Biomedical subjects

Nicola Avenia

Publications and source records attributed to Nicola Avenia.

17 recordsLinked to original sources

PubMed2006

The role of laparoscopy in pancreatic surgery.

Carcinoma of the pancreas is extremely common, with a five-year mortality rate of about 95-99%. Radical surgery requires good technical skill and can cause complications and operative mortality, but should be avoided in patients with extrapancreatic involvement. Advances in dynamic spiral CT-scan have decreased the number of unnecessary laparotomies. VLS is indicated in cases of pancreatic mass deemed resectable or "doubtful" by CT-scan. Direct laparoscopic visualization can be combined with intraoperative laparoscopic ultrasonography (LUS), which has shown a positive predictive value of resectability of 91%. Laparoscopic pancreatoduodenectomy (LPD) shows a high rate of complications and should be performed by very well-trained surgeons. Laparoscopic distal pancreatectomy (LDP) with an "en bloc" splenectomy and spleen preservation should be performed.

Humans↗

PubMed2006

Surgical treatment of differentiated thyroid carcinoma: a retrospective study.

A retrospective study was carried out to assessed reliability of the prognostic factors (histology, age, sex, and stage), and standard procedures for the surgical treatment of differentiated thyroid cancers (DTC). From the 144 DTC cases reviewed with follow-up ranging from 1 to 25 years (m = 6.33 years), total mortality for cancer was found to be 55% (8 patients), with a predictive positive value for recurrence of 95.4% and 91.8% at 12 and 24 months, respectively. Median survival was 8.8 years (range 1 to 25 years). The multivariate analysis showed that factors such as age > 45 years, histology of intermediate malignancy, size up to 1.5 cm, and presence of metastases, significantly worsened the prognosis, regardless of the intervention that was carried out. We suggest total thyroidectomy for the treatment of benign pathologies and confirmed or suspected cases of cancer. We reserve loboisthmectomy for the treatment of benign pathologies confined to one lobe or those with FNAB suggesting a follicular neoplasm.

Adult↗

PubMed2006

Genotyping of an Italian papillary thyroid carcinoma cohort revealed high prevalence of BRAF mutations, absence of RAS mutations and allowed the detection of a new mutation of BRAF oncoprotein (BRAF(V599lns)).

OBJECTIVES: The genes RET and RAS, and more recently BRAF, have been shown to be frequently mutated in human papillary thyroid carcinomas (PTC). The aim of this study was to genotype for these mutations a cohort of thyroid tumours collected at our institutions. DESIGN AND PATIENTS: Thyroid tumours removed from 51 subjects were analysed, including 43 PTC and 8 non-PTC tumours [3 follicular adenomas (FA), 4 follicular carcinomas (FTC) and 1 anaplastic carcinoma (AC)]. MEASUREMENTS: RET/PTC1 and RET/PTC3 expression was evaluated by reverse transcriptase-polymerase chain reaction, whereas screening of BRAF (exon 15) and RAS (HRAS, KRAS2 and NRAS) mutations were performed, respectively, by single strand conformation polymorphism and denaturing high-pressure liquid chromatography. RESULTS: RET/PTC expressions was positive in 5/43 (11.6%) PTC and in none of the non-PTC tumour. Similarly, BRAF mutations were positive only in PTC, but with a higher prevalence (24/43 positives, 55.8%). All but one BRAF mutation resulted in the prototypic substitution of valine 600 with a glutamic acid. In one case, a somatic in-frame insertion of three bases at codon 599 resulted in the insertion of an additional valine. RET/PTC expression and BRAF mutations were mutually exclusive. Screening of the RAS gene allowed identification of oncogenic mutations in 1/3 (33.3%) FA and 3/4 (75%) FTC. None of the PTCs was positive for RAS. CONCLUSIONS: These data indicate that BRAF mutations are the most frequent genetic event in PTC and that RAS mutations, besides being a genetic hallmark of follicular tumours, are rare or completely absent in PTC from our area. Together, BRAF mutations and rarer RET rearrangements accounted for a genetic event in two-thirds of PTCs. This study showed a novel and presumably oncogenic mutation of BRAF, which is BRAF(V599Ins).

Adult↗

PubMed2005

Recurrent laryngeal nerve damage and phonetic modifications after total thyroidectomy: surgical malpractice only or predictable sequence?

