[Complications after pulmonary segmentectomy: Impact of the surgical approach]. / Influence de la voie d'abord chirurgicale sur les suites opératoires après segmentectomie pulmonaire.

INTRODUCTION: Pulmonary segmentectomy is becoming increasingly widespread but remains technically challenging. The aim of this study was to evaluate the impact of the surgical approach applied on postoperative complications after pulmonary segmentectomy. METHODS: All patients having undergone pulmonary segmentectomy by thoracotomy, videothoracoscopy or robot-assisted surgery from 1st January 2018 to 31st December 2021 were included. The primary endpoint was the occurrence of postoperative complications. Secondary endpoints were operative time, length of hospital stay, 30-day readmission rate, 30-day and 90-day mortality. RESULTS: Two hundred and twenty-three patients were included, 30% (n=67) in the thoracotomy group, 9.4% (n=21) in the videothoracoscopy group and 60.5% (n=135) in the robot-assisted surgery group. There was no difference in the occurrence of postoperative complications according to type of approach (P=0.564), 26.9% of patients (n=60) had at least one postoperative complication. There was no significant difference between the groups in terms of operative time (P=0.385), length of hospital stay (P=0.107), 30 and 90-day mortality (P=0.124 and P=0.249, respectively). Mini-invasive surgery significantly reduced the 30-day readmission rate (P=0.049). CONCLUSION: The surgical approach applied does not influence the postoperative complications of pulmonary segmentectomy.

Significant decrease of facial cellulitis admissions during COVID-19 lockdown in France: A multicentric comparative study.

During the 2020 coronavirus pandemic, a lockdown was imposed in France during the first wave. An apparent decrease in incidence of cellulitis of odontogenic origin was noticed then. This study aimed to compare the incidence of cellulitis during this extraordinary period with the same period in 2018 and 2019, based on retrospective multicentric data. All maxillofacial surgery departments in French public hospitals were contacted. Responders were asked to include all patients admitted for the surgical drainage of a head and neck abscess of odontogenic origin during the first 2020 lockdown period, and in a similar time frame in 2018 and 2019 (control group), based on screening the French diagnostic and therapeutic classification of medical acts. We report a 44% significant nationwide decrease in the incidence of admissions for cellulitis. There were 187 patients in 2020 for 334 and 333 patients in 2018/2019 respectively. The reasons to explain this finding are hypothetical (organizational reasons leading to earlier management, patients' fear to seek for medical management, usual excess in surgical indications or concomitant decrease of non-steroidal anti-inflammatory drugs delivery). Whatever the explanation, it would be of great interest to find it out in order to improve the prevention of cellulitis.

[Readmissions after lung resection in France: The PMSI database]. / Les réadmissions après résection pulmonaire en France : la base de données du PMSI.

BACKGROUND: Readmission within 30 days is an indicator of the quality of care, because it often reflects post-discharge care that is not optimal. The objective of this work is to measure over time on the one hand the readmission rate and on the other hand the number of hospitals with a standardized readmission rate beyond the national average. METHOD: All patients with major pulmonary resection for lung cancer in France were extracted from the PMSI national database. Readmission within 30 days was defined as any new hospitalization either in the same hospital or in another establishment. RESULTS: From January 1, 2005 to December 31, 2018, 110,603 patients were included. The 30-day all-cause readmissions rate was 24.9% (n=27,540). Patients after pneumonectomy had a readmission rate of 37% (n=4918) and 23% after lobectomy (n=2684) (P<0.0001). For the first period, we counted 10 hospitals with a standardized readmissions rate above the 99.8 limit and 10 hospitals above the 95% limit. For the second period, 8 hospitals had a standardized readmission rate above the 99.8% limit and 11 hospitals above the 95% limit. For the third period, 7 hospitals had a standardized readmission rate above the 99.8% limit and 6 hospitals above the 95% limit. CONCLUSION: Readmissions to hospital 30 days after major lung resection for cancer in France declined little during these three periods. Measures to prevent readmissions should be introduced.

Next generation sequencing in bleeding disorders: two novel variants in the F5 gene (Valencia-1 and Valencia-2) associated with mild factor V deficiency.

