Relationship between the transcriptional expression of PIM1 and local control in patients with head and neck squamous cell carcinomas treated with radiotherapy

Altres ajuts: Acord transformatiu CRUE-CSIC 10.1007/s00405-021-07223-4Purpose Proviral integration site for Moloney murine leukemia virus (PIMs) are proto-oncogenes encoding serine/threonine kinases that phosphorylate a variety of substrates involved in the regulation of cellular processes. Elevated expression of PIM-1 has been associated with poor prognosis in several types of cancer. There are no studies that have analyzed the response to radiotherapy in patients with head and neck squamous cell carcinoma (HNSCC) according to the expression of PIM-1. The aim of our study was to analyze the relationship between the transcriptional expression of PIM-1 and local response to radiotherapy in HNSCC patients. Methods We determined the transcriptional expression of PIM-1 in 135 HNSCC patients treated with radiotherapy, including patients treated with chemoradiotherapy (n=65) and bioradiotherapy (n=15).Results During the follow-up, 48 patients (35.6%) had a local recurrence of the tumor. Patients with local recurrence had a higher level of PIM-1 expression than those who achieved local control of the disease (P=0.017). Five-year local recurrencefree survival for patients with a high expression of PIM-1 (n=43) was 44.6% (95% CI 29.2-60.0%), and for patients with low expression (n=92) it was 71.9% (95% CI 62.5-81.3%) (P=0.007). According to the results of multivariate analysis, patients with a high PIM-1 expression had a 2.2-fold increased risk of local recurrence (95% CI 1.22-4.10, P=0.009). Conclusion Patients with elevated transcriptional expression levels of PIM-1 had a signifcantly higher risk of local recurrence after radiotherapy

Causes of long-term mortality in patients with head and neck squamous cell carcinomas

Altres ajuts: Acord transformatiu CRUE-CSICPurpose: After treatment of a head and neck squamous cell carcinoma (HNSCC), patients with an adequate control of the tumor have a decreased overall survival when compared to age- and gender-matched controls in the general population. The aim of our study was to analyze the causes of long-term mortality in patients with HNSCC. Methods: We carried out a retrospective study of 5122 patients with an index HNSCC treated at our center between 1985 and 2018. We analyzed the survival considering three causes of death: mortality associated with the HNSCC index tumor, mortality associated with a second or successive neoplasm, and mortality associated with a non-cancer cause. Results: After the diagnosis of an HNSCC the most frequent cause of death is the head and neck tumor itself during the first 3.5 years of follow-up. Thereafter, mortality is more frequently associated with competing causes of death, such as second malignancies and non-cancer causes. Mortality associated with second and successive neoplasms was 2.3% per year, a percentage that was maintained constant throughout the follow-up. Likewise, mortality attributable to non-cancer causes was 1.6% per year, which also remained constant. There were differences in the mortality patterns according to the characteristics of the patients. Conclusion: There are differences in the mortality patterns of patients with HNSCC depending on their characteristics. Knowledge of these patterns can help in the design of guidelines to improve the follow-up protocols of this group of patients to optimize the clinical cost-effectiveness

Case report : De novo pathogenic variant in WFS1 causes Wolfram-like syndrome debuting with congenital bilateral deafness

Background: Congenital deafness could be the first manifestation of a syndrome such as in Usher, Pendred, and Wolfram syndromes. Therefore, a genetic study is crucial in this deficiency to significantly improve its diagnostic efficiency, to predict the prognosis, to select the most adequate treatment required, and to anticipate the development of other associated clinical manifestations. Case presentation: We describe a young girl with bilateral congenital profound deafness, who initially received a single cochlear implant. The genetic study of her DNA using a custom-designed next-generation sequencing (NGS) panel detected a de novo pathogenic heterozygous variant in the WFS1 gene related to Wolfram-like syndrome, which is characterized by the presence of other symptoms such as optic atrophy. Due to this diagnosis, a second implant was placed after the optic atrophy onset. The speech audiometric results obtained with both implants indicate that this work successfully allows the patient to develop normal speech. Deterioration of the auditory nerves has not been observed. Conclusion: The next-generation sequencing technique allows a precise molecular diagnosis of diseases with high genetic heterogeneity, such as hereditary deafness, while this was the only symptom presented by the patient at the time of analysis. The NGS panel, in which genes responsible for both syndromic and non-syndromic hereditary deafness were included, was essential to reach the diagnosis in such a young patient. Early detection of the pathogenic variant in the WFS1 gene allowed us to anticipate the natural evolution of the disease and offer the most appropriate management to the patient

