Extended thoracic endovascular aortic repair is optimal therapy in acute complicated type B dissection.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) represents optimal therapy for complicated acute type B aortic dissection (aTBAD). Persistent knowledge gaps remain, including the optimal length of aortic coverage, impact on distal aortic remodeling, and fate of the dissected abdominal aorta. METHODS: Review of the Emory Aortic Database identified 92 patients who underwent TEVAR for complicated aTBAD from 2012 to 2018. Standard TEVAR covered aortic zones 3 and 4 (from the left subclavian to the mid-descending thoracic aorta). Extended TEVAR fully covered aortic zones 3 though 5 (from the left subclavian to the celiac artery). Long-term imaging, clinical follow-up, and overall and aortic-specific mortality were reviewed. RESULTS: Extended TEVAR (n = 52) required a greater length of coverage vs standard TEVAR (n = 40) (240 ± 32 mm vs 183 ± 23 mm; P < .01). In-hospital mortality occurred in 5.4% of patients (7.7% vs 2.5%; P = .27) owing to mesenteric malperfusion (n = 3) or rupture (n = 2). The overall incidences of postoperative stroke, transient paraparesis, paraplegia, and dialysis were 5.4% (3.9% vs 7.5%; P = .38), 3.2% (5.8% vs 0%; P = .18), 0%, and 0% respectively, equivalent between groups. Follow-up was 96.6% complete to a mean of 6.1 years (interquartile range, 3.5-8.6 years). There were significantly higher rates of complete thrombosis or obliteration of the entire thoracic false lumen after Extended TEVAR (82.2% vs 51.5%; P = .04). Distal aortic reinterventions were less frequent after extended TEVAR (5.8% vs 20%; P = .04). Late aorta-specific survival was 98.1% after extended TEVAR vs 92.3% for standard TEVAR (P = .32). CONCLUSIONS: Extended TEVAR for complicated aTBAD is safe, results in a high rate of total thoracic false lumen thrombosis/obliteration, and reduces distal reinterventions. Longer-term follow-up will be needed to demonstrate a survival benefit compared to limited aortic coverage.

Acute Type B Intramural Hematoma: Novel Insights in the Endovascular Era.

BACKGROUND: The pathophysiology and behavior of acute type B intramural hematoma (TBIMH) is poorly understood. The purpose of this study is to characterize the pathophysiology, fate, and outcomes of TBIMH in the endovascular era. METHODS: A retrospective analysis of a US Aortic Database identified 70 patients with TBIMH from 2008 to 2022. Patients were divided into groups and analyzed based upon subsequent management: early thoracic endovascular aortic repair (TEVAR; Group 1) or hospital discharge on optimal medical therapy (OMT) (Group 2). RESULTS: Of 70 total patients, 43% (30/70) underwent TEVAR (Group 1) and 57% (40/70) were discharged on OMT (Group 2). There were no significant differences in age, demographics, or comorbidities between groups. Indications for TEVAR in Group 1 were as follows: 1) Penetrating atheroscletoic ulcer (PAU) or ulcer-like projection (n = 26); 2) Descending thoracic aortic aneurysm (n = 3); or 3) Progression to type B aortic dissection (TBAD) (n = 2). Operative mortality was zero. No patient suffered a stroke or spinal cord ischemia. During the follow-up period, 50% (20/40) of Group 2 patients required delayed surgical intervention, including TEVAR in 14 patients and open repair in 6 patients. Indications for surgical intervention were as follows: 1) Development of a PAU / ulcer-like projection (n = 13); 2) Progression to TBAD (n = 3), or 3) Concomitant aneurysmal disease (n = 4). Twenty patients did not require surgical intervention. Of the initial cohort, 71% of patients required surgery, 9% progressed to TBAD, and 19% had regression or stability of TBIMH with OMT alone. CONCLUSIONS: The most common etiology of TBIMH is an intimal defect. Progression to TBAD and intramural hematoma regression without an intimal defect occurs in a small percentage of patients. An aggressive strategy with endovascular therapy and close surveillance for TBIMH results in excellent short-term and long-term outcomes.

Acute-on-Chronic Aortic Dissection: Management and Outcomes of the Unstable "Triple-Lumen" Aorta.