Inherited bleeding coagulation disorders (IBCDs) have a powerful diagnostic tool in next generation sequencing (NGS) that not only offers confirmation of diagnosis but also aids in genetic counselling, prenatal diagnosis and helps to predict the clinical course and follow-up of a disease. In our group, targeted-NGS using a Custom SureSelect QXT Panel (Agilent Technologies, Inc., Santa Clara, CA, USA) was designed to screen for causal variants in 40 genes related with the coagulation cascade. In this work, we used NGS for screening all the coding and intronic boundary regions of F5 gene in two patients affected by factor V (FV) deficiency (parahemophilia). Two new mutations were found: c.4745A>G (p.Tyr1582Cys, NM_000130.4) and c.1999_2002dupAATT (p.Ser668ter; NM_000130.4), both located in exon 13 of the F5 gene. We designated them Valencia-1 and Valencia-2 respectively. Valencia-1 could provoke loss of the fifth cupredoxin domain of the FV, and would be responsible for its defective activity. Valencia-2 prematurely stops the translation of mRNA, resulting in a truncated FV protein which lacks completely the B domain and the light chain. NGS has permitted to describe an increasing number of FV deficiency-causing mutations and a better understanding of FV's structure and function. The description of deficiency-causing mutations will continue to increase our knowledge of the functional residues of FV, as well as those which are involved in the correct folding of the protein. In this sense, NGS is a useful tool for studying IBCDs, as permits studying the whole coagulation cascade at once and gives a global view of the patient's genetic background.

[Skin shrinkage study for skin oncologic surgery. Clinical study of 79 cases]. / Étude de la rétraction cutanée en chirurgie carcinologique cutanée. Étude clinique de 79 cas.

BACKGROUND: Skin tumors surgery is common and well established. There is discrepancy between recommendations on macroscopic margins to apply and therapeutic decisions taken on histological margins. The purpose of this study is to examine skin shrinkage upon exeresis, then in formalin, to understand the anatomo-clinical discrepancy, which is often found. MATERIAL AND METHODS: It was a prospective study, lasting a month, including patients receiving skin surgery. For each tumor, the surgeon carried out 4 margins measurements before and after exeresis ; margins measured again in histology. The evaluation criterion was the difference between preoperative, postoperative and histological margins measurement. These data was weighting according to factors linked to the patient and the tumor. RESULTS: Seventy-nine tumors for 61 patients had been studied. The study showed a significant shrinkage between preoperative measurements and postoperative, from 0.4 to 0.6mm. It is correlated with no one tested factors. Significant shrinkage between 0.4 and 0.5mm was also established between preoperative and histological measurements. However, there is a significant augmentation between postoperative and histological measurements. CONCLUSION: This last result could be linked to the inflammatory peri-wound skin that surgeon consider as tumoral process so exclude of his margin, while histology could show a healthy area. In front of these results, an expert committee leading a more important study could include histological margins recommendations to the actual clinical recommendations.

[Posttraumatic enophthalmos correction by bone graft: Why the unpredictable results?]. / Correction de l'énophtalmie post-traumatique par greffe osseuse: pourquoi des résultats inconstants?

PURPOSE OF THE STUDY: Posttraumatic enophthalmos cause complex cosmetic problems to fix. In order to get better results, we wanted to calculate the volume of parietal bone graft needed to be put in place, know where to place it in orbit and study soft tissues' participation. PATIENTS AND METHOD: In a retrospective study, we have calculated on scanner the volume of bone and soft tissue as well as the volume and the location of the graft. We have compared, between two groups ("good result" and "insufficient result"), graft volumes, taking into account differences in bone's volume between the healthy and the traumatized orbit. A comparison of the locations of the graft was also made. We were trying to find out if these factors were involved in the quality of the result. RESULTS: Twenty-nine surgeries on 24 patients were analyzed. The average bone's volume of an orbit with enophthalmos was 24.76 cm(3) for 17.12 cm(3) of soft tissue. Retro-lens distance was the most reliable measurement method of enophthalmos (P=0.001). There was a trend to a more substantial over-correction in the group "good result". A significant increase (P=0.0008) of soft tissue volumes in the traumatized orbit was found. CONCLUSION: This last result is surprising. Many authors believe that there is a scar retraction of soft tissues. But Kronish et al. showed an increase of the fat density and connective tissue. This, together with the assumption of a weathering of the ligament suspension of the globe, may affect our aesthetic results. MRI, ultrasound and anatomopathological studies would allow a better understanding of the fat, muscle and ligament pathophysiologies of an orbit with enophthalmos.

