Diagnosis of Metastatic Non-Small Cell Lung Cancer during Hospitalization: Missed Opportunity for Optimal Supportive Care?

PURPOSE: The usual workup for patients newly diagnosed with advanced non-small cell lung cancer (NSCLC) occurs in the ambulatory setting. A subset of patients present with acute care needs and receive the diagnosis while hospitalized. Palliative therapies are typically initiated when patients are outpatients, even when diagnoses are made when they are inpatients. Lengthy admission, rehabilitation needs after discharge, and readmissions are possible barriers to timely and adequate outpatient follow-up. The outcomes for these patients diagnosed in the hospital are not well characterized. We hypothesized that patients have been ill-served by current treatment patterns, as reflected by low rates of cancer-directed treatment and poor survival. PATIENTS AND METHODS: We performed a retrospective study of new inpatient diagnoses of metastatic NSCLC at our institution between 1 January 2012 and 1 January 2022. The primary outcome was the proportion of patients ultimately receiving cancer-directed therapy. Other outcomes included time to treatment, use of targeted therapy, palliative care/hospice utilization, and overall survival (OS). RESULTS: Seventy-three patients were included, with a median age of 57 years. Twenty-seven patients (37%) ultimately received systemic therapy with a median time from diagnosis to treatment of 37.5 days. Overall, 5.4% patients died while admitted, 6.8% were discharged to a hospice, 21.9% were discharged to a facility, and 61.6% were discharged home. Only 20 patients (27%) received palliative care consultation. The median OS for our entire population was 2.3 months, with estimated 6-month and 1-year OS rates of 32% and 22%, respectively. CONCLUSION: Patients with new inpatient diagnoses of metastatic NSCLC have extremely poor outcomes. Current management strategies resulted in few patients starting systemic therapy, yet most of the patients did not receive palliative care or hospice involvement. These findings demonstrate that there is a high unmet need to optimally support and palliate these patients.

Durvalumab Outcomes in Stage III Non-small Cell Lung Cancer: A Single-institution Study.

BACKGROUND/AIM: The PACIFIC trial demonstrated improved survival in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with durvalumab following definitive concurrent chemoradiotherapy (CRT). This study sought to explore real-world outcomes with durvalumab consolidation therapy at our institution. PATIENTS AND METHODS: We retrospectively identified patients diagnosed with stage III NSCLC at our institution from January 2012 to January 2022. We created two cohorts: one who received durvalumab following definitive CRT and a historical one who did not. Primary outcomes of interest included median progression-free survival (PFS) and overall survival (OS). Additionally, we performed subgroup analysis on the durvalumab cohort to explore the associations between survival and time to durvalumab initiation, PD-L1 expression, and neutrophil-to-lymphocyte ratio (NLR). RESULTS: We identified 79 patients with locally advanced NSCLC who were not surgical candidates. Patients treated with durvalumab (n=44) had significantly improved survival compared to the historical cohort (n=35) including a median PFS of 17.4 months versus 8.0 months (p=0.0019) and a median OS of 37.0 months versus 17.0 months (log-rank p-value=0.07, Wilcoxon p-value=0.02). Within the durvalumab group, outcomes did not significantly differ between those who initiated therapy before or after 42 days of finishing CRT, between various PD-L1 expression levels, or between high or low NLR. CONCLUSION: Patients who received durvalumab as consolidation therapy following definitive CRT demonstrated significantly improved survival compared to a historical cohort who did not receive durvalumab. Furthermore, durvalumab appears to benefit patients regardless of time to initiation, PD-L1 expression, or NLR.

Novel Heterozygous Missense Variants in Diacylglycerol Kinase Epsilon and Complement Factor I: Potential Pathogenic Association With Atypical Hemolytic Uremic Syndrome.

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy (TMA), which copresents with microangiopathic hemolytic anemia, thrombocytopenia, and kidney injury. While typical HUS is normally preceded by infections such as Shiga-toxin-producing Escherichia coli, atypical HUS (aHUS) has a genetic component that leads to dysregulation of the alternative complement pathway. We report a case of a 69-year-old female who developed aHUS after undergoing an elective knee surgery. Genetic testing revealed novel mutations affecting diacylglycerol kinase epsilon (DGKE) protein and complement factor I (CFI) that were not reported before as pathogenic. The patient was treated with eculizumab, leading to the complete resolution of TMA with no lasting organ damage.

Current management of uncommon EGFR mutations in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) mutations are frequently implicated in non-small cell lung cancer (NSCLC). Though these typically involve exon 19 in-frame deletions or L858R mutations in exon 21, uncommon EGFR mutations comprise 10-15 % of all EGFR mutations. These most frequently include G719X mutations in exon 18, L861Q mutations in exon 21, S768I mutations in exon 20, and in-frame insertions and/or duplications in exon 20. It is crucial to understand these distinct variants and their specific responses to active treatment options to optimize care. In this review, we discuss these uncommon mutations in depth and dissect the current literature regarding their treatment outcomes and subsequent evidence-based management guidelines.