BACKGROUND: The impact of acute aortic dissection of the chronically dissected distal aorta is unknown. This study sought to describe the incidence and characteristics of the triple-lumen aortic dissection and its impact on survival. METHODS: From 2010 to 2021, a query of a single-institution aortic database identified 1149 patients with chronic distal aortic dissection. Thirty-three (2.9%) patients with at least 3 distinct lumens and 2 separate "primary" intimal tears were identified by analysis of contrast-enhanced cross-sectional imaging. Triple-lumen patients were exactly matched with a cohort of double-lumen patients on a 1:1 ratio using 5 preoperative variables, and outcomes between the groups were assessed. RESULTS: The median age at time of initial dissection in patients with a triple-lumen dissection was 46 years. Initial dissection was a type A in 33% and a type B in 67% of patients. The median time from initial dissection to triple-lumen diagnosis was 4.2 years. On diagnosis of the triple-lumen aorta, 85% of patients required urgent aortic repair for rapid growth (36%), aortic diameter ≥55 mm (30%), malperfusion (6%), intractable pain (6%), and rupture/type A (6%). Thirty-day mortality after triple lumen dissection was 12%. CONCLUSIONS: Acute-on-chronic distal dissection resulting in a triple-lumen aorta should be classified as a "complicated" type B dissection as these patients typically have large aneurysms and a high incidence of rapid false lumen expansion requiring urgent surgical repair.

A tailored strategy for repair of acute type A aortic dissection.

OBJECTIVE: Innumerable surgical techniques are currently deployed for repairing acute type A aortic dissection (ATAAD). We analyzed our results using a conservative approach of root-sparing and hemiarch techniques in higher-risk patients and root and total arch replacement for lower-risk patients. METHODS: We queried our aortic database for consecutive patients who underwent ATAAD repair. Patients who underwent conservative repair (group 1) were compared with those who underwent extensive repair (group 2) using univariable and multivariable analysis. RESULTS: From 1997 to 2019, 343 patients underwent ATAAD repair. Two hundred forty had conservative repair (root-sparing, hemiarch) whereas 103 had extensive repair (root replacement and/or total arch). Group 1 was older with more comorbidities such as hypertension, previous myocardial infarction, and renal dysfunction. Group 2 had more connective tissue disease (2.1% vs 12.6%; P < .01), aortic insufficiency, and longer intraoperative times. The incidence of individual postoperative complications was similar regardless of approach. A composite of major adverse events (operative mortality, myocardial infarction, stroke, dialysis, or tracheostomy) was higher in the conservative group (15.1% vs 5.9%; P = .03). Operative mortality was 5.6% and not different between groups. Ten-year survival was similar with either surgical approach. Ten-year cumulative risk of reintervention was greater in group 2 (5.6% vs 21% at 10 years; P < .01). In multivariable analysis, ejection fraction and diabetes were predictors of major adverse events but not extensive approach. Extensive approach was a predictor of late reoperation (odds ratio, 3.03 [95% confidence interval, 1.29-7.2]; P = .01). CONCLUSIONS: A tailored conservative approach to ATAAD leads to favorable operative outcomes without compromising durability.

Cardiac Surgery Outcomes in an Epicenter of the COVID-19 Pandemic.

As New York State quickly became the epicenter of the COVID-19 pandemic, innovative strategies to provide care for the COVID-19 negative patients with urgent or immediately life threatening cardiovascular conditions became imperative. To date, there has not been a focused analysis of patients undergoing cardiothoracic surgery in the United States during the COVID-19 pandemic. Therefore, we seek to summarize the selection, screening, exposure/conversion, and recovery of patients undergoing cardiac surgery during the peak of the COVID-19 pandemic. We retrospectively reviewed a prospectively maintained institutional database for patients undergoing urgent or emergency cardiac surgery from March 16, 2020 to May 15, 2020, encompassing the peak of the COVID-19 pandemic. All patients were operated on in a single institution in New York City. Preoperative demographics, imaging studies, intraoperative findings, and postoperative outcomes were reviewed. Between March 16, 2020 and May 15, 2020, a total of 54 adult patients underwent cardiac surgery. Five patients required reoperative sternotomy and cardiopulmonary bypass was utilized in 81% of cases. Median age was 64.3 (56.0; 75.3) years. Two patients converted to COVID-19 positive during the admission. There was one operative mortality (1.9%) associated with an acute perioperative COVID-19 infection. Median length of hospital stay was 5 days (4.0; 8.0) and 46 patients were discharged to home. There was 100% postoperative follow up and no patient had COVID-19 conversion following discharge. The delivery of cardiac surgical care was safely maintained in the midst of a global pandemic. The outcomes demonstrated herein suggest that with proper infection control, isolation, and patient selection, results similar to those observed in non-COVID series can be replicated.