Inhibitor development after switching of FVIII concentrate in multitransfused patients with severe haemophilia A.

Switching between different therapeutic FVIII concentrate types has been postulated as a possible cause of inhibitor development in patient with haemophilia A. In this single-centre, retrospective study, the incidence, titre and duration of inhibitor development in multitransfused patients, defined as patients with more than 150 exposure days (ED), were analysed from January 1970 to December 2007 in relation to ED and the number of switches between different products. Inhibitor titre was assessed by Bethesda assay (before 1998) or Nijmegen assay (after 1998). Medical records of 167 patients were screened, of which 97 patients met the inclusion criteria. Fourteen products of plasmatic origin (different purities) and five recombinant (three generations) were used. Nine patients (9%) developed inhibitors, all transient, low-titre (1.41 ± 0.54 BU) after 323 ± 287 ED in average. Seventeen patients had no product switches of which four patients (23%) developed inhibitors (97 ED in average), whereas 13 patients (77%) did not (ED: 230). Fifty patients switched between plasmatic products only (median: 10 changes) of which five patients (10%) developed inhibitors (ED: 503), whereas 45 patients did not (ED: 932). Five patients switched between recombinant products only (seven changes) of which no patient developed inhibitors (748 ED). Twenty-five patients switched between plasmatic and recombinant products (13 changes) of which no patient developed inhibitors (ED: 1654). No statistically significant differences between patient groups were observed. Neither the number of different FVIII products administered nor the switching of products influenced the incidence of inhibitor in multitransfused patients.

[Myoepithelial carcinoma of the lacrimal gland]. / Le carcinome myoépithélial de la glande lacrymale.

INTRODUCTION: Myoepithelial carcinomas are unusual tumors most often located in salivary glands. It is very rarely located in lacrimal glands; only 5 cases have been reported. We report a sixth case. OBSERVATION: An 88-year-old male patient presented with diplopia, painless right sided exophthalmia, as well as eyeball deviation due to a tumor located at upper external quadrant of the orbit. A biopsy initially suggested a sarcoma. The pathological analysis of the biopsy allowed diagnosing a myoepithelial carcinoma of the lacrimal gland. Despite the monoblock resection of the tumor, a recurrence was observed 3 months after removal. The patient died 8 months after the initial surgery. DISCUSSION: This case illustrates the clinical and pathological characteristics of a myoepithelial carcinoma. This tumor has a high grade of malignancy, and is very rarely described in lacrimal glands. The morphological diagnosis of this tumor is difficult with a problematic differential diagnosis with fusiform cells sarcomas (leiomyosarcoma, undifferentiated sarcoma), and epithelial-myoepithelial carcinoma.

Secondary prophylaxis vs. on-demand treatment to improve quality of life in severe adult haemophilia A patients: a prospective study in a single centre.

BACKGROUND: Retrospective publications show a decrease in the bleeding frequency and an improvement in the quality of life (QoL) in severe adult haemophilia A (SAHA) after switching from the on-demand treatment (DT) to secondary prophylaxis (SP). But there are no prospective studies which demonstrate, using a haemophilia-specific questionnaire, an improvement in the QoL after such treatment change. The main objective of this study is to prospectively compare the QoL and the musculoskeletal assessment after switching from DT to SP in SAHA using the A36 Hemofilia-QoL(®) . As secondary objective, we compare the haemarthrosis frequency and factor VIII consumption in DT and SP during a similar period of time (12 months) after switching. MATERIALS AND METHODS: We have designed a prospective study including SAHA who have been under DT and were changed to a protocol, which combines SP (biweekly administration of factor VIII) with individualized physiotherapy programme. RESULTS: Twelve months after switching to SP, the QoL was significantly improved (P = 0·005). Musculoskeletal assessment of pathologic irreversible joints and joints with a reversible alteration was generally improved, although in only a few joints, this improvement was statistically significant. Haemarthrosis was strongly reduced (12·60-1·42, P < 0·001). CONCLUSIONS: This prospective study has demonstrated a statistically significant improvement in the QoL after 1 year from switching patients from DT to SP. The musculoskeletal assessment after 1 year was maintained similar or slightly improved. When we compared retrospective DT and prospective SP, haemarthrosis where strongly reduced requiring a slight increase in the consumption of factor VIII concentrates.

