Response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation: A case report.

BACKGROUND: Although common in lung cancer, somatic epidermal growth factor receptor (EGFR) mutations are rarely found in colorectal cancer, occurring in approximately 3% of cases. Treatment with anti-EGFR antibodies is commonplace, but EGFR tyrosine kinase inhibitors are not standard treatments in colorectal cancer. Here we report a case of sustained response to osimertinib in a colorectal cancer patient with an EGFR T790M mutation on cell-free DNA analysis. CASE SUMMARY: A 72-year old woman with a past medical history of post-polio syndrome confined to a wheelchair, scoliosis and hypothyroidism presented with metastatic sigmoid colon adenocarcinoma with hepatic metastases. Next generation sequencing revealed a RAS/RAF wild-type, microsatellite stable, PD-L1 negative malignancy. Mutations in TP3 and APC were also identified, as well as EGFR amplification. Cell-free DNA analysis revealed an EGFR T790M mutation. She was unable to tolerate first-line treatment with panitumumab, 5-fluorouracil and leucovorin, progressed on second-line treatment with trifluridine/tipiracil plus bevacizumab, and was unable to tolerate third-line treatment with regorafenib. She was started on fourth-line treatment with off-label osimertinib, with clinical response - decrease in size of hepatic metastases and a pericardial effusion. She remained on treatment with osimertinib for seven months. CONCLUSION: This case shows the benefit of multi-gene sequencing assays to identify potential therapeutic options in patients with refractory disease.

Utility of RNA Expression to Determine the Tissue of Origin of Malignancies with an Inconclusive Histopathology.

We present 2 cases of cancer of unknown origin in which RNA-based cancer classification testing provided vital insight and directed treatment management. The tissue of origin could not be determined in both of these patients utilizing morphology and immunohistochemical analysis of the tissue samples. Next-generation sequencing and tumor-of-origin testing using an RNA-based molecular cancer classifier were performed to elucidate the possible tissue of origin. A 61-year-old male with a history of localized basal cell carcinoma presented with a 4.4-cm axillary lymph node in addition to upper extremity edema and supraclavicular lymphadenopathy. RNA-based tumor origin testing revealed skin basal or squamous cell carcinoma as the likely tissue of origin, with a probability of 97%. He received vismodegib, a hedgehog inhibitor, after progression on cemiplimab and experienced a partial response by RECIST criteria, which is currently ongoing for over a year. A 74-year-old female patient with a remote history of ovarian cancer for which she underwent resection and adjuvant chemotherapy presented 15 years later with abdominal pain. The diagnostic workup revealed a 2-cm pancreatic mass and enlarged peritoneal lymph nodes. RNA sequencing revealed a 99% likelihood of the tissue of origin being serous ovarian carcinoma. Subsequently, she underwent surgery and adjuvant chemotherapy and is currently in remission with letrozole maintenance. Genomic data already plays a crucial role in therapeutic decision-making for individuals with cancer. These cases highlight the complementary role of genomic data in the diagnostic workup of cancer, leading to favorable patient outcomes.

Squamous cell carcinoma of the lung: improving the detection and management of immune-related adverse events.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for patients with non-small lung cancer (NSCLC). Currently approved ICIs are monoclonal antibodies that target programmed death receptor 1 (PD-1), its ligand PD-L1, or CTLA-4. With ICIs comes a novel collection of toxicities: immune-related adverse events (IRAEs). Management of IRAEs requires multidisciplinary expertise. We review the biology of IRAEs and their management in patients with squamous NSCLC. AREAS COVERED: We review the pathophysiology of ICIs and IRAEs. For IRAEs related to squamous NSCLC, Cochrane Central, EMBASE, and PubMed were queried for trials with patients with squamous cell carcinoma or adenocarcinoma histology, who were assessed for incidence rates of IRAEs. Thirteen trials met inclusion criteria. National guidelines are reviewed to outline management strategies for IRAEs. EXPERT OPINION: IRAEs are unique compared to standard chemotherapy. As the role of ICIs expand across all stages of squamous cell NSCLC and with different combinations of antineoplastics, management of IRAEs will become crucial. Optimal management of IRAEs requires multidisciplinary teamwork. Further investigation into the pathophysiology of IRAEs can enhance current management strategies.

A Case of Prostate Cancer Presenting with Rash.

Mixed cryoglobulinemia (MC) is well known for its association with chronic hepatitis C virus (HCV) infection. However, it has also been linked to autoimmune disorders and hematological malignancies, particularly of B-cell lymphoid origin. Association with solid malignancies is poorly described in the literature. Non-HCV-related MC, in the setting of prostate cancer, has been reported only twice. Here, we describe a case of MC in a prostate cancer patient complicated by membranoproliferative glomerulonephritis (MPGN) that responded well to plasma exchange therapy and treatment with both corticosteroids and rituximab.

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer.

