Cost analysis of laparoscopic appendectomy in a large integrated healthcare system.

INTRODUCTION: Healthcare expenditure is on the rise placing greater emphasis on operational excellence, cost containment, and high quality of care. Significant variation is seen in operating room (OR) costs with common surgical procedures such as laparoscopic appendectomy. Surgeons can influence cost through the selection of instrumentation for common surgical procedures such as laparoscopic appendectomy. We aimed to quantify the cost of laparoscopic appendectomy in our healthcare system and compare cost variations to operative times and outcomes. METHODS AND PROCEDURES: We performed a retrospective review of laparoscopic appendectomies in a large regional healthcare system during one-year period (2018). Operating room supply costs and procedure durations were obtained for each hospital. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) outcomes and demographics were compared to the costs for each hospital. RESULTS: A total of 4757 laparoscopic appendectomies were performed at 20 hospitals (27 to 522 per hospital) by 233 surgeons. The average supply cost per case ranged from $650 to $1067. Individual surgeon cost ranged from $197 to $1181. The average operative time was 41 min (range 33 to 60 min). There was no association between lower cost and longer operative time. The patient demographics and comorbidities were similar between sites. There were no significant differences in postoperative complications between high- and low-cost centers. The items with the greatest increase in cost were single-use energy devices (SUD) and endoscopic stapler. We estimate that a saving of over $417 per case is possible by avoiding the use of energy devices and may be as high as $ 984 by adding selective use of staplers. These modifications would result in an annual savings of $1 million for our health system and more than $ 125 million nationwide. CONCLUSION: Performing laparoscopic appendectomy with reusable instruments and finding alternatives to expensive energy devices and staplers can significantly decrease costs and does not increase operative time or postoperative complications.

Neoadjuvant chemotherapy in non-metastatic breast cancer: a study on practice trends in a regional cancer treatment service.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is increasingly used for managing locally advanced and high risk non-metastatic breast cancer. AIMS: To describe trends in NACT use, assess compliance to best practice recommendations and determine treatment response rates in a regional cancer treatment service. METHODS: In this retrospective cross- sectional study, electronic records of patients who underwent NACT in centres covered by the MidCentral Regional Cancer Treatment Service in 2013 and 2017 were reviewed. Data pertaining to patient demographics, disease status, compliance to best practice recommendations and treatment outcomes were extracted and analysed. RESULTS: Of a total of 502 referrals for non-metastatic breast cancer, 34 underwent NACT with the estimated NACT rate rising from 3.85% (2013) to 9.92% (2017). Compliance to practice recommendations improved in all domains (pre-treatment tumour and axillary evaluation, marker placement, multidisciplinary discussion). Overall, NACT was well tolerated with only three patients experiencing treatment limiting toxicity. Response rates mirror published data (complete response: 29.4%, partial: 61.8%) with higher responses registered in HER2 positive and triple negative subtypes. Discordance between radiological and pathological response was 28%, with imaging overestimating response in five out of seven cases. Of the 11 (32%) patients who initially underwent breast conserving surgery, six required a second surgery. CONCLUSION: NACT is increasingly used in the Regional Cancer Treatment Service, with improving compliance to practice recommendations. These results are reassuring and can be used to help patients develop a realistic expectation towards NACT.

Regional cost analysis for laparoscopic cholecystectomy.

BACKGROUND: Laparoscopic cholecystectomy is the most common procedure performed by general surgeons in the United States, with approximately 600,000 procedures performed annually. As the cost of care rises, there is increasing emphasis on utilization and quality. Our objective was to evaluate the cost of laparoscopic cholecystectomy in our health system and to compare the operative times and outcomes at high- and low-cost centers. METHODS: We evaluated all laparoscopic cholecystectomies performed in our system over a 1-year period. The operating room supply costs and procedure durations were obtained for each of the hospitals. The American College of Surgeons National Surgical Quality Improvement Program outcomes and demographics were compared to the costs for each hospital. RESULTS: During the study period, 7601 laparoscopic cholecystectomies were performed at 20 hospitals (170-759/hospital) by 227 surgeons. The average cost per case ranged from $296 at the lowest cost center to $658 at the highest cost center. The average operative time varied between sites from 46 to 95 min. There was no association between cost and operative time or case volume. There was a slight trend toward increased cost with higher number of emergency procedures, but this was not well correlated (R2 = 0.03). The patient demographics and comorbidities were similar between sites. There were no significant differences in postoperative complications between high- and low-cost centers. The items with the greatest increase in cost were disposable trocars, disposable hook cautery, disposable endoscissors, and disposable clip appliers. We estimate that a savings of over $300/case is possible by using reusable instruments, which would result in an annual savings of $1.3 million for our health system, and $285 million nationwide. CONCLUSION: Performing laparoscopic cholecystectomy with reusable instruments can significantly decrease costs and does not increase operative time or postoperative complications.