Comparison of a new chemiluminescent immunoassay for von Willebrand factor activity with the ristocetin cofactor-induced platelet agglutination method.

Measuring von Willebrand factor (VWF) activity is essential for the diagnosis of von Willebrand disease (VWD). The VWF activity is usually assessed based on measurement of the ristocetin cofactor (VWF:RCo). However, that test is technically challenging and has high intra- and inter-assay variabilities. A new automated chemiluminescent immunoassay VWF activity has recently become commercially available (HemosIL AcuStar von Willebrand Factor Ristocetin Cofactor Activity). The main objective of this study was to evaluate this new method and to compare it with the VWF:RCo assay as the reference method. We studied 91 samples, 18 healthy volunteers samples and 73 samples from patients (VWF:RCo level <50 IU dL(-1) ): 29 type 1 VWD, 13 type 2A, 5 type 2B, 5 type 2M, 3 type 2N, 5 type 3, 4 type 3 under treatment, 5 type 3 carriers and 4 samples with other pathologies. The HemosIL AcuStar VWF:RCo assay was 96% sensitive and 100% specific for detecting VWF abnormalities. The good analytical performance, and the sensitivity and specificity of HemosIL AcuStar VWF:RCo to detect VWF deficiency renders it a suitable method for VWD screening.

Head-to-head comparison of the pharmacokinetic profiles of a high-purity factor IX concentrate (AlphaNine®) and a recombinant factor IX (BeneFIX®) in patients with severe haemophilia B.

Head-on comparative studies of factor IX (FIX) concentrates performed under standardized conditions are rarely conducted regardless of being a valuable instrument guiding health care providers towards better informed and cost-effective decisions. This study is an extension of a multicentre study that assessed the efficacy, safety and pharmacokinetics (PK) of AlphaNine(®) in 25 previously treated patients with severe haemophilia B (FIX:C ≤ 2%). After a washout period ≥ 7 days following the last PK performed with AlphaNine(®) after a dose of 65-75 IU kg(-1) , an identical PK study was performed with BeneFIX(®) on 22 of the same patients. Venous blood samples for analysis were taken at baseline and at 0.25, 0.5, 1, 3, 6, 9, 24, 48, 72 and 74 h post infusion. The outcomes of the comparison of the PK parameters were as follows: Mean (± SD) in vivo recovery (IVR) was 1.3 ± 0.4 IU dL(-1) per IU kg(-1) for AlphaNine(®) and 1.0 ± 0.3 IU dL(-1) per IU kg(-1) for BeneFIX(®) (P < 0.01). Mean terminal half-life, mean residence time, area under the curve, clearance and volume of distribution of BeneFIX(®) were 36.0 ± 12.8 h, 39.3 ± 13.9 h, 1631 ± 467 IU h dL(-1) , 0.046 ± 0.01 dL kg(-1) min(-1) and 1.75 ± 0.52 mL kg(-1) respectively. These values were not significantly different to those observed in AlphaNine(®), although BeneFIX(®) displayed higher than expected IVR values and lower than expected clearance values. In conclusion, AlphaNine(®) showed a comparable half-life, but an IVR significantly higher than that of BeneFIX(®). This dissimilarity may have implications on dosing requirements for on-demand treatment regimes affecting optimal resource allocation.

Assessment of the thrombin generation assay in haemophilia: comparative study between fresh and frozen platelet-rich plasma.

