The Burden of Obesity in Cardiac Surgery: A 14 years' Follow-Up of 14.754 Patients.

Aims: The prevalence of obesity is rapidly increasing during the past decades. While previous research has focused on the early outcome after cardiac surgery or specific complications, the current study covers the whole burden of obesity in the field of cardiac surgery over short term and long term. Endpoints of the study were all-cause mortality, perioperative outcome, and wound-healing disorders (WHDs). Methods: 14.754 consecutive patients who underwent cardiac surgery over a 14 years' time period were analyzed. BMI classifications were used according to the WHO definition. Results: Mean survival was 11.95 years ± 0.1; CI 95% [12.04-12.14]. After adjustment for clinical baseline characteristics, obesity classes' I-III (obesity) did not affect 30-day mortality or all-cause mortality during the whole observational period. After adjustment for known risk factors, the risk for WHDs doubled at least in obesity patients as follows: obesity I (OR = 2.06; CI 95% [1.7-2.5]; p < 0.0001), obesity II (OR = 2.5; CI 95% [1.83-3.41]; p < 0.0001), and obesity III (OR = 4.12; CI 95% [2.52-6.74]; p < 0.0001). The same applies to the risk for sternal reconstruction that is substantially elevated in obesity I (OR = 2.23; CI 95% [1.75-2.83]; p < 0.0001), obesity II (OR = 2.81; CI 95% [1.91-4.13]; p < 0.0001), and obesity III (OR = 2.31; CI 95% [1.08-4.97]; p=0.03). No significant correlation could be found between obesity and major adverse events in the perioperative course like renal failure, ventilation >24 h, re-exploration, or cerebrovascular events. Conclusions: Cardiac surgery is safe in obesity as short- and long-term mortality are not increased, and major adverse events during the perioperative course are similar to control patients. The burden of obesity lies in substantially increased rates of wound-healing disorders and sternal reconstructions.

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT).

BACKGROUND: Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy. CASE PRESENTATION: A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events. CONCLUSION: This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable.

No association of malignant B-cell non-Hodgkin lymphomas with ipsilateral SARS-CoV-2 vaccination.

PURPOSE: SARS-CoV-2 vaccines cause acute ipsilateral lymph node swelling in an important proportion of vaccines. Thus far, no malignant lymphadenopathies have been reported in temporal context to vaccination in the ipsilateral draining lymph node areas. EXPERIMENTAL DESIGN: Prompted by two cases with unilateral axillary lymphomas that occurred ipsilaterally to prior SARS-CoV-2 vaccination, we systematically retrieved all B-cell non-Hodgkin lymphomas at two German University Medical Centers diagnosed before and after introduction of SARS-CoV-2 vaccines in Germany. Available lymphoma tissue (n=19) was subjected to next-generation immunosequencing of the IGH locus. Malignant clonotypes were mined in the CoVabDab database and published data sets from 342 uninfected individuals, 55 individuals 28 days after anti-SARS-CoV-2 vaccination and 139 individuals with acute COVID-19 together encompassing over 1 million CDR3 sequences in total. RESULTS: Of 313 newly diagnosed cases in the two centers and observation periods, 27 unilateral manifestations in the defined deltoid draining regions were identified. The majority thereof were diffuse large B-cell lymphomas (18 of 27 cases). Eleven unilateral cases were diagnosed in the era of SARS-CoV-2 vaccination and 16 in the control period before introduction of such vaccines. Of the 11 unilateral lymphomas that occurred during the vaccination period, ten had received a SARS-CoV-2 vaccine prior to lymphoma diagnosis. These cases were further evaluated. While left-sided were more frequent than right-sided lymphomas (19 vs 8 cases), no statistically significant association of vaccination site and laterality of the lymphoma manifestation was found. The unilateral lymphomas showed a normal range of B-cell receptors typically found in these lymphoma subtypes with no evidence for anti-SARS-CoV-2 sequences in the malignant clonotype. CONCLUSIONS: Together, we found no evidence that the current SARS-CoV-2 vaccines could serve as a trigger for lymphomagenesis in the draining lymph node areas of the deltoid region used for vaccination.

