Afatinib in Non‐Small Cell Lung Cancer Harboring Uncommon EGFR Mutations Pretreated With Reversible EGFR Inhibitors

Background.

Afatinib, an irreversible ErbB family blocker, is approved for treatment of patients with previously untreated non-small cell lung cancer (NSCLC) harboring activating epidermal growth factor receptor (EGFR) mutations. Efficacy of afatinib in EGFR tyrosine kinase inhibitor-naïve (TKI-naïve) patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 point mutations) has been reported; however, efficacy in TKI-pretreated patients with uncommon EGFR mutations is unknown.

Materials and Methods.

In the afatinib compassionate use program (CUP), patients with advanced or metastatic, histologically confirmed NSCLC progressing after at least one line of chemotherapy and one line of EGFR-TKI treatment were enrolled. Demographic data, mutation type, response rates, time to treatment failure (TTF), and safety in patients harboring uncommon EGFR mutations were reported.

Results.

In 60 patients (63% female, median age 63 years [range: 30–84 years]), a total of 66 uncommon EGFR mutations including 30 T790M mutations were reported (18.4% and 11%, respectively, of known EGFR mutations within the CUP). Most patients (67%) received afatinib as third- or fourth-line treatment. Median TTF was 3.8 months (range: 0.2 to >24.6 months; p = .244) in patients with uncommon mutations compared with 5.1 months (range: 0.1 to >21.1 months) in patients with common mutations (n = 165). Pronounced activity was observed with E709X mutations (TTF >12 months). No new safety signals were detected.

Conclusion.

Afatinib is clinically active and well tolerated in many TKI-pretreated NSCLC patients harboring uncommon EGFR mutations. Compared with results reported in TKI-naïve patients, activity was also indicated in patients with T790M and exon 20 insertion mutations.

Implications for Practice:

This analysis consists of a large database of non-small cell lung cancer patients with uncommon EGFR mutations who were previously treated with reversible EGFR tyrosine kinase inhibitors. Although indirectly assessed, the results indicate that patients with uncommon EGFR mutations can derive benefit from treatment with the irreversible ErbB family blocker afatinib, even in some cases of tumors harboring resistance-mediating exon 20 mutations. In this study, adverse events were modest and consistent with previous reports on afatinib.     

Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen)

Mantle cell lymphoma (MCL) is rarely cured with standard-dose chemotherapy. From January 1997 to February 2000, 28 previously untreated advanced-stage MCL patients younger than 61 years of age were treated at 9 Italian hematologic departments with 3 cycles of standard-dose debulking chemotherapy followed by a high-dose rituximab-supplemented sequence (R-HDS) including intravenous administration of high-dose cyclophosphamide, high-dose cytarabine, high-dose melphalan, and high-dose mitoxantrone plus melphalan. Study end points included toxicity, clinical and molecular response rates, long-term event-free survival (EFS), and overall survival (OS) rates, as well as the ability to harvest tumor-free peripheral blood stem cells. Optimal amounts of polymerase chain reaction-negative (PCR-negative) CD34+ cells were collected from all 20 informative patients. One patient died of toxicity. All 27 patients assessable for response achieved a complete response (CR), of which 24 remain in continuous complete remission (CCR) after a median follow-up of 35 months. Three patients had transient evidence of PCR-detectable disease in the bone marrow. The OS and EFS rates at 54 months were 89% and 79%, respectively. These results compare with the 42% OS rate and the 18% EFS rate observed in 35 age-matched historic controls treated with standard-dose chemotherapy at the participating centers. The use of rituximab in combination with high-dose chemotherapy represents a very effective in vivo purging method. The R-HDS regimen can be safely applied in a multicenter hematology setting and leads to long-term EFS and OS in the majority of patients with an otherwise incurable disease.     