Introduction: Epidermal growth factor receptor (EGFR) mutations are well-described drivers of non-small cell lung cancer (NSCLC) and EGFR tyrosine kinase inhibitors (TKIs) have become key components of the NSCLC front-line treatment landscape. Tumors inevitably develop resistance to these agents, and development efforts continue to focus on identifying mechanisms of resistance and drugs to target these mechanisms. Areas covered: With several EGFR TKIs approved for use in the first-line or in later-line settings, an understanding of the efficacy and safety of these inhibitors in various populations is warranted. Furthermore, given the frequent emergence of drug resistance in NSCLC, examination of tumor tissue throughout the disease course provides the opportunity to select treatments based on the tumor's mutation profile. Here, we discuss: key efficacy and safety findings for approved and investigational EGFR TKIs; known mechanisms of resistance, particularly the T790M acquired EGFR mutation; and recent advances in EGFR mutational testing that may facilitate less invasive tissue testing and guide treatment selection. Expert commentary: The expanding armamentarium of EGFR TKIs, improvements in the understanding of resistance mechanisms and technological developments in the molecular analysis of tumors may help render EGFR mutation-positive NSCLC a chronic disease in many patients by facilitating optimal sequential therapy.

The role of chemotherapy in the treatment of stage II nasopharyngeal carcinoma: Retrospective analysis of the national cancer database.

The standard of care treatment for locally advanced nasopharyngeal carcinoma (NPC) includes both chemotherapy and definitive radiation. However, there are limited data on the optimal management of stage II NPC. We performed a retrospective analysis of the National Cancer Database to analyze the treatment patterns and role of chemotherapy in patients with stage II NPC. We identified 611 patients diagnosed with T1-2, N0-1, M0 NPC, from 2004 to 2013. Five-year survival was calculated using Kaplan Meier (KM) analysis. Multivariable analysis and propensity matched analysis were performed to analyze the impact of chemotherapy on overall survival. Of the 611 patients, 527 underwent concurrent chemoradiation (CCRT) and 84 received radiation only. Unadjusted KM analysis showed improved 5-year survival in the CCRT group compared to radiation only (80.5% vs 65.7%; P = 0.0021). Multivariable analysis also showed improved survival with the addition of chemotherapy (Hazard ratio [HR] 0.59; 95 CI 0.39-0.89; P = 0.0124). Propensity matched analysis confirmed a significant clinical benefit from the addition of chemotherapy to radiation. Age ≥ 65 years (HR 2.41; 95% CI 1.71-3.4; P = <0.0001), Charlson-Deyo comorbidity index >1 (HR 2.82; 95% CI 1.49-5.31; P = 0.0014) and positive lymph node status (HR 1.6; 95% CI 1.04-2.46; P = 0.0340) were associated with worse survival. In this retrospective analysis, patients with stage II NPC had improved survival with CCRT compared to definitive radiation only. Elderly patients with comorbidities had worse outcomes.

The evolving genomic landscape in urothelial cancer.

PURPOSE OF REVIEW: Recent advances in next-generation sequencing have allowed for detailed molecular analysis of urothelial carcinomas, with potentially significant clinical implications for personalized treatment. Our objective in this review is to highlight studies from the past year that have furthered the understanding of urothelial cancer genomics. RECENT FINDINGS: Recent studies by The Cancer Genome Atlas consortium further characterized urothelial carcinomas via molecular subtyping, and a schema was proposed to match each subtype with potential therapeutic implications. Molecular subtyping was also utilized in a separate analysis to determine which tumours benefit from neoadjuvant chemotherapy. Tumour characteristics were also explored pre and postneoadjuvant chemotherapy and a mutational signature associated with postcisplatin treatment was described. We also review a comprehensive analysis of upper tract urinary carcinomas published this past year. SUMMARY: Recent genomic analyses have revealed that the classification of urothelial carcinoma is much more complex than the traditional dichotomy of nonmuscle-invasive and muscle-invasive bladder cancers. Molecular subtyping has provided additional insights into prognoses and treatment options for these patients. Although molecular subtyping is not yet ready for implementation into clinical practice, these latest efforts offer an exciting opportunity to integrate such information into prospective clinical studies that may ultimately lead to improved treatment outcomes.

The Role of Systemic Therapy in the Management of Stage I Large Cell Neuroendocrine Carcinoma of the Lung.

INTRODUCTION: The optimal treatment strategy for resected stage I large cell neuroendocrine carcinoma of the lung (LCNEC) remains unknown. In this analysis, we evaluate the impact of systemic chemotherapy on patients with stage I LCNEC who have undergone surgical resection. METHODS: The study population included patients who underwent surgical resection for LCNEC and had pathologic stage I disease. We compared overall survival between patients who underwent surgical resection alone and those who underwent surgical resection plus chemotherapy. Overall survival was estimated by the Kaplan-Meier method, and comparisons were analyzed by using multivariable Cox models and propensity score-matched analyses. RESULTS: From 2004 to 2013, 1232 patients underwent surgical resection for stage I LCNEC in the National Cancer Database, including 957 patients (77.7%) who underwent surgical resection alone and 275 (22.3%) who received both surgery and systemic chemotherapy. Five-year survival was significantly improved in patients who received chemotherapy (64.5% versus 48.4% [hazard ratio =0.54, 95% confidence interval: 0.43-0.68, p < 0.001]). Multivariable Cox modeling confirmed the survival benefit from chemotherapy for patients with resected stage I LCNEC (hazard ratio = 0.54, 95% confidence interval: 0.43-0.68, p <0.0001). The survival benefit was further confirmed by propensity-matched analysis. In addition, older (age >70 years), comorbid white patients who underwent sublobar resections for tumors larger than 20 mm had worse survival outcomes. CONCLUSION: In this largest-reported retrospective study of patients with resected stage I LCNEC, survival was improved in patients who received chemotherapy in both stage IA and stage IB LCNEC.

