KRAS mutation in colon cancer: a marker of resistance to EGFR-I therapy.

INTRODUCTION AND DESIGN: The introduction of the epidermal growth factor receptor inhibitors (EGFR-I) has increased the treatment options available for patients with metastatic colorectal cancer (mCRC). Two EGFR-I agents currently approved for the treatment of mCRC are the fully human monoclonal antibody panitumumab and the mouse-human chimeric monoclonal antibody cetuximab. While these agents have demonstrated activity across multiple lines of therapy, early studies suggested that clinical benefit was confined to a subset of patients treated. Mutation of the KRAS oncogene has emerged as a powerful negative predictive biomarker to identify patients with mCRC who do not benefit from EGFR-I therapy. Multiple retrospective analyses have demonstrated that clinical benefit from treatment with EGFR-I is limited to patients with tumors harboring the wild-type KRAS gene. In this review, the KRAS pathway and studies evaluating KRAS as a prognostic marker in CRC are discussed along with advances in KRAS gene mutation testing. Clinical trials evaluating the role of KRAS status in response to EGFR-I monotherapy or in combination with chemotherapy are also highlighted along with ongoing studies evaluating the role of EGFR-I treatment on curative resections rates. RESULTS AND CONCLUSION: Future studies investigating EGFR-I therapy in mCRC should incorporate KRAS mutation testing into the study protocol in order to more accurately determine the patient population that will obtain clinical benefit from these novel agents.

Meta-analysis of a master mimicker: endobronchial lipoma.

BACKGROUND: Endobronchial lipomas (ELs) are extremely rare benign tumors that account for 0.1-0.4% of all bronchial tumors. Our study aims to better characterize these lesions based on their baseline demographic characteristics, size, location, association with smoking and establish a treatment modality of choice for such tumors. METHODS: We conducted a retrospective meta-analysis of 29 studies of EL reported from 1994 till present. These 29 studies yielded 36 patient encounters which were included in our study. Categorical outcomes were compared between study groups using chi-square test. P value <0.05 was considered statistically significant. RESULTS: Our study has shown that smaller lesions more likely to be ELs or benign lung tumors. Eighty percent of ELs had a size <1.5 cm (P=0.056) and the other tumor types had a size ≥1.5 cm. CONCLUSIONS: These tumors are difficult to diagnose due to their nonspecific presenting complaints unless pulmonologists maintain a high index of suspicion. Treatment options such surgical resection (SR) or bronchoscopic resection (BR) are available and interventions should be planned on a case-by-case basis by a multidisciplinary team.

Current Perspectives on Diagnostic Assays and Anti-PF4 Antibodies for the Diagnosis of Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a recognized clinical entity in patients receiving unfractionated heparin and low-molecular weight heparin. Currently, diagnosing HIT includes the combination of a physician's clinical suspicion based on a clinical scoring system and a series of laboratory tests. In the present article, we discuss challenges in suspecting and diagnosing HIT in consideration of the turnaround time of available tests and recent advances in techniques and methodologies of newer immunoassays and functional assays.

Hypocalcemia with Immune Checkpoint Inhibitors: The Disparity among Various Reports.

Immune-related adverse events affecting parathyroid function are rarely reported with immune checkpoint inhibitors (ICPIs). Activating calcium-sensing receptor antibodies causing autoimmune hypoparathyroidism with nivolumab was recently reported. KEYNOTE-189 and CHECKMATE-067 trials reported a 21-29% hypocalcemia event rate, but the etiology of hypocalcemia was not reported. A chart review was performed to study patients receiving ICPI from 2015 to 2018 at multiple sites affiliated with Saint Vincent Hospital. The study population was divided into two groups based on the presence or absence of calcium altering conditions or medications. True hypocalcemia incidence was calculated after correcting calcium for albumin from the initiation of ICPI to their last follow-up. Group 1 (n = 83) includes patients with no calcium altering conditions or medications. Group 2 (n = 98) includes patients on calcium supplements (n = 17), vitamin D (n = 44), bisphosphonates (n = 24), >stage IIIB chronic kidney disease (CKD) (n = 5), and bone metastasis (n = 38). Hypocalcemia events in Group 1 vs. Group 2 were 8.4% and 19.3%, respectively. Our entire study demonstrated 26.8% vs. 1.1% of Grade I vs. II hypocalcemia events. However, after correcting the calcium for albumin, hypocalcemia incidence was 0.56% (n = 1). No further workup was done to investigate the etiology as that patient passed away. Our data suggest that the true hypocalcemia incidence after using albumin-corrected calcium values is very low in patients receiving IPCI, even in the presence of calcium altering factors. The percentage of patients with hypocalcemia is much higher and similar to the KEYNOTE-189 and CHECKMATE-067 trials when serum calcium values without albumin correction are used. Thus, the higher reported incidence of hypocalcemia in these trials is likely due to the reporting of serum calcium without albumin correction.