Rearrangements of bcl-6, bcl-2, c-myc and 6q deletion in B-diffuse large-cell lymphoma: Clinical relevance in 71 patients

Background: B-diffuse large-cell lymphomas (DLCL) have been associated with some molecular lesions, but the role of such lesions as prognostic markers is still controversial. This report concerns an investigation of the frequency and clinical correlation of bcl-6, bcl-2, c-myc rearrangements and 6(q) deletions in B-DLCL.Patients and methods: The presence of these genetic lesions was analyzed in samples of lymph nodes or bone marrow collected at diagnosis in 71 patients with B-DLCL, all treated with an antracycline-containing chemotherapy regimen.Results: Rearrangement of bcl-6 was found in 11 patients (15%), rearranged bcl-2 in 12 (17%), 6(q) deletions in 10 patients (14%) and c-myc rearrangement in four (6%). Patients with rearranged bcl-6 tended to have a more aggressive disease than patients with germ-line bcl-6 (intermediate–high/high risk according to IPI criteria: 73% vs. 43%), but there were no differences in three-year survival rates (62% vs. 42%) between the two groups. The numbers of involved extranodal sites were similar in patients with rearranged and those with germ-line bcl-6. Patients with bcl-2 rearrangement appeared to have a less aggressive disease than those with germ-line bcl-2 (low/low–intermediate risk 75% vs. 47%) and a slightly better three-year survival rate (70% vs. 41%) but again the difference was not significant. Both groups with or without 6(q) deletion had similar clinical characteristics and outcomes. The four patients with c-myc rearrangement had aggressive disease and did poorly.Conclusions: The analysis of molecular lesions in B-DLCL may be useful for a better diagnostic definition; however, in this study we were unable to show that the evaluated genetic lesions had a significant impact on clinical outcome.     

Experimental chronic gastric ulcer due to ischemia in rats

Ligation of the left gastric and right gastroepiploic arteries and veins resulted in chronic gastric ulcer formation in the rat. Linear mucosal corpus hemorrhages appeared within 8 hr of ligation. By 2 days large corpus hemorrhagic erosions were present. A single, large ulcer involving nearly the entire corpus was present at 3–5 days. In the ulcerated area the mucosa and muscularis mucosae were destroyed, thick granulation tissue filled the submucosa and the muscularis propria was severely damaged. Progressive healing occurred thereafter and 75% of the ulcers healed completely grossly in 2–8 weeks. Histologic studies showed that healing and mucosal regeneration occurred by the outgrowth of a layer of cells from the adjacent intact epithelium extending over the surface of the ulcer. Invaginations from this covering layer of cells formed a glandular mucosa composed of mucous cells. Later parietal and chief cells appeared, and eventually (6 months) a normal corpus-type mucosa covered the entire corpus. With time smooth-muscle fibers appeared in the outer half of the dense submucosal granulation tissue and eventually a normal muscularis mucosae, submucosa, and muscularis propria were present (6–12 months). These studies show that: (1) ischemia can give rise to chronic gastric ulcer, and (2) all elements of the gastric wall, including the mucosa, the muscularis mucosae, and the muscularis propria can fully regenerate.Supported by Veterans Administration Project Number 3324-02 and NIAMDD Peptic Ulcer Center Grant 17328     

Untersuchungen über die Nitritreduktion bei Bacillus cereus

Zusammenfassung Die dissimilatorische Nitritreduktion intakter Zellen und zellfreier Extrakte von Nitrat-adaptierten Zellen von Bac. cereus wurde untersucht. Als einziges lösliches Folgeprodukt wurde Ammoniak nachgewiesen, gasförmige Folgeprodukte werden nicht gebildet. Verschiedene Intermediate des Kohlenhydratabbaus sind als Elektronendonatoren der Nitritreduktion intakter Zellen geeignet. Aus Glucose wird anaerob CO₂ in stöchiometrischem Verhältnis zur eingesetzten Nitrat- oder Nitritmenge gebildet. Die zellfreie Nitritreduktion kann nur NADH und NADPH als Elektronendonatoren verwenden. Aus dem unterschiedlichen Spektrum der Elektronendonatoren von Nitrat- und Nitritreduktion und dem unterschiedlichen Verhalten der beiden Enzyme gegenüber spezifischen Inhibitoren werden vorläufige Schlüsse auf die Kopplung der Nitritreduktase mit den Cytochromen gezogen. Die zellfreie Nitritreduktion wird durch Kupfer(II)-Ionen in kleiner Konzentration gehemmt.