Safety Profile of Mutant EGFR-TK Inhibitors in Advanced Non-Small Cell Lung Cancer: A Meta-analysis.

Background: Despite the use of platinum-based chemotherapy, lung cancer continues to be the leading cause of cancer-related death in the world. To overcome the rate of lung cancer-related death, scientists discovered advanced therapies, including mutant epidermal growth factor receptor-tyrosine kinase (EGFR-TK) inhibitors. Observations: We conducted a meta-analysis to determine the safety profile of mutant EGFR-TK inhibitors in the management of advanced non-small cell lung cancer (NSCLC). Included in this study are 9 phase 3 randomized controlled trials designed to study the safety profile of mutant EGFR-TK inhibitors in patients with advanced NSCLC. The study showed that mutant EGFR-TK inhibitors have an incidence of adverse effects that is less reported when compared with platinum-based chemotherapy. Conclusions: We recommend continuing using mutant EGFR-TK inhibitors in patients with advanced NSCLC especially in patients having mutant EGFR receptors. Adverse effects caused by mutant EGFR-TK inhibitors are significant but are usually tolerable and can be avoided by reducing the dosage of it with each cycle or by skipping or delaying the dose until patient is symptomatic.

Hereditary Thrombophilia Testing Among Hospitalized Patients: Is It Warranted?

Background Hereditary thrombophilias (HTs) are a group of inherited disorders that predispose the carrier to venous thromboembolism (VTE). It is estimated that 7% of the population has some form of HT. Although testing for HT has become routine for many hospitalized patients, knowing when to order the tests and how to interpret the results remains challenging. In the United States, there are no clear guidelines regarding testing for HT. We conducted a study to evaluate the utilization of HT testing among hospitalized patients to examine its impact on immediate management decisions and overall cost burden. In addition, we discuss the common reasons for healthcare providers to order these tests and review the data behind these reasons in the literature. Methodology A retrospective analysis of 2,402 patients who underwent HT testing between February 1, 2016, and January 31, 2018, was conducted. Eligible patients had at least one HT test ordered during hospitalization. The primary outcome was to determine the incidence of positive actionable tests. A positive actionable test was defined as a positive result that changed the anticoagulation intensity, type, or duration. Patients with a history of previous VTE, ongoing medical conditions requiring life-long anticoagulation, or unprovoked VTE were considered non-actionable. Results Among the 2,402 patients, 954 patients met the inclusion criteria with a mean age of 54 years. A total of 397 (41.6%) tests were ordered for acute VTE, while the rest were for non-VTE conditions, such as stroke, pregnancy complications, peripheral artery diseases, and others. Only 89 positive tests were actionable (14% of the positive tests, and 9.3% of the total ordered tests). There was a statistically significant association between increasing age and having both a positive test result (p = 0.006) and an actionable test (p = 0.046). The total cost of ordering these tests was estimated to be $566,585. Conclusions HT testing in the inpatient setting did not alter management in many cases and was associated with increased healthcare costs. The decision to order these tests should be individualized based on the clinical scenario.

Novel targeted therapies for advanced non-small lung cancer.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for almost 80%-85% of all lung cancer cases. Unfortunately, more than half of the patients will be diagnosed with advanced disease at the time of presentation, which makes their disease incurable. Historically, the 5 year overall survival for advanced NSCLC was 5%. However, there has been a significant increase in our understanding of the genetic basis of NSCLC, which has led to development of both immunotherapy and targeted therapy agents. This has improved the 5 year overall survival to become within the range of 15%-50% depending on certain mutations and biomarkers. Over the last decade the United States Food and Drug Administration (FDA) has approved almost 20 new targeted therapies and clinical trials are still undergoing to evaluate more novel agents. In this review, we will present recent updates on novel targeted therapies.

Laboratory assays of VWF activity and use of desmopressin trials in the diagnosis of VWD: a systematic review and meta-analysis.

von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.

Surgical management of patients with von Willebrand disease: summary of 2 systematic reviews of the literature.

von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.

von Willebrand factor levels in the diagnosis of von Willebrand disease: a systematic review and meta-analysis.

von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.

Bleeding assessment tools in the diagnosis of VWD in adults and children: a systematic review and meta-analysis of test accuracy.