Progressive multifocal leukoencephalopathy associated with chemotherapy induced lymphocytopenia in solid tumors - case report of an underestimated complication.

Background: JC virus reactivation causing progressive multifocal leukoencephalopathy (PML) occurs preferentially in human immunodeficiency virus (HIV) positive individuals or patients suffering from hematologic neoplasms due to impaired viral control. Reactivation in patients suffering from solid malignancies is rarely described in published literature. Case Presentation: Here we describe a case of PML in a male patient suffering from esophageal cancer who underwent neoadjuvant radiochemotherapy and surgical resection in curative intent resulting in complete tumor remission. The radiochemotherapy regimen contained carboplatin and paclitaxel (CROSS protocol). Since therapy onset, the patient presented with persistent and progredient leukopenia and lymphopenia in absence of otherwise known risk factors for PML. Symptom onset, which comprised aphasia, word finding disorder, and paresis, was apparent 7 months after therapy initiation. There was no relief in symptoms despite standard of care PML directed supportive therapy. The patient died two months after therapy onset. Conclusion: PML is a very rare event in solid tumors without obvious states of immununosuppression and thus harbors the risk of unawareness. The reported patient suffered from lymphopenia, associated with systemic therapy, but was an otherwise immunocompetent individual. In case of neurologic impairment in patients suffering from leukopenia, PML must be considered - even in the absence of hematologic neoplasia or HIV infection.

Interobserver Variability in the Assessment of Tumor Budding in pT 3/4 Colon Cancer: Improvement by Supporting Immunohistochemistry?

The prognostic significance of tumor budding in colon cancer is unequivocally documented, and the recommendations of the International Tumor Budding Consensus Conference (ITBCC) are currently the accepted basis for its assessment. Up to now, it is unknown whether the general use of a supporting cytokeratin immunohistochemistry can improve the interobserver variability and prognostic significance. Six investigators with different levels of experience reassessed 229 cases of colon carcinoma (pT3/4, N+/-, M0) with a supporting cytokeratin immunohistochemistry. The results were compared to previous assessments, which have been performed only on H & E. Bd3 was significantly associated with the occurrence of distant metastases according to the assessments of three out of six investigators (p < 0.05). Only one single investigator reached significant results concerning the cancer specific survival (p = 0.01). The pairwise kappa values range between a poor and moderate level of agreement (range 0.17-0.45; median 0.21). In conclusion, the results show no superiority of the use of an additional cytokeratin immunohistochemistry compared to the conventional analysis on sole H & E slides. Therefore, the general supporting use of a cytokeratin immunohistochemical staining seems to be inadvisable in colon cancer in consideration of necessary resources and costs.

Neoadjuvant and Definitive Radiochemotherapeutic Approaches in Esophageal Cancer: A Retrospective Evaluation of 122 Cases in Daily Clinical Routine.

INTRODUCTION: Esophageal cancer (EC) is a common malignant tumor entity with increasing occurrence. The incidence of esophageal adenocarcinoma (AC), particularly, is constantly rising in the Western world. The mainstays of therapy with curative intent for EC in advanced stages are neoadjuvant radiochemotherapy (neoRCT) with surgery and definitive radiochemotherapy (defRCT). METHODS: We examined our internal files to identify patients suffering from EC. Palliative cases were excluded. Statistical testing was performed by χ2 test, Student's t test, Kaplan-Meier analyses, and the Mann-Whitney U test. RESULTS: One hundred and twenty-two cases were included. Histology revealed squamous cell carcinoma in 92 cases and AC in 23 cases. Ninety-five patients underwent defRCT, 27 underwent neoRCT, and 114 (in both therapy regimes) received simultaneous chemotherapy. There was no difference in the overall survival (OS) (p = 0.654; HR 1.145; 95% CI 0.629-2.086) or and progression-free survival (PFS) (p = 0.912) of patients who underwent neoRCT or defRCT. Median OS was 13.5 (2-197) months for defRCT patients and 19.5 (2-134) months for neoRCT patients (p = 0.751). Karnofsky index (KI) with a cut-off of 70% was strongest, but not a significant parameter for OS (p = 0.608) or PFS (p = 0.137). CONCLUSION: defRCT is a valid and an equal alternative to neoRCT for patients suffering from EC. Selection of patients for therapy is of crucial relevance. Further studies and improvements in follow-up are needed when neoRCT has been completed before surgery, in order to spare the patient undergoing operative treatment if there is complete remission. The identification of valid markers urgently needed to limit treatment side effects.

