumferential mucosectomy with stapled proctopexy (CMSP) was first introduced in 1993 as a less painful and highly effective alternative to traditional operative hemorrhoidectomy. Although CMSP has many advantages over traditional hemorrhoidectomy, some authorities and insurers continue to regard it as an inpatient procedure and others have been slow to adopt this progressive technique. This study documents the safe and effective outpatient nature of this procedure. METHODS: From December 2001 through August 2002, 33 patients with mucosal prolapse and prolapsing internal hemorrhoids were treated using circumferential mucosectomy with stapled proctopexy as outpatients at an ambulatory surgery center. Fourteen (42%) patients were treated using local anesthesia with intravenous sedation, 18 (55%) chose spinal anesthesia, and general anesthesia was used in one patient. Patients were evaluated postoperatively by telephone at 1 and 2 weeks, and seen in clinic at 4 weeks. RESULTS: One patient (3%) required an emergency department visit for minor postoperative bleeding. None of our elderly patients required emergency department evaluation and none reported significant complications. Four patients (13%) required urinary catheter placement prior to discharge from the surgery center due to urinary retention. One patient (3%) developed an uncomplicated urinary tract infection, which resolved with antibiotic treatment. Two patients were seen earlier than 4 weeks at the surgeon's request; one was immunocompromised from chemotherapy for metastatic carcinoid, and one reported persistent pain during initial telephone follow-up. No complications were identified in either patient, and no additional complications have been noted to date. CONCLUSIONS: CMSP is a safe, effective, time-efficient procedure for patients with mucosal prolapse and prolapsing hemorrhoids that can be performed safely in the ambulatory surgery center setting. Age is not a limiting factor in selecting patients for this safe outpatient procedure.

CT attenuation of fluid in breast cysts.

RATIONALE AND OBJECTIVES: The authors' purpose was to determine whether computed tomographic (CT) attenuation values of fluid in breast cysts could be in the range of values for soft tissue and could be correlated with protein content of the fluid. MATERIALS AND METHODS: Aspirate samples from 10 simple breast cysts were analyzed for protein content, and CT attenuation values were calculated by means of a breast phantom. A corrected attenuation value for breast-cyst fluid was calculated by using sterile water as a control. RESULTS: The mean corrected attenuation value for the cyst aspirate was 28.1 HU; most simple cysts have an attenuation value of only 10 HU. Protein concentration ranged from 0.9 to 2.4 g/dL. A significant, almost linear relationship was noted between protein content and attenuation value of cyst fluid (r = .85, P < .01). CONCLUSION: The CT attenuation values of breast cysts can be in the range of those of soft tissue. This high attenuation value is correlated with the high protein content of breast-cyst fluid. Therefore, an apparent circumscribed soft-tissue mass seen within the breast at CT may represent a simple cyst.

Cryosurgery and needle ablation of renal lesions.

Laparoscopic renal cryoablation is a minimally invasive alternative for treating renal tumors utilizing narrow probes cooled with a compressed gas such as argon or carbon dioxide. At this time, cryotherapy has shown the most promise as an alternative to partial nephrectomy as a nephron-sparing treatment for renal tumors. Radiofrequency ablation employs needle electrodes placed percutaneously directly into renal lesions to deliver energy, creating high temperatures leading to cell death. High-intensity focused ultrasound is a noninvasive technique in which focused ultrasound energy is applied to cause cell death within the focal zone. Microwave thermotherapy uses small applicators to deliver microwave energy to tissues, resulting in the generation of heat. Although RF, HIFU, and microwave thermotherapy show promise as energy sources for tumor ablation, they are in the early stages of development. Little is known about their acute and chronic histologic effects and long-term efficacy as a treatment for malignant disease. Further work is needed to develop cryosurgery and needle ablation in order to delineate what role these techniques will ultimately play in the management of RCC.