Staged Definitive Repair after Carotid Blowout: A Case Report.

Carotid blowout syndrome is a highly morbid complication of head and neck cancer. We present the case of a 51-year-old woman with common carotid artery blowout, initially temporized with an endovascular stent graft and ultimately reconstructed using autologous superficial femoral artery. The patient recovered without sequelae and continues to be asymptomatic at 1 year. We present the modern hybrid management of this complex case.

Characterization of the direct interaction between KcsA-Kv1.3 and its inhibitors.

Integral membrane proteins (IMPs) are of therapeutic interest and are targeted by a majority of approved drugs. It's difficult to express, purify, and maintain the functional conformation of IMPs. Nanodisc presents a reliable method to solubilize and stabilize IMPs in detergent-free condition. In this study, we demonstrate the assembly and purification of a chimeric ion channel, KcsA-Kv1.3 Nanodisc. We further detail biophysical analysis of the assembled Nanodisc using analytical ultracentrifugation (AUC), surface plasmon resonance (SPR), and back scattering interferometry (BSI). AUC is employed to determine the molecular composition of the empty and KcsA-Kv1.3 Nanodisc. Combination of SPR and BSI overcomes each other's limitation and provides insight of equilibrium binding properties of peptide and small molecule ligands to KcsA-Kv1.3.

Dose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study.

BACKGROUND: Dose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose-intense two weekly schedule of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC). METHODS: 49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m(2) oral BD days 1-7)oxaliplatin (85 mg/m(2)i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited. RESULTS: Over 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred. CONCLUSIONS: Dose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended. TRIAL REGISTRATION: ISRCTN41540878.

Simultaneous on-chip DC dielectrophoretic cell separation and quantitative separation performance characterization.

Through integration of a MOSFET-based microfluidic Coulter counter with a dc-dielectrophoretic cell sorter, we demonstrate simultaneous on-chip cell separation and sizing with three different samples including 1) binary mixtures of polystyrene beads, 2) yeast cells of continuous size distribution, and 3) mixtures of 4T1 tumor cells and murine bone marrow cells. For cells with continuous size distribution, it is found that the receiver operator characteristic analysis is an ideal method to characterize the separation performance. The characterization results indicate that dc-DEP separation performance degrades as the sorting throughput (cell sorting rate) increases, which provides insights into the design and operation of size-based microfluidic cell separation.

Treatment with the PARP-inhibitor PJ34 causes enhanced doxorubicin-mediated cell death in HeLa cells.

Adjuvant therapies can incorporate a number of different drugs to minimize the cardiotoxicity of cancer chemotherapy, decrease the development of drug resistance and increase the overall efficacy of the treatment regime. Topoisomerase IIα is a major target of many commonly used anticancer drugs, where cell death is brought about by an accumulation of double-strand DNA breaks. Poly (ADP-ribose) polymerase (PARP)-1 has been extensively studied for its role in the repair of double-strand DNA breaks, but its ability to add highly negative biopolymers (ribosylation) to target proteins provides a vast number of pathways where it can also be important in mediating cell death. In this study, we combine the classical topoisomerase IIα poison doxorubicin with the PARP inhibitor PJ34 to investigate the potentiation of chemotherapeutic efficiency in HeLa cells. We demonstrate that PJ34 treatment has the capacity to increase endogenous topoisomerase IIα protein by about 20%, and by combining doxorubicin treatment with PJ34, we observed a 50% improvement in doxorubicin-mediated cell death in HeLa cells. These results were correlated with the ribosylation of transcription factor specificity factor 1 after doxorubicin treatment, thereby altering its affinity for binding to known regulatory elements within the human topoisomerase IIα promoter. Taken together, these results highlight the synergistic potential of combining PARP inhibitors with classical topoisomerase IIα-targeting drugs.

