Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.

BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.

Liquid biopsy in the management of advanced lung cancer: Implementation and practical aspects.

Non-small-cell lung cancer (NSCLC) is a major cause of cancer-related death worldwide. In recent years, the discovery of actionable molecular alterations has changed the treatment paradigm of the disease. Tissue biopsies have been the gold standard for the identification of targetable alterations but present several limitations, calling for alternatives to detect driver and acquired resistance alterations. Liquid biopsies reveal great potential in this setting and also in the evaluation and monitoring of treatment response. However, several challenges currently hamper its widespread adoption in clinical practice. This perspective article evaluates the potential and challenges associated with liquid biopsy testing, considering a Portuguese expert panel dedicated to thoracic oncology point of view, and providing practical insights for its implementation based on the experience and applicability in the Portuguese context.

Evaluation of Current Antiemetic Therapy Response in Patients Undergoing MEC or HEC Regimens in Portugal.

Chemotherapy-induced nausea and vomiting (CINV) negatively impact cancer patients' quality of life and treatment outcomes. This study evaluated the achievement of complete response to CINV prophylaxis during the first five days after chemotherapy in adult outpatient cancer clinics with solid malignant tumours receiving Moderate or Highly Emetogenic Chemotherapy (MEC or HEC) in Portugal. During the study, patients completed three evaluations, and nausea severity and CINV impact on patients' daily life was assessed. A complete response (no emetic episodes, no use of rescue antiemetic medication, and no more than mild nausea) was observed in 72% of the cycles (N = 161) throughout the five days after chemotherapy. Amongst the patient population, 25% classified their CINV episodes as severe. Though more than half of the patients achieved a complete response, suggesting that a therapeutic effort is being made to minimise this side effect, the overall scenario is barely optimistic. Significantly, new CINV-control measures in MEC/HEC patients should be adopted, specifically avoiding the single use of dexamethasone and 5-HT3 and raising awareness of using NK1-RAs. Thus, it is critical to improve CINV prophylactic treatment and implement practical international antiemetic guidelines in Portuguese clinical practice, envisaging the improvement of supportive care for cancer patients.

Healthcare resource utilization and associated cost analysis of the PROCLAIM study in patients with stage III non-small-cell lung cancer.

Objective: To analyze patient-reported swallowing difficulties, healthcare resource utilization and associated costs during the PROCLAIM study. Methods: Patients with stage III non-squamous non-small cell lung cancer received pemetrexed-cisplatin (PemCis) combined with concurrent thoracic radiotherapy followed by consolidation pemetrexed, or concurrent chemoradiotherapy with etoposide-cisplatin (EtoCis) followed by standard consolidation chemotherapy. Patient - reported swallowing function was measured using diaries. Resource utilization (hospitalizations, transfusions, concomitant medications) was compared between treatment arms using Fisher's exact test and independent t-test. Medical resource use costs were analyzed using nonparametric Wilcoxon rank sum test. Results: Patient-reported difficulty in swallowing function (diary score ≥4) was 33.8% in the PemCis arm and 29% in the EtoCis arm. Overall resource use, including hospitalizations, was similar between treatment arms; however, fewer patients in the PemCis arm received transfusions and selected concomitant medications. Concurrent phase analyses were consistent with the overall study. A significantly lower percentage of patients (31.1% vs. 40.8%) were hospitalized in the PemCis arm. Total costs were significantly higher in the PemCis arm. Other medical costs (excluding study treatment costs) during the concurrent phase were lower for patients in the PemCis arm, due to significantly lower hospitalization costs and lower use of concomitant medications. Subgroup analysis yielded similar results. Conclusions: Patient-reported difficulty in swallowing post-baseline and resource utilization were consistent with previously reported safety outcomes. In the overall study, higher total costs for PemCis were driven by study drug cost. When adjusting for treatment duration, other monthly medical costs were favorable to PemCis. Patients on pemetrexed remained longer on therapy, suggesting better tolerability. ClinicalTrials.gov identifier: NCT00686959.

Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

OBJECTIVES: To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function. METHODS: In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function. RESULTS: Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (p < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of ≥30% and ≥40% were associated with gender (female), age (<70 years) and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases ≥30% and 7/13 (54%) had pre-existing conditions and/or were receiving nephrotoxic drugs. CONCLUSIONS: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug-related renal event based only on changes in pre-maintenance laboratory values.

Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data.

BACKGROUND: Platinum-based chemotherapy is the standard first-line treatment for patients with advanced non-small-cell lung cancer. However, the optimum number of treatment cycles remains controversial. Therefore, we did a systematic review and meta-analysis of individual patient data to compare the efficacy of six versus fewer planned cycles of platinum-based chemotherapy. METHODS: All randomised trials comparing six versus fewer planned cycles of first-line platinum-based chemotherapy for patients with advanced non-small-cell lung cancer were eligible for inclusion in this systematic review and meta-analysis. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients with an objective response, and toxicity. Statistical analyses were by intention-to-treat, stratified by trial. Overall survival and progression-free survival were compared by log-rank test. The proportion of patients with an objective response was compared with a Mantel-Haenszel test. Prespecified analyses explored effect variations by trial and patient characteristics. FINDINGS: Five eligible trials were identified; individual patient data could be collected from four of these trials, which included 1139 patients-568 of whom were assigned to six cycles, and 571 to three cycles (two trials) or four cycles (two trials). Patients received cisplatin (two trials) or carboplatin (two trials). No evidence indicated a benefit of six cycles of chemotherapy on overall survival (median 9·54 months [95% CI 8·98-10·69] in patients assigned to six cycles vs 8·68 months [8·03-9·54] in those assigned to fewer cycles; hazard ratio [HR] 0·94 [95% CI 0·83-1·07], p=0·33) with slight heterogeneity between trials (p=0·076; I(2)=56%). We recorded no evidence of a treatment interaction with histology, sex, performance status, or age. Median progression-free survival was 6·09 months (95% CI 5·82-6·87) in patients assigned to six cycles and 5·33 months (4·90-5·62) in those assigned to fewer cycles (HR 0·79, 95% CI 0·68-0·90; p=0·0007), and 173 (41·3%) of 419 patients assigned to six cycles and 152 (36·5%) of 416 patients assigned to three or four cycles had an objective response (p=0·16), without heterogeneity between the four trials. Anaemia at grade 3 or higher was slightly more frequent with a longer duration of treatment: 12 (2·9%) of 416 patients assigned to three-to-four cycles and 32 (7·8%) of 411 patients assigned to six cycles had severe anaemia. INTERPRETATION: Six cycles of first-line platinum-based chemotherapy did not improve overall survival compared with three or four courses in patients with advanced non-small-cell lung cancer. Our findings suggest that fewer than six planned cycles of chemotherapy is a valid treatment option for these patients. FUNDING: None.

Nutritional screening of pulmonology department inpatients.

Undernutrition is associated with worse clinical outcomes and so screening is recommended. Given the paucity of information on nutritional status and on the clinical impact of undernutrition in Pulmonology patients who have been hospitalized, it is of the utmost importance that it is studied. Through a longitudinal study conducted of 323 patients consecutively admitted to a Pulmonology hospital department, undernutrition was screened using the Malnutrition Universal Screening Tool and the association between length of hospital stay, pathology type, discharge destination and undernutrition risk was quantified. There was found to be a high proportion of patients at risk of undernutrition, with 18.3% at high risk and 15.5% at moderate risk. Patients at risk of undernutrition had a higher risk of dying during hospitalization (OR=2.72, 95% CI: 1.48- 4.97). One in three patients admitted to this unit is at risk of undernutrition; chronic obstructive pulmonary disease was the pathology most strongly associated with undernutrition risk. Present data reinforces the need for screening for undernutrition on admission.

Advanced lung adenocarcinoma in an EGFR-positive patient treated with Erlotinib for 52 months.