Modifications of phonation occurring after total thyroidectomy (TT) are usually attributed to surgical malpractice, but other causes of voice impairment even in nonoperated subjects should also be taken into account. This study analyzes 208 patients who underwent TT from January 1, 1999 through December 31, 2001. Follow-up ended on December 31, 2003. Only cases in which the surgeon ruled out the possibility of operative damage to the laryngeal nerves were included. All patients underwent pre- and postoperative clinical and instrumental nose and throat examination (NTE). Preoperatively, 86 patients (41%) showed hoarseness or dysphagia: 4 (2%) monoplegia and 12 (6%) hypomobility of the vocal cords due to impaired function of the recurrent laryngeal nerve (RLN); 6 (3%) cord hypotonia due to impairment of the superior laryngeal nerve (SLN); 34 (16%) dysphagia: and 30 (14%) hoarseness due to other causes. At follow-up 1 month after surgery, 71 patients (34%) had an onset of previously absent signs and symptoms: 8 (4%) had palsy of one vocal cord (2% permanent); 6 (3%) had cord hypomobility (all temporary); 12 (6%) had cord hypotonia due to disease of the SLN, 4 of which (2%) were permanent; 44 patients (21%) had symptoms due to scarring and adhesions between the laryngotracheal axis and the prethyroid muscles and between these and the skin. One patient (0.5%) had a nodular cord lesion that occurred after 3 months. Overall, more than one-third of the patients had preoperative voice modifications or swallowing impairment, around one-third had these problems after TT, and less than one-third were free of pre- and postoperative complications. The surgeon's care to avoid damage to the anatomica integrity of the of laryngeal nerves does not exclude functional problems of the nerves and of laryngeal dynamics. In fact, such problems could be referred to outcomes linked to the operation itself (hematoma, edema, scarring adhesion) or to events that only temporarily follow surgery but must be considered as an unavoidable sequel (e.g., neuritis, viral neuritis, myopathy). The patient should undergo a careful clinical and instrumental NTE to detect conditions prior to surgery, and the information provided by the surgeons should be thorough to allow the patient to be aware of all possible sequels and consequences.

Cranial Nerve Diseases↗

PubMed2004

Complications of thyroid surgery: analysis of a multicentric study on 14,934 patients operated on in Italy over 5 years.

Complication rates associated with thyroid surgery can be evaluated only through analysis of case studies and follow-up data. This study covers postoperative data from 14,934 patients subjected to a follow-up of 5 years. Among them, 3130 (20.9%) underwent total lobectomy (TL), 9599 (64.3%) total thyroidectomy (TT), 1448 (9.7%) subtotal thyroidectomy with a monolateral remnant (MRST), and 757 (5.1%) subtotal thyroidectomy with bilateral remnants (BRST). A total of 6% of the patients had already been operated on. Persistent hypoparathyroidism occurred after 1.7% of all the operations, and temporary hypoparathyroidism was noted in 8.3%. Permanent palsy of the laryngeal recurrent nerve (LRN) occurred in 1.0% of patients, transient palsy in 2.0%, and diplegia in 0.4%. The superior laryngeal nerve was damaged in 3.7%; dysphagia occurred in 1.4% of cases, hemorrhage in 1.2%, and wound infection in 0.3%. No deaths were reported. A significant rate of LRN damage was noted, which has an important impact on the patient's social life. Hypoparathyroidism after total thyroidectomy is an important complication that can be successfully treated by therapy, although it is not always easily managed in special circumstances such as in young persons or pregnant women. The complications associated with thyroid surgery must be kept in mind so the surgeon can carefully evaluate the surgical and medical therapeutic options, have more precise surgical indications, and be able to give the patient adequate information.

Adult↗

PubMed2004

Surgical treatment of neuroendocrine tumors of the lung.