The severity of haemophilia A has traditionally been classified by the dosage of factor VIII (FVIII) by one-step coagulation tests. However, an homogeneous group of patients with similar FVIII levels show clinical heterogeneity and 10-15% of the patients classified as severe haemophilia do not have a severe bleeding phenotype. Traditional tests used for measuring FVIII are not capable of detecting other prohaemorrhagic or prothrombotic factors. Global tests as the thrombin generation assay (TGA) may detect these haemostatic factors. So TGA may be an additional tool for classifying the actual severity of haemophilia. Our group is carrying out correlation tests between FVIII and TGA in platelet-poor and -rich plasmas (PPP and PRP, respectively). PRP has the inconvenience that must be done freshly soon after blood extraction. Our aim is to study the differences between TGA performed with fresh and frozen PRP and PPP and its implementation in multicenter studies. We included 70 patients with severe haemophilia A in prophylactic treatment. Venous blood drawing was obtained prior to administration of FVIII, at the trough levels. FVIII measurement and TGA were performed in fresh and frozen PRP and PPP. The platelet absence caused a significant decrease in TGA although PPP and PRP correlated well. Frozen samples gave different results in PPP, but there were no significant differences between fresh and frozen PRP. This fact enables using frozen PRP in multicenter studies with a TGA-specialized laboratory for reclassifying haemophilia severity and for pharmacokinetic studies with TGA.

Kinetics of the interaction between anti-FVIII antibodies and FVIII from therapeutic concentrates, with and without von Willebrand factor, assessed by surface plasmon resonance.

The presence of VWF in plasma-derived FVIII (pdFVIII/VWF) products has been pointed out as a key difference with recombinant FVIII (rFVIII) products with regard to immunogenicity. A Surface Plasmon Resonance (SPR) study was designed to characterize in detail the interaction between anti-FVIII (IgGs) from a severe haemophilia A patient, and FVIII from concentrates of different sources. Full-length rFVIII (preincubated or not with purified VWF), B domain-deleted (BDD)-rFVIII and pdFVIII/VWF were analysed. To ensure reproducible conditions for accurate determination of kinetic constants, a capture-based assay format was developed using protein G surfaces for specific and reversible coupling of endogenous anti-FVIII antibodies. Concentration ranges (nm) of FVIII products tested were 9-0.03 (rFVIII) and 6-0.024 (pdFVIII/VWF). The association with antibodies was monitored for 3-5 min, whereas dissociation of the complex was followed for 5-20-240 min. A strong interaction of rFVIII and BDD-rFVIII with patient's IgG was detected with the K (D) values in the low picomolar range (5.9 ± 3.0 and 12.7 ± 6.9 pm, respectively) and very slow dissociation rates, while pdFVIII/VWF showed only marginal binding signals. The VWF complexed rFVIII displayed reduced binding signals compared with uncomplexed rFVIII, but the K (D) was still in the picomolar range (4.1 ± 1.9 pm) indicating insufficient complex formation. rFVIII, alone or bound to exogenously added VWF, showed high affinity for anti-FVIII IgGs from a severe haemophilia A patient whereas pdFVIII/VWF did not. These results are in agreement with those studies that point towards rFVIII concentrates to be more immunogenic than pdFVIII concentrates.

Is on-demand treatment effective in patients with severe haemophilia?

On-demand therapy enables stopping haemorrhages rapidly, reducing joint pain and restoring joint mobility, but does not prevent the beginning and subsequent development of haemophilic arthropathy. The main objective of this study was to identify the clinical and orthopaedic status of severe haemophilic patients with bleeding phenotype receiving on-demand treatment in Spain. We conducted an epidemiological, observational, retrospective study, recruiting 167 patients from 36 centres (92% of them with haemophilia A), median age at enrolment of 35 years. Forty per cent of the patients received a combination of on-demand and short-term prophylaxis regimen; the rest was under on-demand treatment. One hundred and forty-five patients (87%) reported at least one bleeding episode and 22 (13%) of the biologically severe patients had no bleeding phenotype. Seventy-one per cent of the studied population presented established haemophilic arthropathy, reaching 80% if we exclude patients without bleeding phenotype. Forty-three per cent of these patients had one or two joints affected, 28% of them had three or four affected joints, 20% reported five or six affected joints and 9% more than six injured joints. An increase in established haemophilic arthropathy with age was observed. Forty-six patients underwent orthopaedic surgery at least once. These data show that on-demand therapy is not effective in preventing the development of haemophilic arthropathy in severe haemophilic population with bleeding phenotype. Therefore, we suggest that the optimal treatment in these patients should be based on prophylaxis. We recommend analysing the reasons for ending prophylaxis, in case its reinstatement should be necessary.