The authors present a case of a 53-years-old non-smoker Caucasian female who was diagnosed with lung adenocarcinoma (stage IA) and underwent surgical resection in 2002. Five years later, the tumor relapsed (stage IV disease) and she initiated chemotherapy with carboplatin, gemcitabine and bevacizumab as a first-line therapy. Despite partial remission after four cycles, this regimen was discontinued due to unacceptable toxicity. In 2008, the disease progressed and the patient was started on Erlotinib as second-line treatment. The patient had a sustained partial remission which she maintains at present - 52 months after initiation of Erlotinib. Molecular testing performed on the primary lung tumor revealed an Epidermal Growth Factor Receptor (EGFR) gene mutation (deletion in exon 19).

Tracheal bronchus with metachronous tumor.

Tracheal bronchus, a bronchus arising from the lateral wall of the trachea, is a rare congenital anomaly. It is usually asymptomatic but symptoms could occur with relatively poor local drainage. There are a few cases of lung cancer within the tracheal bronchus reported in the literature; however, none of them were reported to be metachronous. A metachronous tumor is a second primary malignancy diagnosed >6 months after the diagnosis of the index tumor. We present a case of a squamous cell carcinoma originating in a tracheal bronchus of a 53-year-old patient previously diagnosed with a supraglottic malignancy.

Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer.

INTRODUCTION: In a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non-small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results. METHODS: After four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D). RESULTS: Frequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p <0.001), anti-infectives (25.3% versus 16.7%; p = 0.028), and hospitalizations because of study drug (8.4% versus 3.3%, p = 0.028) than placebo-treated patients did. No significant treatment-by-time interactions, overall treatment differences, or clinically relevant changes from baseline were observed in EQ-5D scores during treatment. CONCLUSIONS: Long-term use of continuation maintenance pemetrexed was well tolerated; resource use was low, corresponding with known pemetrexed toxicities. The EQ-5D results demonstrate that patients tolerate long-term maintenance pemetrexed without worsening QoL.

Second-line therapy for non-small cell lung cancer in clinical practice: final results and treatment pathways from the SELECTTION observational study.

OBJECTIVES: SELECTTION was a multinational, prospective observational study to assess the choice of and the time from initiation of second-line treatment to treatment discontinuation for any reason in patients with non-small cell lung cancer. METHODS: Treatment cohorts were constructed based on prescribed second-line treatments that were at the discretion of the treating physicians, for 1013 patients enrolled in 11 countries. Propensity score analysis was conducted to assess whether the cohorts were comparable. Time from initiation of second-line treatment to treatment discontinuation was the primary endpoint. Reasons for treatment discontinuation, overall survival, progression-free survival and choice of second-line treatment were secondary endpoints. RESULTS: The treatment cohorts were pemetrexed (46.2%), docetaxel (22.9%), erlotinib (20.4%) and other treatments (10.5%). Analyses of baseline data and propensity scores showed that the erlotinib cohort comprised substantially different patients compared with the pemetrexed and docetaxel cohorts: patients in the erlotinib cohort were more likely to be women, never-smokers, have adenocarcinoma and worse performance status. Therefore, comparisons of outcomes between cohorts were not appropriate. Although disease progression was the most common reason for treatment discontinuation in all cohorts, erlotinib patients tended to continue treatment after disease progression, whereas in the docetaxel and pemetrexed cohorts, discontinuation occurred soon after disease progression. CONCLUSIONS: In real-world clinical practice the profiles of patients assigned to erlotinib were distinctly different from those assigned to pemetrexed or docetaxel. The most common reason for treatment discontinuation was progressive disease, reflecting adherence to clinical recommendations. It is difficult to extrapolate these findings to the present, as both clinical practice and the approved indications for NSCLC treatments have evolved substantially.

Bevacizumab for the treatment of nonsquamous non-small-cell lung cancer in Portugal: a retrospective, multicenter study.