"The Accessory Ethmoidal Canal Does Not Necessarily Contain an Arterial Structure"

Introduction: The aim of our study is to describe the prevalence of the accessory ethmoidal artery in endonasal endoscopic cadaver dissections and to identify its intraorbital origin. Material and Methods: From 2018 to 2020, thirty-four nasal dissections were performed in seventeen adult cadaveric heads. We performed a complete ethmoidectomy to identify the ethmoidal canals. Then, we removed the bony canal and the lamina papiracea to verify the injected vessel and to confirm the vascular structure inside the canal. Results: We found the anterior ethmoidal canal (AEC) and the posterior ethmoidal canal (PEC) in 100% of nasal cavities (34/34). We identified 4 accessory ethmoidal canals (AcEC) in the 34 nasal fossae dissected (12%). All AEC contained an arterial vessel. The AcEC contained an arterial vascular structure in 2 cases, a neural structure in other specimen, and in the fourth case no structure could be verified. In 32 of 34 nasal cavities, the PEC contained an artery and only in 2 cases the PEC did not contain any vascular structure. In these specimens, we observed that the AcEC with an arterial vessel inside (6%) was closer to the posterior canal than the anterior canal. Conclusion: According to our findings, we can suggest that the presence of a canal does not necessarily imply the presence of an arterial vessel, and that presence of the accessory ethmoidal artery could be associated with the absence of posterior ethmoidal artery

Proposta de classificació de les parotidectomies parcials per lesions benignes de paròtide. Estudi clínic i bases anatòmiques

