NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents.

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of <1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.

Induction cetuximab, paclitaxel, and carboplatin followed by chemoradiation with cetuximab, paclitaxel, and carboplatin for stage III/IV head and neck squamous cancer: a phase II ECOG-ACRIN trial (E2303).

BACKGROUND: E2303 evaluated cetuximab, paclitaxel, and carboplatin used as induction therapy and concomitant with radiation therapy in patients with stage III/IV head and neck squamous cell carcinoma (HNSCC) determining pathologic complete response (CR), event-free survival (EFS), and toxicity. PATIENTS AND METHODS: Patients with resectable stage III/IV HNSCC underwent induction therapy with planned primary site restaging biopsies (at week 8 in clinical complete responders and at week 14 if disease persisted). Chemoradiation (CRT) began week 9. If week 14 biopsy was negative, patients completed CRT (68-72 Gy); otherwise, resection was carried out. p16 protein expression status was correlated with response/survival. RESULTS: Seventy-four patients were enrolled; 63 were eligible. Forty-four (70%) were free of surgery to the primary site, progression, and death 1-year post-treatment. Following induction, 41 (23 CR) underwent week 8 primary site biopsy and 24 (59%) had no tumor (pathologic CR). Week 14 biopsy during chemoradiation (50 Gy) in 34 (15 previously positive biopsy; 19 no prior biopsy) was negative in 33. Thus 90% of eligible patients completed CRT. Overall survival and EFS were 78% and 55% at 3 years, respectively. Disease progression in 23 patients (37%) was local only in 10 (16%), regional in 5 (8%), local and regional in 2 (3%), and distant in 5 patients (8%). There were no treatment-related deaths. Toxicity was primarily hematologic or radiation-related. p16 AQUA score was not associated with response/survival. CONCLUSIONS: Induction cetuximab, paclitaxel, and carboplatin followed by the same drug CRT is safe and induces high primary site response and promising survival. CLINICAL TRIALS NUMBER: NCT 00089297.

Development of herpes simplex virus-1 amplicon-based immunotherapy for chronic lymphocytic leukemia.

Herpes simplex virus (HSV)-based vectors have favorable biologic features for gene therapy of leukemia and lymphoma. These include high transduction efficiency, ability to infect postmitotic cells, and large packaging capacity. The usefulness of HSV amplicon vectors for the transduction of primary human B-cell chronic lymphocytic leukemia (CLL) was explored. Vectors were constructed encoding beta-galactosidase (LacZ), CD80 (B7.1), or CD154 (CD40L) and were packaged using either a standard helper virus (HSVlac, HSVB7.1, and HSVCD40L) or a helper virus-free method (hf-HSVlac, hf-HSVB7.1, and hf-HSVCD40L). Both helper-containing and helper-free vector stocks were studied for their ability to transduce CLL cells, up-regulate costimulatory molecules, stimulate allogeneic T-cell proliferation in a mixed lymphocyte tumor reaction, and generate autologous cytotoxic T lymphocytes (CTLs). Although helper-containing and helper-free amplicon stocks were equivalent in their ability to transduce CLL cells, a vigorous T-cell proliferative response was obtained using cells transduced with hf-HSVB7.1 but not with HSVB7.1. CLL cells transduced with either HSVCD40L or hf-HSVCD40L were compared for their ability to up-regulate resident B7.1 and to function as T-cell stimulators. Significantly enhanced B7.1 expression in response to CD40L was observed using hf-HSVCD40L but not with HSVCD40L. CLL cells transduced with hf-HSVCD40L were also more effective at stimulating T-cell proliferation than those transduced with HSVCD40L stocks and were successful in stimulating autologous CTL activity. It is concluded that HSV amplicons are efficient vectors for gene therapy of hematologic malignancies and that helper virus-free HSV amplicon preparations are better suited for immunotherapy.

Dietary management of surgical patients: effects on incisional wound healing

A study of 38 patients was undertaken at the main University Hospital in Alexandria. The sample was divided into a control group and an experimental group. Findings show statistically significant differences between the two groups in the level of education, but no difference in blood picture, body mass index or nutritional status. There was a difference in the rate of wound healing in the two groups, and a relationship between the nutritional status and wound healing in the control group. Total hospital stays for the control group were longer than those for the experimental group. The nutritional status of surgical patients, as well as their food intake, should be evaluated at short intervals before and after surgery

Promiscuous and allele-specific anchors in HLA-DR-binding peptides.

The major histocompatibility complex (MHC) class II molecules are highly polymorphic membrane glycoproteins that bind peptide fragments of proteins and display them for recognition by CD4+ T cells. To understand the effect of human MHC class II polymorphism on peptide-MHC interaction, we have isolated M13 phage from a large M13 peptide display library by selection with DRB1*0401 and DRB1*1101 molecules, as recently described for DRB1*0101. Sequence analysis of the peptide-encoding region of DR-bound phage led to the identification of position-specific anchor residues, defining motifs for peptide binding to DR molecules. The three DR motifs share two anchor residues at relative positions 1 and 4, while allele-specific anchor residues have been identified at position 6. These results provide a biophysical basis for both the promiscuity and the specificity of peptide recognition by DR molecules.

Idiopathic thrombocytopenic purpura in Egyptian children.

350 patients with idiopathic thrombocytopenic purpura (ITP) aged 2/12-15 years (mean 6.3 +/- 2.7) were followed up during the period January 1st, 1975 to March 31, 1992. They constituted 40% of cases with hemorrhagic diathesis attending the Hematology/Oncology Clinic, Children's Hospital, Ain Shams University (relative frequency of 37.4/100.000 of the general Out-Patient Clinic in the same hospital). These patients presented with acute (71.4%), chronic (22.9%) and recurrent (5.7%) forms. The age of presentation was younger in acute ITP. In the recurrent form there was significant female predominance. Most cases of acute ITP (66%) presented in winter and spring, with a positive history of preceding viral illness in 50% in contrast to 10% in chronic form. Four chronic ITP cases developed lupus erythematosus; all were females > 9 years. As regards therapy, acute ITP cases with initial platelet count (PC) < 10 x 10(9)/l were randomized to receive either high-dose methyl prednisolone (HDMP) 10 mg/kg/day for 5 days i.v. (n = 10) or intravenous immunoglobulin (IVIG) 0.4 g/kg/day for 5 days (n = 10) or conventional-dose prednisone (CDP) 2 mg/kg/day 4 weeks p.o. (n = 10). A dramatic response was noticed in the first two groups. In chronic ITP, (n = 80) CDP induced complete response (CR) in 30% and partial response (PR) in 20%; 50% were nonresponders. Twenty-four refractory ITP with persistent PC < or = 20 x 10(9)/l received second-line therapy: vincristine 1.5 mg/m2/week i.v. 4 doses (n = 4) with no clinical or hematological improvement. IVIG 0.4 g/kg/day for 5 days (n = 8) with sustained CR only in 2 patients (25%) and PR in 2 patients (25%). Splenectomy was performed (n = 12) with CR in 50%; out of them, 2 patients had shown no improvement on prior IVIG therapy. In conclusion, ITP is a benign condition with no fatality reported, but it could run a chronic refractory course.

A field survey on child health in a rural community in Egypt.

A field survey in a village was carried out to study child health in a rural area. The vaccination scheme was found to be inadequate and the value of health education is stressed. Parasitic infestation was found to be higher than urban areas but significantly lower than 1959 and the latter is attributed to a safer water supply. Growth and development lagged behing the whole national standards particularly during the 1 - 6 years age period. Health care for the pre-school age, taking advantage of co-operation from medical faculties and local health authorities, is recommended.