OBJECTIVE: This report reviews the pattern of neuroendocrine (NE) differentiation, lymph-node involvement, extension of surgery, and survival in 125 NE lung tumor patients. METHODS: Standard diagnostic workup included CT scan, bronchoscopy, bronchial biopsy or Fine Needle Aspiration Biopsy, (111)In-pentetreotide scan (OctreoScan) and mediastinoscopy in selected patients. NE differentiation was assessed based on the morphology and immunohistochemical reactivity for pan-neuroendocrine markers NSE, CGA, and Synaptophysin. For small cell carcinoma (SCC), only clinical stage I and II patients underwent surgery. Several different surgical procedures were utilized, from limited resections to lobectomy, pneumonectomy, and bronchoplastic procedures. Survival was assessed using Kaplan-Meyer method at 5 years. RESULTS: There were 79 typical carcinoid (TC), eight atypical carcinoid (AC), 18 large cell carcinoma (LCC) and 20 SCC patients. Mean age at diagnosis was 54.6+/-15.2 (ranges from 16 to 77 years) for TC, 68.5+/-9.1 (range 53-81) for AC, 68.7+/-4.6 (range 58-77) for LCC, 64.6+/-7.9 (range 48-82) for SCC. Male/female ratio was 1/1 for TC and AC, 2.6/1 for LCC and 9/1 for SCC. Lymph-node involvement was present in 14% of TC, 0% of AC, 31.5% of LCC, and 45% of SCC. Cancer specific survival was 96% for TC, 87.5% for AC, 37.5% for LCC, and 30% for SCC at 5 years from surgery. Presenting symptoms were invariably of respiratory-related. None had the carcinoid syndrome. History of tobacco abuse ranged from 46% for TC to 100% in SCC. Survival ranged from a minimum of 1 month for SCC to a maximum of 168 months with no evidence of disease for TC. Synchronous multicentric forms were found in 14% of TC. Twenty-one percent (4/19) of the patients with SCC treated by induction therapy and surgery, and in few cases by surgery and adjuvant chemotherapy are alive without the evidence of the disease for 5 years. CONCLUSIONS: Due to the high percentage of lymph-node involvement and multicentric forms found in our series lobectomy with radical lymph-node dissection appears, in our opinion, the most appropriate surgical treatment in well-differentiated forms, while more limited resection appears sub-optimal. Also, due to the finding of recurrences many years after surgery, the follow-up must be accurate and protracted in this subgroup. Only Small Cell Lung Carcinoma patients in clinical stage I and II underwent surgery with good long-term results.

Adolescent↗

PubMed2004

BRAF(V599E) mutation is the leading genetic event in adult sporadic papillary thyroid carcinomas.

Activating mutations of BRAF have been identified in a variety of human cancers, most notably melanomas and papillary thyroid carcinomas (PTCs). The aim of the present study was to disclose the role of BRAF mutations in thyroid carcinoma development. Seventy-two thyroid tumors, including 60 PTCs, six follicular adenomas, five follicular carcinomas, and one anaplastic carcinoma, were studied. BRAF mutation screening focused on exon 15 and exon 11 of the gene by single-stranded conformational polymorphism and sequence analysis. Search of RET/PTC expression was conducted with the RT-PCR technique. The molecular genetic study of the BRAF gene showed the presence of a missense thymine to adenine transversion at nucleotide 1796, resulting in the V599E substitution, in 24 of 60 PTCs (40%), none of six follicular adenomas, and none of five follicular carcinomas or one anaplastic carcinoma. Moreover, nine of 60 PTCs (15%) presented RET/PTC expression. A genetico-clinical association analysis showed a statistically significant correlation between BRAF mutation and development of PTCs of the classic papillary histotype (P = 0.038). On the contrary, no link could be detected between expression of BRAF(V599E) and age at diagnosis, gender, dimension, and local invasiveness of the primary cancer, presence of lymph node metastases, tumor stage, and multifocality of the disease. These data clearly confirm that BRAF(V599E) is the more common genetic alteration found to date in adult sporadic PTCs, that it is unique for this thyroid cancer histotype, and that it might drive the development of PTCs of the classic papillary subtype.

Adult↗

PubMed2003

Ret/PTC activation does not influence clinical and pathological features of adult papillary thyroid carcinomas.