Von Willebrand disease (VWD) can be associated with significant morbidity. Patients with VWD can experience bruising, mucocutaneous bleeding, and bleeding after dental and surgical procedures. Early diagnosis and treatment are important to minimize the risk of these complications. Several bleeding assessment tools (BATs) have been used to quantify bleeding symptoms as a screening tool for VWD. We systematically reviewed diagnostic test accuracy results of BATs to screen patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using the revised tool for the quality assessment of diagnostic accuracy studies and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 7 cohort studies that evaluated the use of BATs to screen adult and pediatric patients for VWD. The pooled estimates for sensitivity and specificity were 75% (95% confidence interval, 66-83) and 54% (29-77), respectively. Certainty of evidence varied from moderate to high. This systematic review provides accuracy estimates for validated BATs as a screening modality for VWD. A BAT is a useful initial screening test to determine who needs specific blood testing. The pretest probability of VWD (often determined by the clinical setting/patient population), along with sensitivity and specificity estimates, will influence patient management.

Current Management of Refractory Germ Cell Tumors.

PURPOSE OF REVIEW: Germ cell tumors (GCTs) are the most common solid tumors affecting men between ages of 20 and 34 years. Most of the cases, even in advanced disease, will have good prognosis. However, around 20-30% of advanced disease will be refractory or develop relapse after treatment. Herein, we review the current management of refractory/relapsed GCTs. RECENT FINDINGS: Salvage treatment of GCTs has been a controversial topic for the last few decades. Conventional dose chemotherapy (CDCT), high-dose chemotherapy (HDCT) with stem cell infusion, and surgical salvage were proven to be effective and curative options in some cases. The international randomized trial (TIGER) will ultimately answer which chemotherapy approach may be optimal. Furthermore, the usage of immunotherapy is still under investigation with limited data so far in the setting of relapsed/refractory GCTs. Curative paradigms including with CDCT and HDCT are possible, although novel approaches beyond HDCT are still needed to eliminate mortality from this disease.

Venous thromboembolism prophylaxis in inflammatory bowel disease flare-ups.

BACKGROUND: Inflammatory bowel disease (IBD) is a set of chronic inflammatory diseases associated with significant morbidity. Generally, IBD patients have twice the risk of venous thromboembolism (VTE) compared to healthy controls. VTE in IBD is associated with greater morbidity and mortality. This is compounded by the underutilization of pharmacological anticoagulation in hospitalized patients with IBD. One study showed that half the IBD patients who developed VTE were not receiving any thrombotic prophylaxis. METHOD: We carried out a retrospective chart review of VTE prophylaxis use and safety in patients admitted with IBD flare-up between 2014 and 2017. RESULTS: We evaluated 233 patients (mean age 36.7 years; 53.6% male). Of these patients, 55.2% were Caucasian and 40.5% were African American; 72.5% had Crohn's disease and 21% ulcerative colitis. About one-third of our patients were on chronic steroids. Pharmacological prophylaxis was used in 39.7% of the patients. This significantly correlated with male sex, recent surgery, history of VTE, smoking, and chronic steroid use. Meanwhile, hematochezia, aspirin use, and a history of gastrointestinal bleeding were correlated with less use of pharmacological prophylaxis. Patients receiving pharmacological prophylaxis showed no difference in the incidence of bleeding events. CONCLUSIONS: Multiple factors were associated with the use of pharmacological prophylaxis in hospitalized patients, including sex, steroid use, history of VTE events or gastrointestinal bleeding, and hematochezia. The incidence of major bleeding was not significantly greater in IBD patients receiving pharmacological prophylaxis.

Maxillary Osteomyelitis with an Incidental Diagnosis of Maxillary Diffuse Large B-Cell Lymphoma: A Case Report.

Raoultella planticola osteomyelitis is rarely reported in the literature. The most likely source in our case is the oral microbiome secondary to the tooth extraction. Herein we present a case of Raoultella planticola osteomyelitis of the jaw that leads to the diagnosis of diffuse large B-cell lymphoma (DLBCL) of the jaw. A 75-year-old male with no significant medical history, presented to the emergency department with right upper jaw pain after he had a tooth extraction a week before his presentation. Computed tomography (CT) scan of the face showed concerns of right maxillary osteomyelitis with soft tissue swelling and prominent cervical lymph nodes. He underwent a bone biopsy of the maxilla and was started on intravenous ampicillin-sulbactam. His bone culture grew pan-sensitive Raoultella planticola. in addition to that, his bone biopsy revealed diffuse large B-cell lymphoma of the jaw. The patient underwent staging imaging, and he was found to have metastasis to the liver. He was started on chemotherapy and had a good response. In conclusion, Raoultella planticola osteomyelitis is extremely rare. The diagnosis of maxillary DLBCL can be a challenge. Fortunately, our patient had an infection at the same site that led to the diagnosis of DLBCL.

An Unusual Case of Diffuse Alveolar Hemorrhage as a Clinical Manifestation of Atypical Hemolytic Uremic Syndrome: A Case Report.