An Unusual Case of Enteropathy-associated T-cell Lymphoma Type 2 with Pulmonary Metastasis.

Herein, we present a very rare case of enteropathy-associated T-cell lymphoma (EATL) type 2 with pulmonary metastasis which was biopsy-proven. This is a very rare type of lymphoma, and no case reports or studies of enteropathy-associated T-cell lymphoma with pulmonary metastatic disease were found in the literature review. This 64-year-old male, who presented with an acute abdomen, was found to have a perforation. Subsequent pathology of the resected specimen showed neoplastic cells consistent with EATL type 2. Four months post-diagnosis, the patient developed shortness of breath. Positron emission tomography (PET) scan revealed multiple metabolically active pulmonary nodules. A biopsy of the nodules was consistent with metastatic EATL type 2 involving the lungs.

Dying to be Ill: Munchausen meets warfarin overdose.

Patients with severe coagulopathy related to vitamin K deficient proteins can be associated with surreptitious ingestion of vitamin K antagonists. Our patient presented acutely with extensive ecchymosis, gingival bleeding and hematuria. Her initial PT and PTT were prolonged and INR was >12.0. She denies contact with potent rodenticides or warfarin use. She is a healthcare professional. Within a week, she was readmitted with similar complaints and her warfarin levels were markedly high which raised the possibility of Munchausen syndrome. Warfarin overdose can lead to harmful consequences. Therefore, immediate diagnosis and prompt treatment is critically important to minimize morbidity and mortality.

Peripheral T-cell Lymphoma, Not Otherwise Specified: An Unusual Presentation of a Rare Lymphoma.

We present a case of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) masquerading as a skin rash which progressively worsened over a year. After being treated for various dermatologic and infectious etiologies, he did not feel any relief and presented to our hospital. Imaging showed generalized lymphadenopathy. Later, lymph node biopsy and skin biopsy confirmed the diagnosis of CD30 + peripheral T-cell lymphoma. He was soon started on chemotherapy with cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisone (CHOEP). However, because of the aggressive nature of his disease and advanced stage at presentation, he succumbed to complications and died of sepsis.  This case highlights the importance of considering a rash as one of the early symptoms of an underlying life-threatening disease.

Pancytopenia: A Rare and Unusual Initial Presentation of Breast Cancer.

Bone marrow metastasis with profound pancytopenia is an extremely uncommon presentation of breast cancer. Advanced breast cancer can frequently metastasize to bone marrow, but bone marrow failure is not typically seen. Very limited data exist regarding the appropriate management of patients with metastatic breast cancer with profound pancytopenia. Our patient's initial presentation of anemia and thrombocytopenia was a diagnostic dilemma, later confirmed as metastatic breast cancer on bone marrow biopsy. After diagnosis, treatment was another challenge as there are no predefined treatment guidelines for these patients. After the initial hormonal therapy failed, our patient showed a good clinical response to chemotherapy and her platelet count improved to baseline. This dramatic response to chemotherapy is rare. Therefore, this case represents a rare instance of a diagnostic and therapeutic dilemma with unusual clinical response to chemotherapy.

Hypertriglyceridemia Induced Pancreatitis Due to Brentuximab Therapy: First Case Report.