OBJECTIVE: RET proto-oncogene rearrangements (ret/PTCs) represent the most common genetic alterations found in papillary thyroid carcinomas (PTCs). Correlation of ret/PTC expression with clinical outcome is controversial. The aim of the present study was to analyze the frequency of RET rearrangements in adult PTCs, and to investigate if ret/PTCs influence biological behavior and clinical features of the cancers. DESIGN: Ret/PTC rearrangements were looked for in tIssue samples of 48 PTCs collected at our institution. Data about clinical and pathological features of the tumors were also reviewed. Three separate association analyses were carried out on the cohort evaluating the effects of, respectively, ret/PTC positivity, preferential RET tyrosine kinase domain (RET-TK) expression, and ret/PTC plus RET-TK positivity, on age, sex, tumor size, staging, number of neoplastic foci, and histological subtype. METHODS: The genetic study was conducted with the RT-PCR-Southern blot technique. Standard Student's t-test and Fisher exact test were applied for the association analyses. RESULTS: The molecular genetic study demonstrated the positivity of ret/PTC1 and ret/PTC3 in 13 of 48 tumors (27.1%), and an exclusive or preferential RET-TK expression in 17 cases (35.4%). None of the three genetico-clinical analyses showed any significant association between ret/PTC expression and the clinical and pathological features of the cancers. CONCLUSIONS: These data indicate that RET rearrangements may not play any distinctive role in driving histotype development and cancer progression in these neoplasms. Moreover, they weaken the possibility of using ret/PTC as a prognostic marker for papillary thyroid carcinomas.

Adult↗

PubMedDate not supplied

[Prevalence of the neuroendocrine phenotype in thymus neoplasms].

To determine the prevalence of neuroendocrine differentiation in human thymic neoplasms, which are unusual tumours that may range from well-differentiated to overtly malignant, poorly differentiated lesions, an immunohistochemical study was conducted in 23 thymic neoplasms re-classified on the basis of the new 1999 WHO classification. Immunohistochemical evidence of neuroendocrine differentiation in the form of reactivity to the markers synaptophysin, neuron-specific enolase and chromogranin A was found in 6 of 23 tissues (26%). Two of 3 patients with thymic carcinoids (or well-differentiated thymic neuroendocrine carcinoma) were affected by multiple endocrine neoplasia type 1 (MEN-1). Myasthenia gravis was present in 2/6 patients with neuroendocrine differentiation. This study demonstrates the high prevalence of neuroendocrine markers in human thymic neoplasms. Whether and in what percentage of cases immunohistochemical reactivity may be correlated with clinical behaviour and outcome remains a controversial issue. Finally, the association between thymic carcinoids and MEN-1 is a strong indication for clinical and possibly genetic screening of all patients presenting this feature, just as all MEN-1 patients have to undergo thoracic imaging and prophylactic thymectomy in selected cases.

Carcinoma, Neuroendocrine↗

PubMedDate not supplied

[Complications of total thyroidectomy: incidence, prevention and treatment].

The range of indications for total thyroidectomy in the treatment of thyroid disease is steadily increasing, but any attempt to assess its real efficacy necessarily calls for a knowledge of the incidence of complications, amongst other things in order to provide the patient with complete information regarding the operation before obtaining his or her consent. Retrospective and observational analysis of 14,934 thyroidectomies performed in 42 Endocrine Surgery Units in Italy has made it possible to compare total thyroidectomy (TT) versus subtotal thyroidectomy with a bilateral remnant (ST-BR), subtotal thyroidectomy with a unilateral remnant (ST-UR) and total lobectomy-isthmectomy (TLI). The correlation between the number of total thyroidectomies and each of the other surgical procedures and the number of complications occurring with each of them was also assessed in order to quantify the effective risk of complications by determining the Odds Ratios on the basis of univariate analysis of the variables considered. The cases reviewed consisted of 9,599 TT (64%), 3,130 TLI (21%), 1,448 ST-UR (22%) and 757 ST-BR (5%); 13,023 (87%) cases were suffering from benign disease and 1,911 (13%) from malignancies. Recurrent laryngeal nerve injuries were present in 4.3% of the TT cases with 2.4% transient and 1.3% definitive (as against 3% in ST-BR and 2% in ST-UR with 1.4% and 1.1% transient, and 1% and 0.6% definitive, respectively; and 1.4% transient and 0.6% definitive in TLI). Hypocalcaemia after TT was transient in 14% and definitive in 2.2% (as against transient rates of 5% in ST-BR and ST-UR and 0.4 in TLI; and definitive hypocalcaemia in 0.6%, 0.8% and 0.07%, respectively). Haemorrhage occurred in 1.6% of TT cases (as against 2.1%, 0.5% and 0.4% in ST-BR, ST-UR and TLI, respectively). The Odds Ratios showed that TT presented a 16% higher complication rate than ST-UR which was assigned a value of 1, a 3% higher rate than ST-BR and a 5% lower rate than TLI. This greater incidence of complications with TT is attributable mainly to the greater incidence of transient hypoglycaemia and to a lesser extent to the slightly higher incidence of definitive hypoglycaemia, whereas the incidences of recurrent laryngeal nerve injuries were very similar in TT and ST-BR. Haemorrhagic complications were more frequent in ST-BR than in TT. Bearing in mind that TT is the absolute indication in the more demanding thyroid diseases (tumours, retrosternal goitre, Basedow's disease, recurrences) and in view of its fairly low complication rate, we believe that TT is a safe, reliable procedure, provided it is performed in a technically scrupulous manner. ST-BR is a technique which should be abandoned owing to the fact that its complication rate is comparable to that of TT and to the recurrences it may give rise to. ST-UR may be indicated if the surgeon is not sure of safeguarding the anatomical integrity of the recurrent nerve on one side.