Tumor proportion in colon cancer: results from a semiautomatic image analysis approach.

The tumor stroma ratio (TSR) is a promising prognostic biomarker in colon cancer, which could provide additional risk stratification for therapy adaption. The objective of our study was the investigation of the prognostic significance of TSR at different tumor sites in a simple semiautomatic approach with the open-source program ImageJ. We investigated 206 pT3 and pT4 adenocarcinomas of no special type. According to our established thresholds, 31 tumors (15%) were classified as low tumor proportion (TP) (≤ 15% TP), 42 tumors (20%) were classified as high TP (≥ 54% TP), and 133 tumors (65%) were classified as medium TP. High and low TP were associated with an adverse overall survival in comparison to medium TP (p = 0.001 and p = 0.03). Furthermore, the TP was an independent risk factor of occurrence of distant metastasis next to T status, microsatellite status, and tumor budding. The 5-year survival rate was 49% in patients with high TP, 48% in patients with low TP, and 68% in patients with medium TP (p = 0.042, n = 160). Patients with a high TP had less often tumor budding (p = 0.012), lymphovascular invasion (p = 0.049), and less harvested lymph nodes (p = 0.042) in comparison to low TP tumors. The results provide first evidence that a high tumor proportion/low stroma proportion is also associated with an adverse prognosis and that this subgroup might be difficult to identify with other classical histopathologic characteristics that are linked to an adverse prognosis.

Predicting factors for long-term survival in patients with out-of-hospital cardiac arrest - A propensity score-matched analysis.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death worldwide, with acute coronary syndromes accounting for most of the cases. While the benefit of early revascularization has been clearly demonstrated in patients with ST-segment-elevation myocardial infarction (STEMI), diagnostic pathways remain unclear in the absence of STEMI. We aimed to characterize OHCA patients presenting to 2 tertiary cardiology centers and identify predicting factors associated with survival. METHODS: We retrospectively analyzed 519 patients after OHCA from February 2003 to December 2017 at 2 centers in Munich, Germany. Patients undergoing immediate coronary angiography (CAG) were compared to those without. Multivariate regression analysis and inverse probability treatment weighting (IPTW) were performed to identify predictors for improved outcome in a matched population. RESULTS: Immediate CAG was performed in 385 (74.1%) patients after OHCA with presumed cardiac cause of arrest. As a result of multivariate analysis after propensity score matching, we found that immediate CAG, return of spontaneous circulation (ROSC) at admission, witnessed arrest and former smoking were associated with improved 30-days-survival [(OR, 0.46; 95% CI, 0.26-0.84), (OR, 0.21; 95% CI, 0.10-0.45), (OR, 0.50; 95% CI, 0.26-0.97), (OR, 0.43; 95% CI, 0.23-0.81)], and 1-year-survival [(OR, 0.39; 95% CI, 0.19-0.82), (OR, 0.29; 95% CI, 0.12-0.7), (OR, 0.43; 95% CI, 0.2-1.00), (OR, 0.3; 95% CI, 0.14-0.63)]. CONCLUSIONS: In our study, immediate CAG, ROSC at admission, witnessed arrest and former smoking were independent predictors of survival in cardiac arrest survivors. Improvement in prehospital management including bystander CPR and best practice post-resuscitation care with optimized triage of patients to an early invasive strategy may help ameliorate overall outcome of this critically-ill patient population.

Malignancies associated with GIST: a retrospective study with molecular analysis of KIT and PDGFRA.