Brentuximab vedotin is used for relapsed classical Hodgkin's lymphoma and mature T-cell lymphomas. We present a unique case of severe hypertriglyceridemia after one dose of single-agent brentuximab therapy. A Middle-Eastern male with a history of primary progressive cutaneous gamma/delta T-cell lymphoma was started on single-agent brentuximab vedotin therapy. Two weeks after single dose brentuximab therapy, he complained of severe epigastric pain, nausea, vomiting and was admitted to the intensive care unit with acute pancreatitis. Physical examination revealed an acutely ill patient with abdominal tenderness and laboratory data showed triglyceride levels of 3175 mg/dL, glycated hemoglobin (HbA1C) 9%, lipase 145 U/L and glucose 594 mg/dL. Computed tomography scan of the abdomen and pelvis confirmed acute interstitial pancreatitis. With medical management patient triglyceride levels decreased and the patient improved. This is the first case report in literature depicting, brentuximab induced hypertriglyceridemia leading to acute pancreatitis. It is a serious complication and can be lethal. Therefore, it is critical to maintain a high index of suspicion for hypertriglyceridemia induced pancreatitis after single dose brentuximab therapy.

Splenic infarction secondary to myelodysplastic syndrome: unravelling more etiologies.

Myelodysplastic syndrome (MDS) is a neoplastic disorder resulting in dysplasia and apoptosis of the hematopoietic clonal cells. The presenting features of MDS are usually dependent on the cellular lineage affected in the bone marrow (BM). Generally, MDS presents in older adults with recurrent infections, anemia, and bleeding tendencies. However, until now, there are no cases of splenic infarction in MDS. Splenic infarction is a rare event and is often reported in myeloproliferative or thromboembolic disorders. In this case report, we present splenic infarction; a never reported clinical manifestation in an MDS patient.

The Appropriateness of Testing Platelet Factor 4/Heparin Antibody in Patients Suspected of Heparin-induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is an adverse reaction to the administration of heparin due to the activation of the platelets by the immunoglobulin G (IgG) antibody-platelet factor 4 (PF4)/heparin immune complex. Since the clinical outcome is uncertain (as it could be associated with significant morbidity and sometimes death), an early diagnosis and appropriate treatment are necessary. The 4Ts pretest clinical scoring system and testing for all anti-PF4/heparin antibodies can markedly improve the diagnosis and prompt adequate treatment. Our study was undertaken to retrospectively evaluate the appropriateness of ordering the PF4 enzyme-linked immunosorbent assay (ELISA) test by using the 4Ts scoring system in a tertiary institution. We examined a database of 118 patients who had the PF4 ELISA test and calculated their 4Ts scores retrospectively. A total of 107 patients were evaluated; 95 patients (88.79%) had a negative PF4 ELISA assay and 12 patients tested positive (11.21%). Only one patient tested weakly positive in the low probability group (negative predictive value 98%). In the intermediate group, six patients were strongly positive (optical density (OD) > 1.0). In this latter group, further confirmatory testing using serotonin release assays (SRAs) could have been done. We also evaluated the setting where the tests were performed and found that the majority of patients (63.55%) were tested in the intensive care unit (ICU) where thrombocytopenia is multifactorial. We concluded that the large majority of patients were not appropriately evaluated prior to testing, which incurred unnecessary expense and patient distress. For the proper identification of patients suspected of HIT who should undergo PF4/heparin antibody testing, further education of the ordering physicians is recommended.

Coexistence of inversion 16 and the Philadelphia chromosome in patients with acute myelogenous leukemia.

The coexistence of the Philadelphia chromosome and inversion 16 abnormality in de novo acute myelogenous leukemia (AML) has only rarely been reported. We report the case of a 23-year-old man with these cytogenetic abnormalities. He is in a durable remission following intensive chemotherapy. The literature on this subject is reviewed.

Evaluation of temozolomide in patients with myelodysplastic syndrome.

In our previous phase I study of temozolomide in patients with acute leukemia, temozolomide was well tolerated and demonstrated significant anti-leukemic activity. The maximum tolerated dose was 200 mg/m2/d for 7 days, repeated approximately every 5-6 weeks. In the current study, we evaluated the same dose of temozolomide in patients with myelodysplastic syndrome. Fourteen patients received 19 courses of temozolomide. The median age was 71 years. In this study, treatment was poorly tolerated with patients requiring admission in 9 of 19 courses. Toxicity included worsening cytopenias, neutropenic fever, and exacerbation of cardiac disease, the latter due to worsening anemia. An unusual finding was the development of leukocytoclastic vasculitis in 4 patients. There were no formal responses to therapy. The current schedule of temozolomide is not efficacious in patients with myelodysplastic syndrome.