One-stage and chromogenic FVIII:C assay discrepancy in mild haemophilia A and the relationship with the mutation and bleeding phenotype.

The discrepancy of the levels of factor VIII activity (FVIII:C) by different assays in some mild and moderate haemophilic A patients has been long known. Specific mutations affecting FVIII:C discrepancies have been described. No consensus exit as to which method most accurately represents the FVIII cofactor function in vivo and which has a better correlation with the haemorrhagic clinical expression. We studied 163 mild A haemophiliacs, and detected discrepancies in 20% of the patients, most of whom presented higher levels of FVIII:C with the one-stage assay. In nine families, the FVIII mutation was found, while three showed mutations not previously described (Leu1978Phe and Ser1791Pro associated with higher levels of FVIII:C by one-stage method; Arg1639His in a patient with low level of FVIII:C by the one-stage, but normal, chromogenic assay). Assessing the level of FVIII:C by different methods could help to learn the possible haemorrhagic expressions of patients.

[Highlights 2007 in hospital-based internal medicine: the point of view from the chief residents]. / Nouveautés en médecine interne hospitatière 2007: perspective des chefs de clinique.

In 2007, several international studies brought useful information for the daily work of internists in hospital settings. This summary is of course subjective but reflects the interests and questions of the chief residents of the Department of internal medicine who wrote this article like an original trip in medical literature. This trip will allow you to review some aspects of important fields such as heart failure, diabetes, endocarditis, COPD, and quality of care. Besides the growing diversity of the fields covered by internal medicine, these various topics underline also the uncertainty internists have to face in a practice directed towards evidence.

Inhibitors in haemophilia A: current management and open issues.

The incidence of inhibitors in haemophilia A is 21-33%. The development of inhibitors to factor VIII (FVIII) is one of the most serious complications in haemophilia therapy and is an important challenge in haemophilia care. The main short-term objective of the treatment of haemophilic patients with inhibitors is to control bleeding episodes, and the long-term one is to eradicate the inhibitor by means of immune tolerance induction (ITI). The choice of treatment for bleeding in inhibitor patients is dictated by the current inhibitor titre, the severity of the bleed and the previous anamnesic response to FVIII. In low responder inhibitor patients the best treatment is large doses of concentrates of FVIII to attain haemostatic levels of the factor infused. The same approach can also be considered in high responders who have a temporarily low inhibitor level and major haemorrhage. High responders patients with high inhibitors titre or with minor haemorrhage must be treated with bypassing agents, such as FEIBA (factor VIII inhibitor bypassing activity) or recombinant activated FVII (rVIIa); there is no agreement which of both agents should be chosen in the different clinical situations. Only in patients waiting to start ITI treatment the rFVIIa use is clearly recommended, in order to avoide an anamnesic responce. In case of failure with this agents, extracorporeal immunoadsortion may be considered. All haemophiliac children who develop an inhibitor should be considered for ITI. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda units/mL (BU ml(-1)) where possible. Starting the treatment when inhibitor titre is below 10 BU ml(-1) is the strongest predictor of success. However, there are many other points to clarify: recommended FVIII doses in the ITI; if the results can be affected by concomitant infections during ITI; if there are any differences using plasma derived or recombinant concentrates, even more if the plasma-derived concentrate contains large amounts von willebrand factor or not; age of starting the ITI and the delay in beginning it; if using immunosupresors can help in the treatment of patients with a bad prognosis; and when the treatment must be left in patients without a clear failure.