Introducció. Les tècniques quirúrgiques emprades en el tractament de les lesions tumorals benignes de la glàndula paròtide han evolucionat de forma important en els darrers 50 anys, essent actualment diverses i amb una nomenclatura confusa i poc clarificadora respecte a l'extensió de les reseccions dutes a terme. S’identifica per tant la necessitat de plantejar un sistema d'estandarització dels termes i nomenclatura emprats per referir-se a aquests tipus de cirurgia. La classificació "Sant Pau", que segmenta el volum glandular en nivells parotidis, és un sistema informatiu, exhaustiu, additiu i simple que permet definir l'extensió de les reseccions realitzades per aquest tipus de tumors. Objectius. La present tesi doctoral consta de dues parts: l'objectiu principal de la primera part consisteix en la caracterització anatòmica dels nivells plantejats en la classificació Sant Pau, establint-ne el seu tamany i relacions amb altres estructures, principalment el nervi facial. Els objectius principals de la segona part són determinar si exiteix una correlació entre l'extensió de les reseccions (definida a partir de la classificació Sant Pau) i les complicacions postquirúrgiques associades a aquestes tècniques, així com descriure l'evolució en l'extensió de les reseccions realitzades al llarg de les tres darreres dècades. Materials i mètodes. L'estudi anatòmic s'ha realitzat a partir de 19 disseccions en cadàver per tal de determinar les dimensions i paràmetres pertinents. L'estudi clínic s'ha realitzat a partir de l'anàlisi clínica de 248 intervencions sobre lesions tumorals benignes de paròtide, recollides en una base de dades específica de l'Hospital de la Santa Creu i de Sant Pau de Barcelona. Resultats. S'han descrit les dimensions en alçada, amplada i profunditat dels 5 nivells parotidis, així com el seu pes absolut i relatiu al pes total. El nivell II és el més voluminós, representant el 40-50% del total, seguit dels nivells I i III que suposen al voltant del 20%. Exceptuant les branques bucals, les branques temporofacials es situen sempre entre els nivells cranials, mentre que les branques cervicofacials es situen sempre entre els nivells caudals. Les branques bucals es poden situar entre els nivells cranials, caudals o be entre ambdós. El pla de ramificació del nervi facial és superficial al pla venós en un 73,7 % de les disseccions. El conducte de Stensen es situa sempre més caudal que el tronc del nervi facial. S'ha observat com algunes complicacions postoperatories, com la disfunció del nervi facial, els defectes estètics i l'aparició d'hematomes, presenten una correlació estadísiticament significativa amb la extensió resecada quan aquesta es codifica o defineix a partir del nombre de nivells resecats (Classificació de Sant Pau). Altres complicacions com la formació de seromes o les parestesies del pabelló auricular no han presentat una correlació amb la extensió resectiva. Conclusions. S'han establert els valors mitjos de les dimensions i pesos absoluts, així com el tamany relatiu dels diferents nivells proposats en la classificació. També s'han determinat les relacions d'aquests nivells amb les ramificacions del nervi facial i altres estructures relacionades amb la glàndula. En l'aspecte clínic, s'observa com les indicacións parcials o limitades a un sol nivell (parotidectomies parcials) han augmentat en les darreres dues dècades. S'ha pogut observar una relació entre l'aparició de certes complicacions i seqüeles postquirúrgiques i l'extensió de les parotidectomies quan aquestes es classifiquen segons els nivells parotidis resecats.Introduction. Surgical techniques used in the treatment of benign tumoral lesions of the parotid gland have evolved significantly over the past 50 years, being at the moment quite diverse and named under a confusing nomenclature that does not help in clarifying the extent of resection carried out. The need for a system of standardization of the terminology and nomenclature used to refer to these types of surgery is therefore identified. The "Sant Pau classification", which segments the parotid gland volume in different levels, is an informative, comprehensive and simple system that makes it possible to define the extent of the resections performed for these types of tumours.   Objectives. The present doctoral thesis has two parts: the main objective of the first part consists in the anatomical characterization of the levels defined in the Sant Pau classification, describing its size and relationships with other structures, mainly the facial nerve. Two objectives of the second part are to correlate the extension of the resections defined with the "Sant Pau classification" with the surgical complications and sequelae associated with these techniques, as well as to observe the evolution of the extent of resection carried out over the past three decades.   Materials and methods. The anatomical study was carried out in 19 cadaver dissections in order to determine the dimensions and relevant parameters. The clinical outcome has been carried out from the clinical analysis of 248 interventions on benign tumours of parotid lesions, with data collected in a specific database of the Hospital de la Santa Creu and Sant Pau in Barcelona.   Results. The dimensions in height, width and depth of the 5 parotid levels have been described, as well as their absolute weight relative to the total weight. Level II is the most bulky, representing 40-50% of the total, followed by the levels I and III that account for around 20%. Except buccal branches, the temporofacial branches are always located between the cranial levels, while the cervicofacial branches are always located between the caudal levels. The buccal branches can be placed between the cranial levels, caudal levels or between both. The facial nerve branching plane is superficial to the venous plane in 73,7% of the disections. Stensen's duct is always found caudal to the facial nerve trunk. It has been observed how some postoperative complications, such as dysfunction of the facial nerve, aesthetic defects and post-surgical haematoma, present a statistically significant correlation with the resected extension, when this is coded or defined as number of resected levels (Sant Pau Classification). Other complications such as serome formation or auricular paraesthesiae have not presented a correlation with the resective extension.   Conclusions. The average values for the absolute dimensions and weights have been established, as well as the relative size of the different levels proposed in the classification. The relationships of these levels with the ramifications of the facial nerve and other structures related to the gland have been described. In the clinical aspect, it has been observed an increase in the indication of partial resections or those limited to one level (partial parotidectomies) in the last two decades. We observed a relationship between the appearance of some postoperative complications and sequelae and the extension of the parotidectomies when these are classified by the number of parotid levels resected

Proposta de classificació de les parotidectomies parcials per lesions benignes de paròtide. Estudi clínic i bases anatòmiques