PURPOSE: Gastrointestinal stromal tumors (GISTs) are the most common soft tissue tumors of the GI tract. Studies have been published reporting additional neoplasms in GIST patients. This study aimed to evaluate possible associations of mutation type, morphology, and clinical aspects of GISTs. METHODS: All cases of GIST were identified from our pathology files. Coding exons of KIT and PDGFRA in GISTs with additional malignancies were sequenced. RESULTS: A total of 70 of 188 (37%) retrieved patients with confirmed diagnosis of GIST showed at least one additional malignant neoplasm. Fifty of these GISTs were located in the stomach (71%), 8 in the small intestine (11%), 5 in the colon/rectum (7%), and 7 cases (6.2%) were of undetermined sites of origin. The distribution of identified mutations was similar to that described in GISTs without secondary malignancies. A total of 37 of 57 cases (65%) showed mutations in the KIT gene exon 11, 3 (5%) cases in exon 9, and 1 (2%) case in exon 13. Nine tumors (16%) had mutations of the PDGFRA gene. KIT and PDGFRA wild-type status were found in seven cases (12%). Most of the secondary neoplasms were located within the GI tract (34%), in the urogenital system (24%), or the breast/female genital tract (20%). CONCLUSION: This study confirms the high rate of additional malignant tumors in GIST patients. GIST features in these cases are very similar to those with sole GIST.

Level of interobserver variability estimation as a valuable tool: assessment of tumour budding in colon cancer.

AIMS: Tumour budding is considered to be a good marker for progression and prognosis in colorectal carcinomas. A uniform classification system has been established recently. The natural element of uncertainty in the practice of human medicine is also exhibited in the assessment of tumour budding. We tested the hypothesis that interobserver variability can be estimated during the assessment process and investigated its potential clinical implication. METHODS AND RESULTS: Six investigators with different levels of experience could perceive different levels of difficulty (LOD) and estimated different levels of interobserver variability (LOIV) (Li1, lower than average; Li2, average; Li3, higher than average) during the assessment of tumour budding in 244 cases of colon cancer (pT3/4). In total, the LOIV showed following distribution: Li1: 36.1%, Li2: 43.9% and Li3: 20.0%. The LOIV was correlated significantly with the LOD given by the investigator. In total, the agreement rates with the final consensus classification were: Li1: 93.4%, Li2: 78.5% and Li3: 58.4%. The relative risk of disagreement with the final consensus classification was more than six times higher when a case was estimated to have a high rather than a low interobserver variability. CONCLUSION: Our data show that the investigator can estimate the interobserver variability during the ongoing rating process in pT3/4 colon cancer. The LOIV/LOD seems to be a valuable parameter of the assessment quality. For Li3 cases further measures seem mandatory.

Interobserver variability in the H&E-based assessment of tumor budding in pT3/4 colon cancer: does it affect the prognostic relevance?

Tumor budding is a mostly accepted adverse prognostic factor in colorectal carcinoma. It is on the cusp of a widespread use after agreement was reached recently on uniform assessment criteria. We investigated whether the interobserver variability has a direct influence on the prognostic relevance in pT3/4 colon cancer in the background of different levels of experience of the investigators. In total, six investigators with different levels of experience evaluated tumor budding on H&E slides in 244 cases with primary diagnosed (2002-2011) colon carcinoma (pT3/4, N+/-, M0). High-grade tumor budding/budding grade 3 (defined as majority assessment among the investigators) was significantly associated with an adverse outcome (overall survival p = 0.03, cancer-specific survival p = 0.08) and the occurrence of distant metastasis (p = 0.009). However, a detailed analysis of the rating results of the individual investigators revealed that only ratings of one investigator (advanced resident) were associated with an adverse outcome (p = 0.01 cancer-specific survival, overall survival p = 0.09, distant metastasis p = 0.002). The results of another investigator (consultant) were significantly associated with distant metastasis (p = 0.007). The kappa values among the investigators have a range between 0.077 and 0.357 (median 0.166). Total agreement of all investigators existed in 109 cases (44.7%). Our results demonstrate that the evaluation of tumor budding on H&E slides in pT3/4 colon cancer goes along with a considerable interobserver variability among investigators of different levels of experience. Furthermore, our results reveal that these findings directly influence the prognostic value.