INTRODUCTION: Lung cancer is the leading cause of cancer-related mortality. In patients with nonsquamous non-small-cell lung cancer (NSCLC) stage IIIB/IV treatment with chemotherapy plus bevacizumab led to significant improvements in progression-free and median overall survival (OS). AIM: To report the experience of five Portuguese centers in treating patients with nonsquamous NSCLC in stage IIIB or IV with bevacizumab and chemotherapy regarding survival and toxicity outcomes. MATERIALS AND METHODS: This was a retrospective, multicenter study on patients with nonsquamous stage IIIB/IV NSCLC treated with bevacizumab and chemotherapy from November 2007 to August 2010 through special use permits. We reviewed the medical records, registry of demographic characteristics, treatments provided, treatment responses, adverse events, and dates of death. Statistical analysis was performed with SPSS statistics software. Median OS and event-free survival (EFS) were calculated using the Kaplan-Meier method. RESULTS: From an eligible population of 41 patients, 37 participants were registered. Study participants were predominantly male (78.4%) with a median age of 53 years (29-75 years). In total, 83.8% patients had stage IV disease (TNM, 6th Ed.). The OS was 21.5 months (95% confidence interval [CI]: 12.6-30.5] and median EFS was 9.4 months (95% CI9: 7.1-11.7). Hematologic toxicity grade 3/4 occurred in 35.1% of patients, and nonhematologic toxicity in 24.3% patients. One fatal thromboembolic event was recorded (2.7%). CONCLUSIONS: The results of chemotherapy plus bevacizumab treatment for nonsquamous NSCLC obtained from the daily clinical practice of the centers involved in this study were similar to those of published clinical trials. Collaboration between the different Portuguese centers is crucial for this kind of study.

Dyspnea and wheezing: still a challenge for pulmonologists.

Schwannoma is a neurogenic tumor originating from the nerve sheath Schwann cells. Intrathoracic location is rare, and the endobronchial location is exceptional. Schwannoma is a rare tumor; the majority of lesions are benign and usually asymptomatic. The authors present a case report of a 83-year-old woman, nonsmoker, observed in the emergency department for wheezing and cough lasting for 2 months. Chest tomography showed a right hilar pulmonary mass, ill defined, with thick and irregular walls, centered on the upper lobe bronchus, which was obliterated. Fiberoptic bronchoscopy showed a necrotic mass obstructing the right upper lobe bronchus whose biopsy allowed the diagnosis of benign schwannoma. Subsequently, the patient carried tumor ablation by laser bronchoscopy, with the resolution of the respiratory symptoms. This case stands out for its rarity but also because it is an excellent example of the importance of endoscopic techniques for therapeutic purposes. Schwannoma is a benign tumor in which surgical or endoscopic intervention generally prevents local recurrence and associated clinical manifestations.

Second-line therapy for NSCLC in clinical practice: baseline results of the European SELECTTION observational study.

OBJECTIVE: Although the efficacy of a number of drugs for the second-line treatment of non-small cell lung cancer (NSCLC) has been demonstrated in Phase III trials, very limited evidence exists on optimal duration of second-line treatment or the reasons why this treatment is stopped in standard clinical practice. SELECTTION (Survey in European Lung Cancer Evaluating Choice of Treatment and Tolerability In Observed NSCLC) was designed to assess the time from initiation of second-line treatment for NSCLC to treatment discontinuation for any reason, the reasons for discontinuation, and the impact of discontinuation on outcomes. METHODS: From October 2006 to January 2008, 1012 patients with advanced/metastatic NSCLC who completed or discontinued first-line treatment were enrolled in a multi-national, prospective observational cohort study (SELECTTION). Treatment cohorts were constructed based on the patients' distribution across second-line treatments that were assigned by physician decision (pemetrexed, docetaxel, erlotinib, other treatments). This report presents a descriptive analysis of the baseline data collected, including patient/disease characteristics, treatment history and planned second-line treatments. Factors that may have affected treatment choice, selected by physicians from a range of options, were also identified. RESULTS: Overall, 468 patients (46.2%) were enrolled in the pemetrexed cohort, 232 (22.9%) in docetaxel cohort, 206 (20.4%) in erlotinib cohort and 106 (10.5%) received other treatments. The profile of patients enrolled in the erlotinib cohort differed from those of patients enrolled in the pemetrexed or docetaxel cohorts in that erlotinib was more frequently planned for women, never-smokers and patients with adenocarcinomas. The primary reasons physicians gave for selection of the second-line treatment were tolerance and efficacy for pemetrexed, and preferred regimen for the particular patient and efficacy for the other treatments. CONCLUSIONS: In this observational study, pemetrexed, then docetaxel and erlotinib were the most frequently prescribed second-line treatments, which is in line with international guidelines. Erlotinib was most commonly prescribed to that subset of patients expected to gain the greatest benefit (those with adenocarcinoma, never-smokers and females). Pemetrexed was more frequently prescribed than docetaxel, with physicians most commonly choosing to prescribe the former agent because of its tolerability profile.