Introducció. Les tècniques quirúrgiques emprades en el tractament de les lesions tumorals benignes de la glàndula paròtide han evolucionat de forma important en els darrers 50 anys, essent actualment diverses i amb una nomenclatura confusa i poc clarificadora respecte a l'extensió de les reseccions dutes a terme. S’identifica per tant la necessitat de plantejar un sistema d'estandarització dels termes i nomenclatura emprats per referir-se a aquests tipus de cirurgia. La classificació "Sant Pau", que segmenta el volum glandular en nivells parotidis, és un sistema informatiu, exhaustiu, additiu i simple que permet definir l'extensió de les reseccions realitzades per aquest tipus de tumors. Objectius. La present tesi doctoral consta de dues parts: l'objectiu principal de la primera part consisteix en la caracterització anatòmica dels nivells plantejats en la classificació Sant Pau, establint-ne el seu tamany i relacions amb altres estructures, principalment el nervi facial. Els objectius principals de la segona part són determinar si exiteix una correlació entre l'extensió de les reseccions (definida a partir de la classificació Sant Pau) i les complicacions postquirúrgiques associades a aquestes tècniques, així com descriure l'evolució en l'extensió de les reseccions realitzades al llarg de les tres darreres dècades. Materials i mètodes. L'estudi anatòmic s'ha realitzat a partir de 19 disseccions en cadàver per tal de determinar les dimensions i paràmetres pertinents. L'estudi clínic s'ha realitzat a partir de l'anàlisi clínica de 248 intervencions sobre lesions tumorals benignes de paròtide, recollides en una base de dades específica de l'Hospital de la Santa Creu i de Sant Pau de Barcelona. Resultats. S'han descrit les dimensions en alçada, amplada i profunditat dels 5 nivells parotidis, així com el seu pes absolut i relatiu al pes total. El nivell II és el més voluminós, representant el 40-50% del total, seguit dels nivells I i III que suposen al voltant del 20%. Exceptuant les branques bucals, les branques temporofacials es situen sempre entre els nivells cranials, mentre que les branques cervicofacials es situen sempre entre els nivells caudals. Les branques bucals es poden situar entre els nivells cranials, caudals o be entre ambdós. El pla de ramificació del nervi facial és superficial al pla venós en un 73,7 % de les disseccions. El conducte de Stensen es situa sempre més caudal que el tronc del nervi facial. S'ha observat com algunes complicacions postoperatories, com la disfunció del nervi facial, els defectes estètics i l'aparició d'hematomes, presenten una correlació estadísiticament significativa amb la extensió resecada quan aquesta es codifica o defineix a partir del nombre de nivells resecats (Classificació de Sant Pau). Altres complicacions com la formació de seromes o les parestesies del pabelló auricular no han presentat una correlació amb la extensió resectiva. Conclusions. S'han establert els valors mitjos de les dimensions i pesos absoluts, així com el tamany relatiu dels diferents nivells proposats en la classificació. També s'han determinat les relacions d'aquests nivells amb les ramificacions del nervi facial i altres estructures relacionades amb la glàndula. En l'aspecte clínic, s'observa com les indicacións parcials o limitades a un sol nivell (parotidectomies parcials) han augmentat en les darreres dues dècades. S'ha pogut observar una relació entre l'aparició de certes complicacions i seqüeles postquirúrgiques i l'extensió de les parotidectomies quan aquestes es classifiquen segons els nivells parotidis resecats.Introduction. Surgical techniques used in the treatment of benign tumoral lesions of the parotid gland have evolved significantly over the past 50 years, being at the moment quite diverse and named under a confusing nomenclature that does not help in clarifying the extent of resection carried out. The need for a system of standardization of the terminology and nomenclature used to refer to these types of surgery is therefore identified. The "Sant Pau classification", which segments the parotid gland volume in different levels, is an informative, comprehensive and simple system that makes it possible to define the extent of the resections performed for these types of tumours.   Objectives. The present doctoral thesis has two parts: the main objective of the first part consists in the anatomical characterization of the levels defined in the Sant Pau classification, describing its size and relationships with other structures, mainly the facial nerve. Two objectives of the second part are to correlate the extension of the resections defined with the "Sant Pau classification" with the surgical complications and sequelae associated with these techniques, as well as to observe the evolution of the extent of resection carried out over the past three decades.   Materials and methods. The anatomical study was carried out in 19 cadaver dissections in order to determine the dimensions and relevant parameters. The clinical outcome has been carried out from the clinical analysis of 248 interventions on benign tumours of parotid lesions, with data collected in a specific database of the Hospital de la Santa Creu and Sant Pau in Barcelona.   Results. The dimensions in height, width and depth of the 5 parotid levels have been described, as well as their absolute weight relative to the total weight. Level II is the most bulky, representing 40-50% of the total, followed by the levels I and III that account for around 20%. Except buccal branches, the temporofacial branches are always located between the cranial levels, while the cervicofacial branches are always located between the caudal levels. The buccal branches can be placed between the cranial levels, caudal levels or between both. The facial nerve branching plane is superficial to the venous plane in 73,7% of the disections. Stensen's duct is always found caudal to the facial nerve trunk. It has been observed how some postoperative complications, such as dysfunction of the facial nerve, aesthetic defects and post-surgical haematoma, present a statistically significant correlation with the resected extension, when this is coded or defined as number of resected levels (Sant Pau Classification). Other complications such as serome formation or auricular paraesthesiae have not presented a correlation with the resective extension.   Conclusions. The average values for the absolute dimensions and weights have been established, as well as the relative size of the different levels proposed in the classification. The relationships of these levels with the ramifications of the facial nerve and other structures related to the gland have been described. In the clinical aspect, it has been observed an increase in the indication of partial resections or those limited to one level (partial parotidectomies) in the last two decades. We observed a relationship between the appearance of some postoperative complications and sequelae and the extension of the parotidectomies when these are classified by the number of parotid levels resected