Impact of left ventricular ejection fraction on the outcomes of open repair of descending thoracic and thoracoabdominal aneurysms.

OBJECTIVE: To discern the impact of depressed left ventricular ejection fraction (LVEF) on the outcomes of open descending thoracic aneurysm (DTA) and thoracoabdominal aneurysms (TAAA) repair. METHODS: Restricted cubic spline analysis was used to identify a threshold of LVEF, which corresponded to an increase in operative mortality and major adverse events (MAE: operative death, myocardial infarction, stroke, spinal cord injury, need for tracheostomy or dialysis). Logistic and Cox regression were performed to identify independent predictors of MAE, operative mortality, and survival. RESULTS: DTA/TAAA repair was performed in 833 patients between 1997 and 2018. Restricted cubic spline analysis showed that patients with LVEF <40% (n = 66) had an increased risk of MAE (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.22-3.87; P < .01) and operative mortality (OR, 2.72; 95% CI, 1.21-6.12; P = .02) compared with the group with LVEF ≥40% (n = 767). The group with LVEF <40% had a worse preoperative profile (eg, coronary revascularization, 48.5% vs 17.3% [P < .01]; valvular disease, 82.8% vs 49.39% [P < .01]; renal insufficiency, 45.5% vs 26.1% [P < .01]; respiratory insufficiency, 36.4% vs 21.2% [P = .01]) and worse long-term survival (35.5% vs 44.7% at 10 years; P = .01). Nonetheless, on multivariate regression, depressed LVEF was not an independent predictor of operative mortality, MAE, or survival. CONCLUSIONS: LVEF is not an independent predictor of adverse events in surgery for DTA.

A Perspective from New York of COVID 19: Effect and impact on cardiac surgery.

BACKGROUND AND AIM: First reported in December of 2019, the COVID-19 pandemic caused by SARS-CoV-2 has had a profound impact on the implementation of care. Here, we describe our institutional experience with a rapid influx of patients at the epicenter of the pandemic. METHODS: We retrospectively review our experience with the departments of cardiology, cardiothoracic surgery, anesthesia, and critical care medicine and summarize protocols developed in the midst of the pandemic. RESULTS: The rapid influx of patients requiring an intensive level of care required a complete restructuring of units, including the establishment of a new COVID-19 negative unit for the care of patients requiring urgent or emergent non-COVID-19 related care including open-heart surgery. This unique unit allowed for the delivery of safe and effective care in the epicenter of the pandemic. CONCLUSIONS: Here, we demonstrate the response of a large tertiary academic medical center to the COVID-19 pandemic. Specifically, we demonstrate how rapid structural changes can allow for the continued delivery of cardiac surgical care with similar outcomes as those reported before the pandemic.

Comparative plasma pharmacokinetics of ceftiofur sodium and ceftiofur crystalline-free acid in neonatal calves.

The objective of this study was to compare the plasma pharmacokinetic profile of ceftiofur crystalline-free acid (CCFA) and ceftiofur sodium in neonatal calves between 4 and 6 days of age. In one group (n = 7), a single dose of CCFA was administered subcutaneously (SQ) at the base of the ear at a dose of 6.6 mg/kg of body weight. In a second group (n = 7), a single dose of ceftiofur sodium was administered SQ in the neck at a dose of 2.2 mg/kg of body weight. Concentrations of desfuroylceftiofur acetamide (DCA) in plasma were determined by HPLC. Median time to maximum DCA concentration was 12 h (range 12-48 h) for CCFA and 1 h (range 1-2 h) for ceftiofur sodium. Median maximum plasma DCA concentration was significantly higher for calves given ceftiofur sodium (5.62 µg/mL; range 4.10-6.91 µg/mL) than for calves given CCFA (3.23 µg/mL; range 2.15-4.13 µg/mL). AUC0-∞ and Vd/F were significantly greater for calves given CCFA than for calves given ceftiofur sodium. The median terminal half-life of DCA in plasma was significantly longer for calves given CCFA (60.6 h; range 43.5-83.4 h) than for calves given ceftiofur sodium (18.1 h; range 16.7-39.7 h). Cl/F was not significantly different between groups. The duration of time median plasma DCA concentrations remained above 2.0 µg/mL was significantly longer in calves that received CCFA (84.6 h; range 48-103 h) as compared to calves that received ceftiofur sodium (21.7 h; range 12.6-33.6 h). Based on the results of this study, CCFA administered SQ at a dose of 6.6 mg/kg in neonatal calves provided plasma concentrations above the therapeutic target of 2 µg/mL for at least 3 days following a single dose. It is important to note that the use of ceftiofur-containing products is restricted by the FDA and the use of CCFA in veal calves is strictly prohibited.