Two for One: B-Cell Lymphomas with Features of Marginal and Follicular Lymphomas.

Low-grade follicular lymphomas are genetically characterized by the translocation t(14; 18)(q32;q21) with BCL2 gene rearrangements. Marginal zone lymphomas are often associated with translocations or transcriptional deregulations of the MALT gene. We report 2 cases of lymphomas which harbor both the t(14;18)(q32;q21) translocation and MALT gene upregulation. Patients presented with numerous circulating atypical lymphocytes. Lymph node biopsy in both cases on HE staining demonstrated vague nodularity readily highlighted by CD10, CD23, or BCL6. Staining with CD20 and BCL2 demonstrated monotonous diffuse effacement of normal architecture with tumor cells without obvious follicular structures. Morphologically, tumor cells were consistent with centrocytes. Bone marrow biopsy demonstrated a combined peritrabecular and interstitial distribution of the tumor cells. These cases present substantial difficulties for diagnosis and classification. Clinical and morphological features were mostly consistent with follicular lymphoma, with a few features more often seen in marginal zone lymphomas (leukemic presentation, no CD10 in circulating cells, interstitial location of tumor cells in bone marrow); therefore, these cases were finally classified as follicular lymphoma grade I. Both patients were treated with standard chemotherapy regimens for follicular and nongastric MALT lymphomas with a good response to date.

Disparities in the Management of Patients With Stage I Small Cell Lung Carcinoma (SCLC): A Surveillance, Epidemiology and End Results (SEER) Analysis.

INTRODUCTION: Patients with stage I small cell lung carcinoma (SCLC) are candidates for surgery; however, not much is known regarding the utilization of surgical resection in the management of stage I SCLC and the factors that determine the patient's ability to receive surgery. METHODS: The Surveillance, Epidemiology and End Results database was used to identify patients with stage I SCLC from 2007 to 2013. Continuous variables were compared with 1-way analysis of variance, and categorical variables were compared with χ2 testing. Multivariable logistic regression analyses were used to obtain odds ratios. RESULTS: Of the 1902 patients with stage I SCLC, 427 (22.4%) underwent resection, 116 (6.1%) resection and radiation, 815 (42.8%) received radiation alone, and 544 (28.6%) did not undergo surgery or radiation. Median overall survival for patients with surgery plus radiation was 60+ months, followed by surgery alone at 50 months, radiation at 27 months, and no resection/radiation 16 months. Patients with ≥ 4 lymph nodes removed during surgery had better overall survival of 60+ months compared with patients with < 4 lymph nodes removed (25 months); P < .001. Multivariate analysis demonstrated that elderly patients, men, African American individuals, Medicaid recipients, and patients with left-sided tumors were less likely to undergo resection. However, county-level socioeconomic factors, such as level of poverty, education, unemployment, and median income did not affect the likelihood of undergoing resection. CONCLUSIONS: Fewer than one-third of all patients with stage I SCLC undergo resection despite better outcomes with resection. Elderly African American men with Medicaid insurance were less likely to receive resection.

Acroparesthesia in a female: diagnostic dilemma.

Fabry disease is an X-linked lysosomal storage disorder caused by deficient activity of a-galactosidase A (also known as ceramide trihexosidase) and resultant accumulation of globotriaosylceramide (Gb3) and related glycophospholipids. The disease affects nearly all major organ systems, with the primary sites damaged by Gb3 including renal glomeruli, myocardium, neurons of the dorsal ganglion and autonomic nervous system, and vascular endothelial and smooth muscle. Progressive deposition in these organ systems leads to renal and heart failure; debilitating pain as a result of nervous system involvement also occurs.

Acute endocarditis in intravenous drug users: a case report and literature review.

Infective endocarditis (IE) is a notorious complication of intravenous drug use (IDU). It typically affects the cardiac valves. Among these, the tricuspid is the most common affected valve, although the mitral and/or aortic valves can also be involved. Methicillin sensitive staphylococcus aureus (MSSA) is the most common etiological microbial agent of IE in IDU. Once IE is diagnosed, antibiotic treatment should start immediately after blood cultures have been obtained. However, IE in this particular patient population is more difficult to treat, and has a high recurrence rate compared to other patient populations, because of continuing IDU and medical non-compliance. Here, we present an interesting case of IE in a relatively young IDU patient with severe MSSA positive sepsis. The updated diagnostic and treatment strategies, as well as the ethical issues involved in the management of IE patients in the setting of current active IDU will also be discussed.