SUMMARY The PI3K/AKT/mTOR pathway is commonly activated in non-small-cell lung cancer. It plays important roles in promoting oncogenesis in lung cancer and mediating resistance to EGF receptor tyrosine kinase inhibitors. Targeted agents against the components of this pathway are currently in development and their clinical benefits remain to be defined. This review provides an overview of the pathway dysregulation and novel agents targeting the pathway in lung cancer. In addition, potential predictive biomarkers guiding patient selection for targeted PI3K/AKT/mTOR inhibition is also discussed.
IL1RAP is an emerging target for AML therapy. Studying its cell-intrinsic function revealed that IL1RAP interacts with and amplifies signaling through c-KIT and FLT3 in AML cells. This novel promiscuous role of IL1RAP in AML has implications for therapeutic targeting.
Key Points Targeting of PAK1 inhibits primary AML and MDS patients' cells including leukemia stem cells but spares healthy stem and progenitor cells. Inhibition of PAK1 induces differentiation and apoptosis of AML cells through downregulation of MYC and a core network of MYC target genes.
Manipulation of co-stimulatory or co-inhibitory checkpoint proteins allows for the reversal of tumor-induced T-cell anergy observed in cancer. The field has gained credence given success with CTLA-4 and PD-1 inhibitors. These molecules include immunoglobulin family members and the B7 subfamily as well as the TNF receptor family members. PD-L1 inhibitors and LAG-3 inhibitors have progressed through clinical trials. Other B7 family members have shown promise in preclinical models. TNFR superfamily members have shown variable success in preclinical and clinical studies. As clinical investigation in tumor immunology gains momentum, the next stage becomes learning how to combine checkpoint inhibitors and agonists with each other as well as with traditional chemotherapeutic agents.
Acute splenic sequestration crisis (ASSC), characterized by rapidly progressive anemia and circulatory compromise in the setting of sudden splenic enlargement, is an uncommon entity among adult sickle cell patients. We reviewed cases of adult ASSC encountered at our institution to generate insight into the recognition, diagnosis, and treatment of the condition. Cases of adult ASSC during a 10-year period were identified retrospectively. Patient charts were reviewed for laboratory and imaging results; demographic data and clinical course were collected and reviewed. Sixteen cases of adult ASSC were identified. Most patients presented with pain crisis; only four of 16 patients presented with abdominal pain. The maximum decreases in hemoglobin (Hb) (42.0%) and platelets (62.1%) occurred at day 2.9, delaying identification and treatment. Hemodynamic instability played a large role in dictating risk stratification. Therapy consisted of transfusion (14/16) and splenectomy (5/16). No recurrences were noted in a mean follow-up time of 5.3 years but review of patients' charts demonstrated that at least one of the patients had two prior episodes. Adult ASSC may present with non specific findings and patients may not deteriorate until several days into a previously uneventful hospital course. Changes in platelet counts may be more reliable markers than changes in Hb level since red cell transfusions may interfere with assessments of the sequestration process. This case series of adult ASSC, the largest reported in the literature to date, highlights common clinical, laboratory, radiological, and pathological features of this uncommon entity and helps to guide recognition, diagnosis, and treatment.
Background: Patients with metastatic colorectal cancer (mCRC) who progress on standard therapies may be eligible for phase I trials. To better delineate the risk-benefit ratio, we assessed toxicities, clinical outcomes and prognostic factors. Methods: Records of mCRC patients on phase I trials at our institution over 18 years were reviewed. Univariable (UVA) and multivariable analyses (MVA) were undertaken and a prognostic model developed. Results: There were 187 enrollments on 37 phase I trials. Median age was: 59 (29-83) years and number of prior therapies: 3 (0-8). The clinical benefit rate (CBR): response (5.6%)+stable disease, was 43.1%. Median progression free survival (PFS) and overall survival (OS) was 7.7 weeks and 43.7 weeks, respectively. The MVA identified age>60 years (HR 1.63, p<0.004), albumin<3.5g/dL (HR 3.69, p<0.001), direct bilirubin>ULN (HR1.69, p<0.01), and WBC≥5.2k/uL (HR 1.97, p<0.001) as negative prognostic factors. A risk score based on the MVA revealed that patients with a score of 0-1 had an improved OS (58.7 weeks) compared to a score of 2 (49.9 weeks, p<0.01) and 3 (14.1 weeks, p<0.001). Conclusions: Phase 1 trials may offer similar or better clinical outcome for mCRC patients than standard third line therapies; the prognostic model could assist in selecting appropriate patients.
The bone marrow procedure (BMP) is a frequently performed procedure, with over 700,000 recorded in the U.S. annually. It is a fundamental component in the evaluation and management of both malignant and benign hematologic conditions. Adult patients are generally assured that the BMP is a safe procedure with minimal risk, albeit briefly painful. Traditionally performed using a manual Jamshidi needle, the procedure is increasingly being performed using powered bone marrow kits, which have shown consistently good results. In the current review we describe three cases of gluteal artery injuries following the powered driver procedure, one of which resulted in the formation of a pseudoaneurysm requiring radiology-guided intervention. We highlight the need for both hematologists and patients to be aware of this potentially life threatening complication as well as how to recognize it clinically and institute timely diagnostic and therapeutic measures.
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