Senile transthyretin cardiac amyloidosis in patients with plasma cell dyscrasias: importance of cardiac biopsy for making the correct diagnosis.

Amyloidosis refers to a group of widely diverse conditions characterized by the deposition of insoluble protein within the extracellular space, leading to disruption of normal organ function. AL primary amyloidosis is associated with plasma cell dyscrasias and is caused by the deposition of insoluble kappa or lambda light chains. Cardiac involvement by AL primary amyloidosis has a very poor prognosis, and patients are treated with systemic chemotherapy. Clinically, the presence of cardiac amyloidosis in patients with plasma cell disorders is usually presumed to represent AL primary amyloidosis, and they are often managed as such. We reported four cases of elderly patients with plasma cell disorders who were found to have biopsy-proven cardiac senile transthyretin amyloidosis. Our cases demonstrated that cardiac amyloidosis in patients with plasma cell disorders does not necessarily represent AL primary amyloidosis. Cardiac biopsy is important in making the correct diagnosis. Accurate subtyping of the amyloid has significant implications in the management of patients and discussion of prognosis.

Plasma cell disorders in HIV-infected patients: epidemiology and molecular mechanisms.

Highly active antiretroviral therapy (HAART) has significantly improved the outcome and survival of human immunodeficiency virus (HIV)-infected patients. Subsequently, long-term morbidities including cancer have become of major public health and clinical interest for this patient population. Plasma cell disorders occur at higher incidence in HIV-infected patients; however, the molecular mechanisms driving the plasma cell disease process and the optimal management for these patients remain to be defined. This article provides an up-to-date review of the characteristics and management of HIV-infected patients with plasma cell disorders. We first present 3 cases of plasma cell disorders in HIV-infected patients, ranging from polyclonal hypergammaglobulinemia to symptomatic multiple myeloma. We then discuss the epidemiology, clinical presentation, and management of each of these plasma cell disorders, with an emphasis on the molecular events underlying the progression of plasma cell diseases from monoclonal gammopathy to symptomatic multiple myeloma. We propose a three-step hypothesis for the development of multiple myeloma. Finally, we discuss the use of high dose chemotherapy and autologous hematopoietic stem cell transplantation in the treatment of HIV-infected patients with multiple myeloma. Our review includes the care of HIV-infected patients with plasma cell disorders in the current era of HAART and novel agents available for the treatment of multiple myeloma.

Relationships between the posterior interosseous nerve and the supinator muscle: application to peripheral nerve compression syndromes and nerve transfer procedures.

BACKGROUND AND STUDY AIMS: Little information can be found in the literature regarding the relationships of the posterior interosseous nerve (PIN) while it traverses the supinator muscle. Because compression syndromes may involve this nerve at this site and researchers have investigated using branches of the PIN to the supinator for neurotization procedures, the authors' aim was to elucidate information about this anatomy. MATERIALS AND METHODS: Dissection was performed on 52 cadaveric limbs to investigate branching patterns of the PIN within the supinator muscle. RESULTS: On 29 sides, the PIN entered the supinator muscle as a single nerve and from its medial side provided two to four branches to the muscle. On 23 sides, the nerve entered the supinator muscle as two approximately equal-size branches that arose from the radial nerve on average 2.2 cm from the proximal edge of this muscle. In these cases, the medial of the two branches terminated on the supinator muscle, and the lateral branch traveled through the supinator muscle; in 13 specimens, it provided additional smaller branches to the supinator muscle. The length of PIN within the supinator muscle was 4 cm on average, and the diameter of its branches to the supinator muscle ranged from 0.8 to 1.1 mm. In 10 specimens, the PIN left the supinator muscle before the most distal aspect of the muscle. In two specimens with a single broad PIN, muscle fibers of the supinator muscle pierced the PIN as it traveled through it. CONCLUSION: This knowledge of the anatomy of the PIN as it passes through the supinator muscle may be useful to neurosurgeons during decompressive procedures or neurotization.