Hemolytic uremic syndrome (HUS) is a constellation of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal injury. HUS is subcategorized into primary or secondary HUS. Primary HUS is synonymous with atypical HUS (aHUS) and is attributed to genetic complement deficiency. Diffuse alveolar hemorrhage (DAH) is a serious condition complicating multiple systemic conditions. aHUS presenting as DAH is exceedingly rare. In this case, we present a 75-year-old male patient who presented with generalized weakness, malaise, and hemoptysis. He was found to have hemolytic anemia and thrombocytopenia, with elevated creatinine. Bronchoscopy confirmed DAH. He was started on plasmapheresis with a suboptimal response. aHUS was suspected and the patient was started on eculizumab with subsequent laboratory and clinical improvement. HUS and aHUS can present as DAH. It is very important to recognize both conditions as both are life threatening with high morbidity and mortality.

Isolated Renal Metastasis from Primary Lung Squamous Cell Carcinoma with Synchronous Small Cell Lung Cancer.

Synchronous multiple primary lung cancer is a unique type of lung carcinomas that are diagnosed with more than two different pathological types in the same or different lung lobes. Isolated metastasis to the kidney is considered rare. Herein, we present a case of a 58-year-old male with a history of chronic obstructive pulmonary disease (COPD) and 40 pack-year of cigarette smoking, who was diagnosed with synchronous small cell lung cancer (SCLC) and squamous cell carcinoma (SCC) with isolated metastasis to the kidney. Isolated kidney metastasis from lung cancer is an infrequent finding; it should be considered when the patient is diagnosed with lung cancer. In the absence of disseminated disease and contraindications, nephrectomy is an option for treatment with chemotherapy or as a palliative measure if the patient is symptomatic.

Hepatocellular Carcinoma with Tumor Thrombus Extending from the Portal Vein to the Right Atrium.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Tumor thrombus formation in advanced HCC stages is common and usually involves the hepatic or portal veins. The formation of tumor thrombus is considered a poor prognostic factor. Herein, we report a rare case wherein the thrombus extended to the inferior vena cava (IVC) reaching the right atrium without affecting the hemodynamic status. This is a 59-year-old male who presented with melena. He was found to have grade 3 esophageal varices with findings suggestive of recent bleeding associated with a large amount of blood in the gastric body that required banding. Computed tomography (CT) of the abdomen and pelvis showed multiple liver masses with an intraluminal IVC mass extending from the hepatic vein into the right atrium. A CT scan of the chest confirmed the presence of a tumor thrombus in the IVC extending to the right atrium. The patient declines surgical intervention and he was discharged. Unfortunately, he passed after a short period of time. In conclusion, tumor thrombus formation is common in HCC. However, expansion of the thrombus to IVC and right atrium is rare and indicates poor prognosis.

Acute Appendicitis and Small Bowel Obstruction Secondary to Metastatic Breast Cancer.

Breast cancer is the most common cancer in women; it is well-known to metastasize to lymph nodes, lungs, liver, brain, and bones. However, luminal gastrointestinal metastasis is rare, especially to the appendix. Herein, we report a case where cancer metastasized to the ileum and appendix, causing acute appendicitis and small bowel obstruction. This is a 44-year-old female with a history of stage IV metastatic breast cancer to bones, lungs, and ovaries, presented with acute abdominal pain for one day. Her abdomen was soft, distended with generalized tenderness. Computed tomography (CT) of the abdomen and pelvis showed a partial small bowel obstruction and swollen appendix. After her symptoms worsened on conservative treatment, she was taken to the operating room where she was found to have a markedly dilated ileum with signs of acute appendicitis, so she underwent ileocecectomy, appendectomy, and lysis of adhesions. Pathology showed metastatic breast cancer in the appendix with findings consistent with acute appendicitis. She tolerated surgery well without complications. In conclusion, small intestinal and appendiceal metastases of breast cancer are very rare though they should be considered in the differential diagnosis in cancer patients presenting with acute abdominal pain.

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.

Zieve's Syndrome: An Under-reported Cause of Anemia in Alcoholics.

Anemia is a common finding in alcoholics. It is often multifactorial and caused by a combination of liver dysfunction, ineffective erythropoiesis, and poor nutrition. Zieve's syndrome (ZS) is a clinical syndrome that presents with a triad of jaundice, hemolytic anemia, and hyperlipidemia secondary to alcohol use. Herein, we present a case of a 58-year-old male with a history of liver cirrhosis who presented after a fall due to binge drinking and was found to have severe anemia. Workup was consistent with hemolytic anemia with no source of active bleeding. The patient was managed with supportive treatment and blood transfusions which improved his anemia. However, given his advanced liver disease, he developed encephalopathy and subsequently severe aspiration pneumonia. He died 18 days after admission.