Papillary adenocarcinoma of the thymus: case report and review of the literature.

A 44-year-old male with a mediastinal mass measuring 3.5 × 3.5 × 3 cm was diagnosed with papillary adenocarcinoma of the thymus. Other origins of papillary adenocarcinoma were excluded by clinical, imaging, and immunocytochemical methods before assuming this diagnosis. Residual thymus was seen under the microscope. Focal CD5 immunoreactivity was present. There was no associated thymoma. The patient underwent surgery, radiotherapy, and chemotherapy. He disclosed systemic recurrence at 18 months (subcutaneous nodule). He is alive after 24 months of follow-up with active disease. There had been only 7 cases of this rare entity published before.

Description and management of cutaneous side effects during erlotinib and cetuximab treatment in lung and colorectal cancer patients: a prospective and descriptive study of 19 patients.

Erlotinib and cetuximab are human epidermal growth factor receptor inhibitors (EGFRI) that are approved in monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Papulopustular eruptions are the most frequent adverse effect, their occurrence being associated with increased survival in some studies. We describe 19 patients who presented with a rash located mainly to the face and trunk, without presence of comedones, shortly after initiation of EGFRI therapy. We present our algorithm to manage these patients and their respective responses. We also report other therapeutic options and cutaneous alterations that may be seen.

Mesothelioma treatment. / Terapêutica do mesotelioma.

Malignant mesothelioma (MM) is a locally aggressive advanced tumour, with bad prognosis and many times fatal, who have been growing in the last two decades with possibilities to be continue in all the world until 2020, showing use of pic asbestos to the years 1960/1970. Next 35 years the previsions of the deaths is more than 250 000. In Portugal (ROR) incidence is 1,2/1 000 000/year for total of the patients. Until now any new therapy showed advantage in the median survival and time to progression. The more important change whose the news than the antifolatos, particularly pemetrexed in combination with cisplatinum were actives in MM. Chemoterapy as soon as possible and second lines treatment it is very important thinking in the survival this fatal tumor. Rev Port Pneumol 2008; XIV (Sup.2): S35-S44.

Treatment of advanced non small cell lung cancer with erlotinib. Two clinical cases. / Erlotinib no tratamento do carcinoma pulmonar de não pequenas células, doença avançada. A propósito de dois casos clínicos.

Early studies with tirosine kinase inhibitors (TKI), namely Erlotinib and Gefitinib, in patients with non small cell lung cancer (NSCLC), showed that although most patients did not respond radiologically, a small percentage of those patients (about 10%) had an excellent response to treatment, with radiological regression and clinical response duration. Four patient populations are known as having better response to TKI as opposed to other patients: adenocarcinoma patients, non-smokers, women and asians. Nevertheless, a good general status remains a predictive factor for treatment response. The discovery of the EGFR mutation in NSCLC patients' tumors and its association with clinical response to Erlotinib and Gefitinib, confirmed by a considerable number of retrospective and prospective studies, showed that response rates are between 75-80% in patients carrying this mutation. Although several mutations have been identified, the two commonest (approximately 90%) are located in exons 19 and 21. The authors present two patients studied and treated at the Pulmonology Department's Lung Oncology Unit of CHVNGaia, where Erlotinib was used as 3(rd) line treatment: in one patient, which was part of the population with good response to TKI, a classic exon 19 was identified, and was treated with Erlotinib for twenty months with clinical stability; the other patient did not belong to the above mentioned population and an Exon 20 mutation was identified (a mutation not yet described in literature, being not clear its association with response to treatment with TKI) - treatment was stopped after 7.4months due to disease progression. Rev Port Pneumol 2008; XIV (Supl 3): S43-S51.