Analysis of Variance↗

PubMedDate not supplied

[Acute mediastinitis: clinical features and review of a case load].

The term acute mediastinitis describes a number of clinical conditions, usually secondary to diseases of other aetiology with which they tend to share the severity of the clinical picture. In these situations even a timely diagnosis and adequate therapeutic management are not always enough to ensure healing. Over the period 1987-2002 15 patients with acute mediastinitis were observed (8 male, 7 female), aged from 22 to 90 years (mean age: 57.9), distributed as follows: descending necrotising mediastinitis, 4 cases; iatrogenic oesophageal rupture, 2 cases; iatrogenic tracheal rupture, 3 cases; oesophageal perforation (foreign body), 4 cases; Boerhaave's syndrome, 1 case; oesophageal perforation (lye ingestion), 1 case. All patients except one--managed medically--were submitted to mediastinal drainage (surgical or by mediastinoscopy), combined with cervical debridement and drainage in cases of descending necrotising mediastinitis, alimentary tract diversion (cervical oesophagostomy + feeding jejunostomy + gastric decompression) in cases of large oesophageal lesions or if the lesion occurred more than 24 hours before observation, and uni- or bilateral tube thoracostomy. Furthermore, antibiotic therapy was always administered, initially choosing broad-spectrum medications, and subsequently adjusting according to bacterial cultures. Four patients died. In 4 cases (2 descending necrotising mediastinitis, 2 acute mediastinitis secondary to oesophageal perforation) repeated interventions were necessary in order to drain pleural or mediastinal effusions. Acute mediastinitis remains a serious clinical entity, the outlook of which is often poor. Factors influencing outcome are the patient's age and general condition (adequate immune response), a timely diagnosis, preoperative localisation of effusions, an aggressive therapeutic approach including drainage of infection sites in the mediastinum, neck and/or pleural cavities, alimentary tract diversion in cases of oesophageal lesions observed late, adequate antibiotic therapy, and nutritional support (total parenteral/enteral nutrition).

Acute Disease↗

PubMedDate not supplied

[Thyroidectomy for thyroid carcinoma. Our experience].

The surgical management of thyroid carcinoma involves different degrees of lymphadenctomy, according to features such as the nature, the site and the severity of the disease. The authors present their experience in order to contribute to the debate on the standard management of nodal metastasis in well-differentiated thyroid cancers. The authors describe their six years of experience in 302 thyroid cancer patients with a total of 291 thyroidectomies performed. According to the different pathological findings, the treatment involved a monolateral dissection in 42 patients and a bilateral modified neck dissection in 21. A number of anatomical considerations regarding the pathway of lymphatic drains are summarized and follow-up results are also presented. The slow progression of the disease and its low incidence make long-term prospective studies difficult, thus hindering any definitive assessment of lymph node management in well-differentiated thyroid cancers.

Adult↗

PubMedDate not supplied

Locally advanced thyroid cancer: therapeutic options.