P3 optimization of functional potency, in vivo efficacy and oral bioavailability in 3-aminopyrazinone thrombin inhibitors bearing non-charged groups at the P1 position.

Although the S3 pocket of the thrombin active site is lined with lipophilic amino acid residues, the accommodation of polarity within the lipophilic P3 moiety of small molecule inhibitors is possible provided that the polar functionality is capable of pointing away from the binding pocket outwards toward solvent while simultaneously allowing the lipophilic portion of the P3 ligand to interact with the S3 amino acid residues. Manipulation of this motif provided the means to effect optimization of functional potency, in vivo antithrombotic efficacy and oral bioavailability in a series of 3-aminopyrazinone thrombin inhibitors which contained non-charged groups at the P1 position.

Design, synthesis and SAR of a series of 1,3,5-trisubstituted benzenes as thrombin inhibitors.

A novel 1,3,5-trisubstituted benzamide thrombin inhibitor template was designed via hybridization of a known aminopyridinoneacetamide and a known 1,3,5-trisubstituted phenyl ether. Optimization of this lead afforded a novel potent series of biaryl 1,3,5-trisubstituted benzenes with excellent functional anticoagulant potency.

A prospective audit on the use of prophylactic antiemetics and rates of CINV in patients receiving carboplatin AUC≥4 or combination anthracycline-cyclophosphamide.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are two of the most frequently experienced and distressing side effects of cancer treatment. Recent updates by ESMO/MASCC and ASCO on guidelines for prevention of CINV have recommended the addition of a neurokinin-1 receptor antagonist to antiemetic regimens for patients receiving carboplatin-based chemotherapy area under the curve (AUC) ≥4 mg/mL per minute, and an addition of olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy. AIMS: To assess current use of prophylactic antiemetics and rates of CINV in patients under the care of MidCentral Regional Cancer Treatment Service (MRCTS) receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide. METHODS: Data was prospectively collected on patients under the care of MRCTS receiving carboplatin AUC≥4 or combination anthracycline/cyclophosphamide chemotherapy, including breast cancer patients receiving 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and lymphoma patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Questionnaires were given to eligible patients to be completed daily from day two to day six of first cycle of chemotherapy only. Data on each patient's gender, age, types of chemotherapies, types of malignancies, presence of nausea or vomiting, number of dry retching or vomiting episodes and anti-emetics were recorded. RESULTS: From 15 September 2018 to 10 August 2019, a total of 44 patients receiving carboplatin-based chemotherapy AUC≥4 and 30 patients receiving combination anthracycline/cyclophosphamide were included. Twenty-two patients (50%) had either emesis or significant nausea in the overall and delayed phase when treated with carboplatin AUC≥4, and only three (7%) in the acute phase. Fourteen patients (56%) had either emesis or significant nausea in the overall phase when treated with FEC chemotherapy, mostly in the acute phase (13 patients) rather than in the delayed phase (9 patients). CONCLUSION: The rates of CINV are high with the existing antiemetic regimens used at MidCentral Regional Cancer Treatment Service. Therefore, in accordance with international guidelines, we will add a neurokinin-1 antagonist to the antiemetic regimens for patients receiving carboplatin-based chemotherapy AUC≥4, and olanzapine for those receiving combination anthracycline/cyclophosphamide chemotherapy, in an attempt to improve the rates of CINV in these groups. Repeating this audit post-implementation of above recommendations will be important to assess for any improvement.

Escalation triggers and expected responses in obstetric early warning systems used in UK consultant-led maternity units.