Proposta de classificació de les parotidectomies parcials per lesions benignes de paròtide : estudi clínic i bases anatòmiques /

Introducció. Les tècniques quirúrgiques emprades en el tractament de les lesions tumorals benignes de la glàndula paròtide han evolucionat de forma important en els darrers 50 anys, essent actualment diverses i amb una nomenclatura confusa i poc clarificadora respecte a l'extensió de les reseccions dutes a terme. S'identifica per tant la necessitat de plantejar un sistema d'estandarització dels termes i nomenclatura emprats per referir-se a aquests tipus de cirurgia. La classificació "Sant Pau", que segmenta el volum glandular en nivells parotidis, és un sistema informatiu, exhaustiu, additiu i simple que permet definir l'extensió de les reseccions realitzades per aquest tipus de tumors. Objectius. La present tesi doctoral consta de dues parts: l'objectiu principal de la primera part consisteix en la caracterització anatòmica dels nivells plantejats en la classificació Sant Pau, establint-ne el seu tamany i relacions amb altres estructures, principalment el nervi facial. Els objectius principals de la segona part són determinar si exiteix una correlació entre l'extensió de les reseccions (definida a partir de la classificació Sant Pau) i les complicacions postquirúrgiques associades a aquestes tècniques, així com descriure l'evolució en l'extensió de les reseccions realitzades al llarg de les tres darreres dècades. Materials i mètodes. L'estudi anatòmic s'ha realitzat a partir de 19 disseccions en cadàver per tal de determinar les dimensions i paràmetres pertinents. L'estudi clínic s'ha realitzat a partir de l'anàlisi clínica de 248 intervencions sobre lesions tumorals benignes de paròtide, recollides en una base de dades específica de l'Hospital de la Santa Creu i de Sant Pau de Barcelona. Resultats. S'han descrit les dimensions en alçada, amplada i profunditat dels 5 nivells parotidis, així com el seu pes absolut i relatiu al pes total. El nivell II és el més voluminós, representant el 40-50% del total, seguit dels nivells I i III que suposen al voltant del 20%. Exceptuant les branques bucals, les branques temporofacials es situen sempre entre els nivells cranials, mentre que les branques cervicofacials es situen sempre entre els nivells caudals. Les branques bucals es poden situar entre els nivells cranials, caudals o be entre ambdós. El pla de ramificació del nervi facial és superficial al pla venós en un 73,7 % de les disseccions. El conducte de Stensen es situa sempre més caudal que el tronc del nervi facial. S'ha observat com algunes complicacions postoperatories, com la disfunció del nervi facial, els defectes estètics i l'aparició d'hematomes, presenten una correlació estadísiticament significativa amb la extensió resecada quan aquesta es codifica o defineix a partir del nombre de nivells resecats (Classificació de Sant Pau). Altres complicacions com la formació de seromes o les parestesies del pabelló auricular no han presentat una correlació amb la extensió resectiva. Conclusions. S'han establert els valors mitjos de les dimensions i pesos absoluts, així com el tamany relatiu dels diferents nivells proposats en la classificació. També s'han determinat les relacions d'aquests nivells amb les ramificacions del nervi facial i altres estructures relacionades amb la glàndula. En l'aspecte clínic, s'observa com les indicacións parcials o limitades a un sol nivell (parotidectomies parcials) han augmentat en les darreres dues dècades. S'ha pogut observar una relació entre l'aparició de certes complicacions i seqüeles postquirúrgiques i l'extensió de les parotidectomies quan aquestes es classifiquen segons els nivells parotidis resecats.Introduction. Surgical techniques used in the treatment of benign tumoral lesions of the parotid gland have evolved significantly over the past 50 years, being at the moment quite diverse and named under a confusing