Parallel suture technique with ProGlide: a novel method for management of vascular access during transcatheter aortic valve implantation (TAVI).

AIMS: The aim of this study was to evaluate vascular complications using the "parallel suture technique" in patients receiving an Edwards SAPIEN XT (SXT) or SAPIEN S3 (S3) transcatheter heart valve (THV). METHODS AND RESULTS: Two hundred consecutive patients with symptomatic severe aortic stenosis treated with TF-TAVI were included in this study where the "parallel suture technique" was applied for vascular access-site closure. This was achieved by placing the sutures medial and lateral to the puncture site. Vascular access-site complications were defined as vascular dissection, perforation, obstruction, arteriovenous fistula or pseudoaneurysms, and classified according to the Valve Academic Research Consortium-2 (VARC-2) criteria. Duplex sonography was performed routinely in every patient. In patients receiving the S3, the sheath to femoral and iliac artery ratio was significantly lower than in the SXT group, reflecting reduction in sheath sizes for S3. More endovascular interventions were required after SXT implantation as compared to S3 (4% versus 1%, p=0.02). This was due to vascular obstruction or device failure. Moreover, increased life-threatening, major bleedings, and pseudoaneurysms were found in the SXT group (6% versus 1%, p=0.06, 13% versus 3%, p=0.009, 7% versus 1%, p=0.03, respectively). CONCLUSIONS: The "parallel suture technique" using the ProGlide is associated with a low number of vascular complications, even when using larger sheath sizes.

Number of Intratumoral T Lymphocytes Is Associated With Lymph Node Size, Lymph Node Harvest, and Outcome in Node-Negative Colon Cancer.

OBJECTIVES: We postulated that lymph node (LN) harvest and LN size are influenced by immunologic effects. METHODS: To investigate this hypothesis, we performed a retrospective analysis of 170 node-negative colon cancer cases to evaluate the density of intratumoral T lymphocytes (ITLs). CD3- and CD8-positive T cells were counted using a digital system. RESULTS: The ITL density was significantly increased in cases with sufficient LN harvest and high numbers of LNs larger than 5 mm (LN5). High ITL numbers were associated with improved cancer-specific survival. The analysis of the immune score revealed a significantly different cancer-specific outcome (P = .024), with no cancer-related death in the group with the highest score. The immune score and tumor budding were independently prognostic. CONCLUSIONS: ITL density is independently prognostic and associated with LN harvest and LN size. The immune response is very likely the true explanation for the known prognostic effect of the LN harvest in colon cancer.

A new simple morphology-based risk score is prognostic in stage I/II colon cancers.

A portion of stage I/II colon cancers (10-20%) exhibit an adverse clinical course. The administration of adjuvant chemotherapy is recommended only in certain high-risk situations. However, these risk factors recently failed to predict benefit from adjuvant therapy. We composed a new morphology-based risk score that includes pT1/2 versus 3/4 stage, vascular or lymphovascular invasion, invasion type according to Jass, tumor budding and paucity (less than two) of lymph nodes larger than 5 mm. The occurrence of each of these factors accounts for one point in the score (Range 0-5). This score was evaluated in a retrospective study that included 301 cases. The overall survival differed significantly between the three groups with median survival times of 103, 90, and 48 months, respectively. Multivariable analysis revealed morphology-based risk-high risk and low risk-as the sole independent factors for the prediction of death. Morphology-based risk scoring was superior to microsatellite status and NCCN risk stratification. This method identifies a group of patients that comprises 18% of the stage II cases with an adverse clinical course. Further studies are necessary to confirm its prognostic value and the possible therapeutic consequences.

Lymph node hypoplasia is associated with adverse outcomes in node-negative colon cancer using advanced lymph node dissection methods.