BACKGROUND: The use of obstetric early warning systems (OEWS) are recommended as an adjunct to reduce maternal morbidity and mortality. The aim of this review was to document the variation in OEWS trigger thresholds and the quality of information included within accompanying escalation protocols. METHODS: A review of OEWS charts and escalation policies across consultant-led maternity units in the UK (n = 147) was conducted. OEWS charts were analysed for variation in the values of physiological parameters triggering different levels of clinical escalation. Relevant data within the escalation protocols were also searched for: urgency of clinical response; seniority of responder; frequency of on-going clinical monitoring; and clinical setting recommended for on-going care. RESULTS: The values of physiological parameters triggering specific clinical responses varied significantly between OEWS. Only 99 OEWS charts (67.3%) had an escalation protocol as part of the chart. For 29 charts (19.7%), the only escalation information included was generic, for example to "contact a doctor if triggers". Only 76 (51.7%) charts detailed the required seniority of responder, 37 (25.2%) the frequency for on-going clinical monitoring, eight (5.4%) the urgency of clinical response and two (1.4%) the recommended clinical setting for on-going care. CONCLUSION: The observed variations in the trigger thresholds used in OEWS charts and the quality of information included within the accompanying escalation protocols is likely to lead to suboptimal detection and response to clinical deterioration during pregnancy and the post-partum period. The development of a national OEWS and escalation protocol would help to standardise care across obstetric units.

Pimasertib Versus Dacarbazine in Patients With Unresectable NRAS-Mutated Cutaneous Melanoma: Phase II, Randomized, Controlled Trial with Crossover.

This study investigated the efficacy and safety of pimasertib (MEK1/MEK2 inhibitor) versus dacarbazine (DTIC) in patients with untreated NRAS-mutated melanoma. Phase II, multicenter, open-label trial. Patients with unresectable, stage IIIc/IVM1 NRAS-mutated cutaneous melanoma were randomized 2:1 to pimasertib (60 mg; oral twice-daily) or DTIC (1000 mg/m2; intravenously) on Day 1 of each 21-day cycle. Patients progressing on DTIC could crossover to pimasertib. Primary endpoint: investigator-assessed progression-free survival (PFS); secondary endpoints: overall survival (OS), objective response rate (ORR), quality of life (QoL), and safety. Overall, 194 patients were randomized (pimasertib n = 130, DTIC n = 64), and 191 received treatment (pimasertib n = 130, DTIC n = 61). PFS was significantly improved with pimasertib versus DTIC (median 13 versus 7 weeks, respectively; hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.42-0.83; p = 0.0022). ORR was improved with pimasertib (odds ratio 2.24, 95% CI 1.00-4.98; p = 0.0453). OS was similar between treatments (median 9 versus 11 months, respectively; HR 0.89, 95% CI 0.61-1.30); 64% of patients receiving DTIC crossed over to pimasertib. Serious adverse events (AEs) were more frequent for pimasertib (57%) than DTIC (20%). The most common treatment-emergent AEs were diarrhea (82%) and blood creatine phosphokinase (CPK) increase (68%) for pimasertib, and nausea (41%) and fatigue (38%) for DTIC. Most frequent grade ≥3 AEs were CPK increase (34%) for pimasertib and neutropenia (15%) for DTIC. Mean QoL scores (baseline and last assessment) were similar between treatments. Pimasertib has activity in NRAS-mutated cutaneous melanoma and a safety profile consistent with known toxicities of MEK inhibitors. Trial registration: ClinicalTrials.gov, NCT01693068.

Structure-based design of novel groups for use in the P1 position of thrombin inhibitor scaffolds. Part 2: N-acetamidoimidazoles.

Guided by X-ray crystallography of thrombin-inhibitor complexes and molecular modeling, alkylation of the N1 nitrogen of the imidazole P1 ligand of the pyridinoneacetamide thrombin inhibitor 1 with various acetamide moieties furnished inhibitors with significantly improved thrombin potency, trypsin selectivity, functional in vitro anticoagulant potency and in vivo antithrombotic efficacy. In the pyrazinoneacetamide series, oral bioavailability was also improved.

Identification of compounds acting as negative allosteric modulators of the LPA1 receptor.