S-glutathionylated serine proteinase inhibitors as plasma biomarkers in assessing response to redox-modulating drugs.

Many cancer drugs impact cancer cell redox regulatory mechanisms and disrupt redox homeostasis. Pharmacodynamic biomarkers that measure therapeutic efficacy or toxicity could improve patient management. Using immunoblot analyses and mass spectrometry, we identified that serpins A1 and A3 were S-glutathionylated in a dose- and time-dependent manner following treatment of mice with drugs that alter reactive oxygen or nitrogen species. Tandem mass spectrometry analyses identified Cys(256) of serpin A1 and Cys(263) of serpin A3 as the S-glutathionylated residues. In human plasma from cancer patients, there were higher levels of unmodified serpin A1 and A3, but following treatments with redox active drugs, relative S-glutathionylation of these serpins was higher in plasma from normal individuals. There is potential for S-glutathionylated serpins A1 and A3 to act as pharmacodynamic biomarkers for evaluation of patient response to drugs that target redox pathways.

An overview of epigenetic assays.

A significant portion of ongoing epigenetic research involves the investigation of DNA methylation and chromatin modification patterns seen throughout many biological processes. Over the last few years, epigenetic research has undergone a gradual shift and recent studies have been directed toward a genome-wide assessment. DNA methylation and chromatin modifications are essential components of the regulation of gene activity. DNA methylation effectively down-regulates gene activity by addition of a methyl group to the five-carbon of a cytosine base. Less specifically, modification of the chromatin structure can be carried out by multiple mechanisms leading to either the upregulation or down-regulation of the associated gene. Of the many assays used to assess the effects of epigenetic modifications, chromatin immunoprecipitation (ChIP), which serves to monitor changes in chromatin structure, and bisulfite modification, which tracks changes in DNA methylation, are the two most commonly used techniques.

Chronic intermittent hypoxia modulates nNOS mRNA and protein expression in the rat hypothalamus.

Exposure to chronic intermittent hypoxia (CIH) as observed in obstructive sleep apnea (OSA) elicits a sustained elevation of sympathetic activity and arterial blood pressure. Our overall hypothesis is that intermittent hypoxia might increase sympathetic activity, in part by altering neuronal nitric oxide synthase (nNOS) expression in the hypothalamus, where nitric oxide is sympathoinhibitory. In this study, we begin investigation of this hypothesis by testing the more specific hypothesis that the CIH alters nNOS expression in regions of the hypothalamus associated with cardiovascular regulation. To test the effect of CIH on NOS expression we subjected male Sprague-Dawley rats to cyclic intermittent hypoxia for 8h/day, for 35 days. Experimental rats showed an increase in systemic blood pressure. In situ hybridization and immunohistochemistry were performed on hypothalamic sections, respectively. The CIH rats displayed significantly lower levels of both nNOS mRNA and protein in the paraventricular hypothalamic nucleus (PVN) with different changes in the subareas of the PVN. There was a decreased level of nNOS mRNA and protein in the subfornical organ and the periventricular hypothalamic nucleus of the CIH rats, but no significant change in the supraoptic nucleus or the lateral hypothalamic area. This work suggests that examination of central regulation of sympathetic activity may help elucidate the mechanisms of hypertension after CIH.

Stepped-care approach to treating MS: a managed care treatment algorithm.