PURPOSE: Lymph node size as a prognostic parameter has not been investigated well in the past. Recent data, however, have indicated that this parameter could be even more important than the lymph node count. METHODS: Based on the results of earlier studies, we analyzed the lymph node size and number of node-negative colon cancer patients with regard to survival. Data from 115 node-negative cases of colon cancer were analyzed. Lymph nodes with diameters ≤5 mm were defined as small, and all other lymph nodes were classified as intermediate/large in size and labeled LN5. All of the cases were categorized according to the number of LN5s. The LN5 very low (LN5vl) group included cases with less than two LN5s. All of the other cases were assigned to the LN5 low/high (LN5l/h) group. RESULTS: The overall survival analysis revealed significantly worse outcomes for the LN5vl group, with a mean survival of 34 months compared to the LN5l/h group, with a mean survival of 40 months (P = 0.022). After adjusting for the pT1/2 and pT3/4 stages, we still found a significant outcome difference (P = 0.012). Multivariate analysis identified LN5vl and T-stage as being independently correlated with the outcome. The vast majority of LN5vl cases (91 %) were located in the left colon. The location itself, however, was not prognostic (P = 0.478). CONCLUSION: LN5 count, as a marker of immune response, could be shown as being prognostic in node-negative colon cancer. Patients with low LN5 counts showed poor outcomes. These patients could perhaps profit from adjuvant chemotherapy.

Transatrial antegrade approach for double mitral and tricuspid "valve-in-ring" implantation.

Within the last 5 years, the number of transcatheter aortic valve implantation (TAVI) procedures has increased continuously and, in parallel, the indications for TAVI have expanded (eg, failing surgical valves and rings). Furthermore, alternative TAVI access routes such as transaxillary and transaortic have been applied successfully. We report on, to our knowledge, the first-in-human case of a combined off-pump antegrade transatrial implantation of a transcatheter valve within a mitral and tricuspid annuloplasty ring through an anterolateral minithoracotomy. The patient showed severe mitral valve and tricuspid valve stenosis and regurgitation 15 years after mitral valve repair and 7 years after aortic valve replacement and tricuspid valve repair.

Effects of respiratory mechanics on the capnogram phases: importance of dynamic compliance of the respiratory system.

INTRODUCTION: The slope of phase III of the capnogram (SIII) relates to progressive emptying of the alveoli, a ventilation/perfusion mismatch, and ventilation inhomogeneity. S(III) depends not only on the airway geometry, but also on the dynamic respiratory compliance (Crs); this latter effect has not been evaluated. Accordingly, we established the value of SIII for monitoring airway resistance during mechanical ventilation. METHODS: Sidestream capnography was performed during mechanical ventilation in patients undergoing elective cardiac surgery (n = 144). The airway resistance (Raw), total respiratory resistance and Crs displayed by the ventilator, the partial pressure of arterial oxygen (PaO2) and S(III) were measured in time domain (S(T-III)) and in a smaller cohort (n = 68) by volumetry (S(V-III)) with and without normalization to the average CO2 phase III concentration. Measurements were performed at positive end-expiratory pressure (PEEP) levels of 3, 6 and 9 cmH2O in patients with healthy lungs (Group HL), and in patients with respiratory symptoms involving low (Group LC), medium (Group MC) or high Crs (Group HC). RESULTS: S(T-III) and S(V-III) exhibited similar PEEP dependencies and distribution between the protocol groups formed on the basis of Crs. A wide interindividual scatter was observed in the overall Raw-S(T-III) relationship, which was primarily affected by Crs. Decreases in Raw with increasing PEEP were reflected in sharp falls in S(III) in Group HC, and in moderate decreases in S(III) in Group MC, whereas S(T-III) was insensitive to changes in airway caliber in Groups LC and HL. CONCLUSIONS: SIII assessed in the time domain and by volumetry provide meaningful information about alterations in airway caliber, but only within an individual patient. Although S(T-III) may be of value for bedside monitoring of the airway properties, its sensitivity depends on Crs. Thus, assessment of the capnogram shape should always be coupled with Crs when the airway resistance or oxygenation are evaluated.