The Lysophosphatidic Acid 1 Receptor (LPA1 receptor) has been linked to the initiation and progression of a variety of poorly treated fibrotic conditions. Several compounds that have been described as LPA1 receptor antagonists have progressed into clinical trials: 1-(4-{4-[3-methyl-4-({[(1R)-1-phenylethoxy]carbonyl}amino)-1,2-oxazol-5-yl]phenyl}phenyl)cyclopropane-1-carboxylic acid (BMS-986202) and 2-{4-methoxy-3-[2-(3-methylphenyl)ethoxy]benzamido}-2,3-dihydro-1H-indene-2-carboxylic acid (SAR-100842). We considered that as LPA1 receptor function is involved in many normal physiological processes, inhibition of specific signalling pathways associated with fibrosis may be therapeutically advantageous. We compared the binding and functional effects of a novel compound; 4-({(Cyclopropylmethyl)[4-(2-fluorophenoxy)benzoyl]amino}methyl}benzoic acid (TAK-615) with BMS-986202 and SAR-100842. Back-scattering interferometry (BSI) was used to show that the apparent affinity of TAK-615 was enhanced in the presence of LPA. The binding signal for BMS-986202 was not detected in the presence of LPA suggesting competition but interestingly the apparent affinity of SAR-100842 was also enhanced in the presence of LPA. Only BMS-986202 was able to fully inhibit the response to LPA in calcium mobilisation, ß-arrestin, cAMP, GTPγS and RhoA functional assays. TAK-615 and SAR-100842 showed different inhibitory profiles in the same functional assays. Further binding studies indicated that TAK-615 is not competitive with either SAR-100842 or BMS-986202, suggesting a different site of binding. The results generated with this set of experiments demonstrate that TAK-615 acts as a negative allosteric modulator (NAM) of the LPA1 receptor. Surprisingly we find that SAR-100842 also behaves like a NAM. BMS-986202 on the other hand behaves like an orthosteric antagonist.

Down-regulation of human topoisomerase IIalpha expression correlates with relative amounts of specificity factors Sp1 and Sp3 bound at proximal and distal promoter regions.

BACKGROUND: Topoisomerase IIalpha has been shown to be down-regulated in doxorubicin-resistant cell lines. The specificity proteins Sp1 and Sp3 have been implicated in regulation of topoisomerase IIalpha transcription, although the mechanism by which they regulate expression is not fully understood. Sp1 has been shown to bind specifically to both proximal and distal GC elements of the human topoisomerase IIalpha promoter in vitro, while Sp3 binds only to the distal GC element unless additional flanking sequences are included. While Sp1 is thought to be an activator of human topoisomerase IIalpha, the functional significance of Sp3 binding is not known. Therefore, we sought to determine the functional relationship between Sp1 and Sp3 binding to the topoisomerase IIalpha promoter in vivo. We investigated endogenous levels of Sp1, Sp3 and topoisomerase IIalpha as well as binding of both Sp1 and Sp3 to the GC boxes of the topoisomerase IIalpha promoter in breast cancer cell lines in vivo after short term doxorubicin exposure. RESULTS: Functional effects of Sp1 and Sp3 were studied using transient cotransfection assays using a topoisomerase IIalpha promoter reporter construct. The in vivo interactions of Sp1 and Sp3 with the GC elements of the topoisomerase IIalpha promoter were studied in doxorubicin-treated breast cancer cell lines using chromatin immunoprecipitation assays. Relative amounts of endogenous proteins were measured using immunoblotting. In vivo DNA looping mediated by proteins bound at the GC1 and GC2 elements was studied using the chromatin conformation capture assay. Both Sp1 and Sp3 bound to the GC1 and GC2 regions. Sp1 and Sp3 were transcriptional activators and repressors respectively, with Sp3 repression being dominant over Sp1-mediated activation. The GC1 and GC2 elements are linked in vivo to form a loop, thus bringing distal regulatory elements and their cognate transcription factors into close proximity with the transcription start site. CONCLUSION: These observations provide a mechanistic explanation for the modulation of topoisomerase IIalpha and concomitant down-regulation that can be mediated by topoisomerase II poisons. Competition between Sp1 and Sp3 for the same cognate DNA would result in activation or repression depending on absolute amounts of each transcription factor in cells treated with doxorubicin.