The authors report on their experience in the management of thyroid cancer, with specific regard to advanced disease. Thyroid carcinomas behave differently according to: pathology, sex, age, grading and size. Differentiated lesions have a favourable outlook, while for less-differentiated tumours the prognosis is dismal. Extent of resection, lymphectomy technique and management of advanced disease remain matters of debate. Of particular interest are those neoplasms invading the upper aerodigestive tract, characterised by a worse prognosis in the case of differentiated tumours (1-6%), indicating an exceedingly aggressive behaviour in what is usually a slowly evolving disease. Surgery, with a curative intent or for palliation, is mandatory. The tumour progressively invades the tracheal lumen and is seldom manageable by alternative, non-surgical methods, and in any case only for short periods of time. Total thyroidectomy with tracheal resection and anastomosis is the surgical technique of choice and, when combined with radiometabolic therapy and/or external radiotherapy, yields survival data comparable with those relating to less advanced differentiated lesions. Tracheal stents and tracheotomy improve the quality of life. Laser therapy is indicated in cases of asphyxia, and as a preliminary step with a view to subsequent radical or palliative treatments.

Adolescent↗

PubMedDate not supplied

[Diagnostic, therapeutic and healtcare management protocols in thyroid surgery. I consensus conference (UEC club)].

The aim of the study was to draw up a management protocol in thyroid surgery promoted by the Italian Association of Endocrine Surgery Units (Club delle UEC), shared by the experts and applied by the operators in the sector. The management protocols already presented in February 2002 and drawn up by the first Author of the present publication on the occasion of the current review were examined by the I Consensus Conference called on the topic by the Italian Endocrine Surgery Units. The conference comprised two distinct sessions, the first on 18 June 2005 within the framework of the 4th National Congress of the Club delle UEC in Naples, and the second on 17 September 2005 within the framework of the 8th Multidisciplinary Scanno Prize Meeting. A selected board of endocrinologists and endocrine surgeons, chaired by Aldo Pinchera and comprising the first nine Authors of this paper, examined the individual chapters in close collaboration with the other Authors, comparing their findings with the opinions of the experts cited in the text and submitting the consensus text for the approval of all those present. The diagnostic, therapeutic and healtcare management protocols in thyroid surgery approved by the I Consensus Conference are officially those proposed by the Italian Association of Endocrine Surgery Units (Club delle UEC) and are subject to review by October 1, 2007.

Clinical Protocols↗

PubMedDate not supplied

[Quality sharing between the national health service and citizens: a diagnostic and therapeutic planning experience at the "S. Maria" Hospital in Terni].

The Diagnostic and Therapeutic Programs are instruments of clinical management. The authors report on their experience with the construction of a Diagnostic and Therapeutic Program in the field of breast cancer. This is the result of collaboration between the Breast Unit, an administrative team and a computer team at the "S. Maria" Hospital in Terni. The implementation of the guidelines in the hospital setting makes it possible to systematise the clinical activities, to quantify the economic impact for each disease, and to plan any changes in the use of resources. The application of this method, moreover, makes it possible to develop a common language between medical and nursing staff which can be easily understood by the patients and to inform patients adequately with regard to the diagnostic and therapeutic program they will have to comply with for their respective conditions.

Breast Neoplasms↗

PubMedDate not supplied

[Role of minimally invasive surgery in the treatment of primary hyperparathyroidism].

The minimally invasive approach to parathyroid surgery is considered an efficient alternative to traditional cervicotomy when the pre-operative diagnostic work-up indicates a single parathyroid adenoma. Imaging techniques (ultrasound, SPECT), on the one hand, and intraoperative diagnostic techniques (radio-guided surgery, intraoperative parathyroid hormone assay), on the other, contribute to the success and development of specialized centres which prefer to use this type of surgery. The postoperative pain control and aesthetic results achieved with these techniques are today the main subjects of interest in the minimally invasive approach.

Adult↗

PubMedDate not supplied

[Diagnostic-therapeutic pathways as instruments of clinical management: experience at the S. Maria Hospital in Terni].

Diagnostic-therapeutic itineraries and treatment profiles are instruments of clinical management. The authors report on their experience with the experimental creation of such itineraries in thyroid nodular pathology. These are the fruit of collaboration between the management team, endocrinological surgeons, and the hospital computer staff. The drawing-up of guidelines in the hospital setting allows the systematic organisation of clinical activities to be accomplished in the health-care facility, quantifying costs for all diseases in order to be able to plan and implement changes in resources and staff utilisation. Application of the method, in addition, helps to develop a common language among hospital doctors and nurses, facilitates proper communication with patients, and ensures adequate patient information regarding the clinical itinerary the patient will have to take for his or her condition.

Critical Pathways↗