OBJECTIVE: To introduce a model treatment algorithm for use in the managed care setting as a strategy to provide ongoing disease management and long-term care for patients with multiple sclerosis (MS), with the goal of delaying disease progression and the associated disability and cognitive dysfunction. SUMMARY: MS is a chronic inflammatory disorder of the central nervous system that is associated with progressive disability and cognitive dysfunction. Currently, management of MS involves planning an effective long-term treatment strategy that can delay the progression of the disease. This article reviews a typical stepped-care approach to treating MS that is based on the concept of a platform drug, which is an agent that provides baseline immunomodulatory action throughout the course of the disease. Considerations for selecting a platform therapy include the effect on the full spectrum of MS (disability, relapses, lesion load, and atrophy as well as patient compliance and the potential impact of neutralizing antibodies [NAbs]). Currently, 4 first-line therapies are approved for relapsing MS: the 3 interferon beta (IFNbeta) products and glatiramer acetate. Of these, the IFNbetas are generally recommended as platform therapy because all have shown significant effects on relapses, magnetic resonance imaging parameters of the disease, and because intramuscular (i.m.) IFNbeta-1a (Avonex) and subcutaneous (s.c.) IFNbeta-1a (Rebif) have been shown to slow the progression of sustained disability. Patients being treated with IFNbetas can develop NAbs to the drug, which can lead to a loss of efficacy and subsequent occurrence of breakthrough disease. The 3 different formulations of IFNbeta are associated with a varying incidence of NAbs (i.m. IFNbeta-1a, 5%; s.c. IFNbeta-1a, 24%; IFNbeta-1b [Betaseron], 45%). Antibodies also form against glatiramer acetate, although their clinical significance needs to be elucidated. As the disease progresses or has periods of aggressive activity, the stepped-care approach is to add other agents onto the platform therapy to improve control of the disease. CONCLUSION: Stepped care, as outlined in this model treatment algorithm for the managed care setting, is an effective method to achieve the fundamental goal of MS treatment, that is, to delay disease progression and the associated disability and cognitive impairment.

Predicting pesticide emissions and downwind concentrations using correlations with estimated vapor pressures.

Pesticide emissions to air have been shown to correlate with compound vapor pressure values taken from the published literature. In the present study, emissions correlations based on vapor pressures derived from chemical property estimation methods are formulated and compared with correlations based on the literature data. Comparison was made by using the two types of correlations to estimate emission rates for five herbicides, a fungicide, and an insecticide, for which field-measured emission rates from treated soil, foliage, and water were available. In addition, downwind concentrations were estimated for two herbicides, three fungicides, four insecticides, and two fumigants, for which concentration measurements had been made near treated sources. The comparison results demonstrated that correlations based on vapor pressures derived from chemical property estimation methods were essentially equivalent to correlations based on literature data. The estimation approach for vapor pressures is a viable alternative to the inherently more subjective process of selecting literature values.

Bathocuproine-assisted reduction of copper(II) by human albumin.

Human albumin (studied here as the recombinant protein rHA), a copper-binding protein in blood plasma, is shown to reduce Cu(II) to Cu(I) in the presence of a Cu(I) chelator, bathocuproinedisulfonate (BD). This reaction was accelerated at low pH, when there was little binding of Cu(II) to rHA. The addition of a competitive metal ion, Ni(II), or an increase in the concentration of BD, enhanced the reduction of Cu(II) to Cu(I). It was concluded that the oxidant was the Cu(II) complex of BD, which is likely to bind strongly to albumin. The free thiol at Cys34 was ruled out as the sole reducing agent, since Cys34-blocked albumin also gave rise to Cu(I) in the presence of BD. Reactions with amino acids and peptides suggested that Tyr and possibly His side-chains are potential reductants. BD and its homologues are frequently used as Cu(I)-specific chelators in biological experiments, but the strong oxidant activity of [Cu(II)(BD)2]2- and its ability to bind to biological macromolecules should not be overlooked, and may artificially trigger/accelerate Cu(II) reduction.

Cisplatin binding sites on human albumin.

Reactions of cisplatin (cis-[PtCl2(NH3)2]) with albumin are thought to play an important role in the metabolism of this anticancer drug. They are investigated here via (i) labeling of cisplatin with 15N and use of two-dimensional 1H,15N NMR spectroscopy, (ii) comparison of natural human serum albumin with recombinant human albumin (higher homogeneity and SH content), (iii) chemical modification of Cys, Met, and His residues, (iv) reactions of bound platinum with thiourea, and (v) gel filtration chromatography. In contrast to previous reports, it is shown that the major sulfur-containing binding site involves Met and not Cys-34, and also a N ligand, in the form of an S,N macrochelate. Additional monofunctional adducts involving other Met residues and Cys-34 are also observed. During the later stages of reactions of cisplatin with albumin, release of NH3 occurs due to the strong trans influence of Met sulfur, which weakens the Pt-NH3 bonds, and protein cross-linking is observed. The consequences of these findings for the biological activity of cisplatin-albumin complexes are discussed.