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Summary Cells ofBac. cereus ATCC8035 grown anaerobically in the presence of nitrate contain a dissimilatory nitrite reductase, which under anaerobic conditions reduces nitrite to ammonia in intact cells and cell free extracts. Other soluble intermediates or nitrogen containing gaseous products could not be detected.In an anaerobic system composed of intact cells, glucose and limiting amounts of nitrate or nitrite, 1Mol CO₂ perMol nitrate and 0.5Mol CO₂ perMol nitrite are liberated, suggesting that nitrate and nitrite oxygen is available for glucose oxidation only to the hyponitrite level.Among several inhibitors tested in a cell free nitrite reducing system with NADH as electron donor, the inhibition by Cu^II-ions at low concentrations (2 to 6×10^–6 M) is remarkable.

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Die Arbeit wurde durch Mittel der Deutschen Forschungsgemeinschaft und der Strebelstiftung für Krebs- und Scharlachforschung unterstützt.     

Application of artificial palpation in vascular surgeries for detection of peripheral arterial stenosis

Palpation is one of the applied methods that surgeons usually use during surgery in order to verify the health condition of a tissue/organ. In fact, most of surgical assessments are based on analysis of the force feedback received from tissue/organ via palpation. Although palpation has a key role in efficient progress of surgery operations, it depends very much on the experience and skill of the surgeons. This limits the application of this technique in some cases to a large extent. In this regard, an artificial tactile sensing approach is an innovative technology that tries to make tactile data more available for surgeons, especially in situations where doing the palpation is not possible or is too difficult. In this paper, having considered the present problems of artery bypass surgery in peripheral arterial occlusive disease (PAOD), applicability of a new tactile sensory system capable of detecting arterial stenosis during surgery was evaluated. Presenting the modelling and numerical solution of the problem, it was demonstrated that the artificial tactile sensing approach is not only capable of detecting the presence of an arterial stenosis in an artery, but also its type. Furthermore, it was shown that the new tactile sensory system (previously designed, fabricated and tested in laboratory) is efficiently capable of detecting the simulated artery in the simulated biological tissue as well as diagnosis of the stenosis occurred inside it.     

Neurectomy for palliation of primary erythermalgia

Ankle nerve crushing followed 6 months later by neurectomy was used for relief of a burning sensation and pain in a 32-year-old woman who had symptoms of unilateral primary erythermalgia. The patient continues to experience considerable improvement of the preceding symptoms and no complications from the insensate foot 1 year after neurectomy, although redness and tenseness of the ankle and the foot have persisted.     

Patient-controlled antiemesis for cancer chemotherapy-induced nausea and vomiting

Nausea and emesis during cancer chemotherapy are very common, but can often be controlled with repetitive boli of antiemetic drugs. However, some patients, especially those with anticipatory symptoms, experience nausea and emesis despite antiemetic prophylaxis. An increased participation of these patients in the prophylaxis and treatment of these highly subjective symptoms may lead to better palliation. A patient controlled infusion pump was assessed in nine patients receiving cisplatin, in whom high-dose metoclopramide (5 mg/kg) had failed (>3 emetic episodes) during previous treatment cycles. Improved palliation was achieved in every case with on-demand boli in combination with a continuous infusion of metoclopramide or droperidol. Eight of the nine patients preferred the patient-controlled system to the conventional fixed-dose bolus regimens. The infusion pump functioned safely and reliably. Antiemetic treatment with the patient-controlled device was superior to previous conventional methods in this group of diffcult-to-treat patients.