Analytical challenges in the confirmative identification of dipyrone as an adulterant in illicit drug samples.

Dipyrone is an analgesic and antipyretic drug that is sometimes encountered as an adulterant in illicit drug samples, particularly illicit fentanyl containing samples. It undergoes thermal decomposition to aminopyrine and 4-methylaminoantipyrine during analysis via gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). During analysis via high pressure liquid chromatography (HPLC) and high pressure liquid chromatography-mass spectrometry (HPLC-MS), it undergoes hydrolytic decomposition solely to 4-methylaminoantipyrine. Given that mass spectrometry is a widely used confirmatory analytical technique, these instabilities present challenges for the forensic chemist seeking to confirm the presence of dipyrone. Studies were conducted to determine rigorous confirmative protocols for the identification of dipyrone in multicomponent illicit drug samples.

SIRFLOX: Randomized Phase III Trial Comparing First-Line mFOLFOX6 (Plus or Minus Bevacizumab) Versus mFOLFOX6 (Plus or Minus Bevacizumab) Plus Selective Internal Radiation Therapy in Patients With Metastatic Colorectal Cancer.

PURPOSE: SIRFLOX was a randomized, multicenter trial designed to assess the efficacy and safety of adding selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres to standard fluorouracil, leucovorin, and oxaliplatin (FOLFOX)-based chemotherapy in patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Chemotherapy-naïve patients with liver metastases plus or minus limited extrahepatic metastases were randomly assigned to receive either modified FOLFOX (mFOLFOX6; control) or mFOLFOX6 plus SIRT (SIRT) plus or minus bevacizumab. The primary end point was progression-free survival (PFS) at any site as assessed by independent centralized radiology review blinded to study arm. RESULTS: Between October 2006 and April 2013, 530 patients were randomly assigned to treatment (control, 263; SIRT, 267). Median PFS at any site was 10.2 v 10.7 months in control versus SIRT (hazard ratio, 0.93; 95% CI, 0.77 to 1.12; P = .43). Median PFS in the liver by competing risk analysis was 12.6 v 20.5 months in control versus SIRT (hazard ratio, 0.69; 95% CI, 0.55 to 0.90; P = .002). Objective response rates (ORRs) at any site were similar (68.1% v 76.4% in control v SIRT; P = .113). ORR in the liver was improved with the addition of SIRT (68.8% v 78.7% in control v SIRT; P = .042). Grade ≥ 3 adverse events, including recognized SIRT-related effects, were reported in 73.4% and 85.4% of patients in control versus SIRT. CONCLUSION: The addition of SIRT to FOLFOX-based first-line chemotherapy in patients with liver-dominant or liver-only metastatic colorectal cancer did not improve PFS at any site but significantly delayed disease progression in the liver. The safety profile was as expected and was consistent with previous studies.

A model for initial DNA lesion recognition by NER and MMR based on local conformational flexibility.

Initial recognition of DNA damage is the crucial but poorly understood first step in DNA repair by the human nucleotide excision repair(NER) and mismatch repair (MMR) systems. Failure by NER or MMR to recognize DNA damage threatens the genetic integrity of the organism and may play a role in carcinogenesis. Both NER and MMR recognize and repair a wide variety of structurally dissimilar lesions against the background of normal DNA. Previous studies have suggested that detection of thermodynamic destabilization of DNA caused by covalent damage and base mismatches is a potential mechanism by which repair pathways with broad specificity such as NER and MMR recognize their substrates. However, both NER and MMR respectively, repair a wide variety of stabilizing and destabilizing covalent DNA lesions and base pair mismatches. A common feature of lesions that are both thermodynamically stabilizing and destabilizing is the alteration of the local DNA flexibility (dynamics). In this review we describe the experimental evidence for altered dynamics from NMR and thermodynamic studies on normal and damaged DNA molecules with respect to recognition by NER and MMR. Based on these data, we propose a model for initial detection of lesions by both NER and MMR that occurs through an indirect readout mechanism of alternative DNA conformations induced by covalent damage and base mismatches.