nomenclature that does not help in clarifying the extent of resection carried out. The need for a system of standardization of the terminology and nomenclature used to refer to these types of surgery is therefore identified. The "Sant Pau classification", which segments the parotid gland volume in different levels, is an informative, comprehensive and simple system that makes it possible to define the extent of the resections performed for these types of tumours. Objectives. The present doctoral thesis has two parts: the main objective of the first part consists in the anatomical characterization of the levels defined in the Sant Pau classification, describing its size and relationships with other structures, mainly the facial nerve. Two objectives of the second part are to correlate the extension of the resections defined with the "Sant Pau classification" with the surgical complications and sequelae associated with these techniques, as well as to observe the evolution of the extent of resection carried out over the past three decades. Materials and methods. The anatomical study was carried out in 19 cadaver dissections in order to determine the dimensions and relevant parameters. The clinical outcome has been carried out from the clinical analysis of 248 interventions on benign tumours of parotid lesions, with data collected in a specific database of the Hospital de la Santa Creu and Sant Pau in Barcelona. Results. The dimensions in height, width and depth of the 5 parotid levels have been described, as well as their absolute weight relative to the total weight. Level II is the most bulky, representing 40-50% of the total, followed by the levels I and III that account for around 20%. Except buccal branches, the temporofacial branches are always located between the cranial levels, while the cervicofacial branches are always located between the caudal levels. The buccal branches can be placed between the cranial levels, caudal levels or between both. The facial nerve branching plane is superficial to the venous plane in 73,7% of the disections. Stensen's duct is always found caudal to the facial nerve trunk. It has been observed how some postoperative complications, such as dysfunction of the facial nerve, aesthetic defects and post-surgical haematoma, present a statistically significant correlation with the resected extension, when this is coded or defined as number of resected levels (Sant Pau Classification). Other complications such as serome formation or auricular paraesthesiae have not presented a correlation with the resective extension. Conclusions. The average values for the absolute dimensions and weights have been established, as well as the relative size of the different levels proposed in the classification. The relationships of these levels with the ramifications of the facial nerve and other structures related to the gland have been described. In the clinical aspect, it has been observed an increase in the indication of partial resections or those limited to one level (partial parotidectomies) in the last two decades. We observed a relationship between the appearance of some postoperative complications and sequelae and the extension of the parotidectomies when these are classified by the number of parotid levels resected

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien\u2013Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9\ub72 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4\u20137) and 7 (6\u20138) days respectively (P < 0\ub7001). There were no significant differences in rates of readmission between these groups (6\ub76 versus 8\ub70 per cent; P = 0\ub7499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0\ub790, 95 per cent c.i. 0\ub755 to 1\ub746; P = 0\ub7659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34\ub77 versus 39\ub75 per cent; major 3\ub73 versus 3\ub74 per cent; P = 0\ub7110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients