Oxygen saturation thresholds in managing sickle cell disease at US children's hospitals.

BACKGROUND: Adequate oxygen saturation (SpO2 ) is crucial for managing sickle cell disease (SCD). Children with SCD are at increased risk for occult hypoxemia; therefore, understanding SpO2 threshold practices would help identify barriers to oxygen optimization in a population sensitive to oxyhemoglobin imbalances. We investigated SpO2 cutoff levels used in clinical algorithms for management of acute SCD events at children's hospitals across the United States, and determined their consistency with recommended national guidelines (SpO2  > 95%). METHODS: Clinical pathways and algorithms used for the management of vaso-occlusive crisis (VOC) and acute chest syndrome (ACS) in SCD were obtained and reviewed from large children's hospitals in the United States. RESULTS: Responses were obtained from 94% (140/149) of eligible children's hospitals. Of these, 63 (45%) had available clinical algorithms to manage VOC and ACS. SpO2 cutoff was provided in 71.4% (45/63) of clinical algorithms. Substantial variation in SpO2 cutoff levels was noted, ranging from ≥90% to more than 95%. Only seven hospitals (5% of total hospitals and 15.6% of hospitals with clinical algorithms available) specified oxygen cutoffs that were consistent with national guidelines. Hospitals geographically located in the South (46.8%; n = 29/62) and Midwest (54.8%; n = 17/31) were more likely to have VOC and ACS clinical algorithms, compared to the Northeast (26.5%; n = 9/34) and West (36.4%; n = 8/22). CONCLUSION: There is inconsistency in the use of clinical algorithms and oxygen thresholds for VOC and ACS across US children's hospitals. Children with SCD could be at risk for insufficient oxygen therapy during adverse acute events.

A multifaceted role of bisphosphonates from palliative care to anti-cancer therapy in solid tumors.

INTRODUCTION: Bisphosphonates (P-C-Ps) also called diphosphonates are the structural analogs of naturally occurring pyrophosphates. Bisphosphonates are traditionally used and shown to provide long-term success in the treatment and prevention of osteoporosis and other bone loss pathologies. Furthermore, bisphosphonates are gaining popularity in the present era of cancer therapeutics and prevention. The usage of bisphosphonates as adjuvant or neoadjuvant therapy, either as a single agent or combined with other chemotherapy, has been studied in different solid tumors. This review aims to present the various roles of bisphosphonates in solid tumors. DATA SOURCES: Articles in MEDLINE/PubMed and the National Institutes of Health Clinical Trials Registry (http://www. Clinicaltrials.gov) between 1 January 2011 and 1 February 2022 were extracted using MeSH terms "bisphosphonates/diphosphosphonates and mechanism," "bisphosphonates and breast cancer," "bisphosphonates and prostate cancer," "bisphosphonates and lung cancer," "bisphosphonates and cancer risk," and "bisphosphonates and adverse events." Manual searches of some major oncology journals were also conducted. DISCUSSION: This review article focuses on the antitumor activity of bisphosphonates, safety profile, and the role of bisphosphonates as preventive, neoadjuvant, and adjuvant chemotherapy. A significant improvement in overall survival and cancer-specific survival and recurrence-free survival with the usage of bisphosphonates is noted in breast cancer patients, particularly in post-menopausal women. Though great progress has been achieved in over 20 years, further research is needed to identify the subgroup of patients that are most likely to benefit from adjuvant bisphosphonate therapy and to determine regimens with greater efficacy and better safety profile.

Pulmonary hypertension screening in children with sickle cell disease.

BACKGROUND: Screening for pulmonary hypertension (PHT) is recommended in children with sickle cell disease (SCD). However, best approaches are poorly described. We examined the utility of PHT symptoms, echocardiogram (ECHO), N-terminal-pro hormone brain natriuretic peptide (NT-proBNP), and BNP to screen for PHT in the SCD pediatric population. METHODS: Children (8-18 years old) with SCD-HbSS and HbSthal° were prospectively included and underwent PHT screening. The screening consisted of a comprehensive PHT symptoms evaluation, ECHO measurement, and NT-proBNP and BNP levels. RESULTS: A total of 73 patients were included (mean age 12 ± 5.7 years; >80% on hydroxyurea), of which 37% had a symptom consistent with PHT, including exertional dyspnea (26.5%), fatigue (17.6%), palpitation (14.7%), and chest pain (10.3%). ECHO was obtained in 53 (72.6%) patients, with only ECHO of 48 patients included in the final analysis. Elevated ECHO peak tricuspid regurgitant jet velocity (TRV) >2.5 m/s or indirect findings to suggest PHT were seen in only two of 48 (4.2%). No significant differences were seen between those with and without PHT symptoms when compared for NT-proBNP, BNP, hemoglobin, pulmonary function testing, fractional exhaled nitric oxide, asthma, oxygen saturation, and sleep apnea. CONCLUSION: PHT symptoms are not consistent with ECHO, NT-proBNP nor BNP findings in children with SCD. PHT prevalence based on TRV was low in children on hydroxyurea, therefore screening may not be warranted for this group.

Screening for asthma in preschool children with sickle cell disease.

BACKGROUND: Asthma in preschool children is poorly defined, proving to be a challenge for early detection. The Breathmobile Case Identification Survey (BCIS) has been shown to be a feasible screening tool in older SCD children and could be effective in younger children. We attempted to validate the BCIS as an asthma screening tool in preschool children with SCD. METHODS: This is a prospective, single-center study of 50 children aged 2-5 years with SCD. BCIS was administered to all patients and a pulmonologist blinded to the results evaluated patients for asthma. Demographic, clinical, and laboratory data were obtained to assess risk factors for asthma and acute chest syndrome in this population. RESULTS: Asthma prevalence (n = 3/50; 6%) was lower than atopic dermatitis (20%) and allergic rhinitis (32%). Sensitivity (100%), specificity (85%), positive predictive value (30%), and negative predictive value (100%) of the BCIS were high. Clinical demographics, atopic dermatitis, allergic rhinitis, asthma, viral respiratory infection, hematology parameters, sickle hemoglobin subtype, tobacco smoke exposure, and hydroxyurea were not different between patients with or without history of ACS, although eosinophil was significantly lower in the ACS group (p = 0.0093). All those with asthma had ACS, known viral respiratory infection resulting in hospitalization (3 RSV and 1 influenza), and HbSS (homozygous Hemoglobin SS) subtype. CONCLUSION: The BCIS is an effective asthma screening tool in preschool children with SCD. Asthma prevalence in young children with SCD is low. Previously known ACS risk factors were not seen, possibly from the beneficial effects of early life initiation of hydroxyurea.

From the archives of MD Anderson Cancer Center Castleman disease involving the thymus gland: Case report and literature review.

Castleman disease is a nodal based disease and very rarely involves the thymus gland. We report a 52-year-old man who was found incidentally to have a single thymic mass by computerized tomography scan. Thymectomy was performed, and the gross specimen showed a well-circumscribed, multi-loculated cystic mass. Histologic examination showed thymus involved by Castleman disease, hyaline-vascular variant. The lesion was characterized by lymphoid follicles with wide mantle zones, variably lymphocyte-depleted germinal centers with sclerotic radial blood vessels, and prominent interfollicular/stromal changes including numerous endothelial venules with sclerotic walls and hyaline sclerosis, scattered and frequent dysplastic follicular dendritic cells and foci of dystrophic calcification. Immunohistochemical analysis showed that the follicle mantle zones were composed of numerous B-cells positive for CD20, PAX5, and IgD. Antibodies specific for CD21 and CD23 highlighted prominent follicular dendritic cell networks within follicles. There was no evidence of human herpes virus 8. We searched the literature and could identify only 10 additional cases of thymic CD. Previously reported cases included 8 unicentric and 2 multicentric, classified pathologically as plasma cell variant (n = 4), hyaline vascular variant (n = 3), and mixed (n = 3). Thymectomy, as was done in the currently reported case, most often leads to the diagnosis of Castleman disease and was a mainstay of treatment in other reported cases.

Weakness and elevated creatinine kinase as the initial presentation of coronavirus disease 2019 (COVID-19).

COVID-19 is a global public health emergency with more than one million positive cases across the globe. COVID-19 has a multifaceted presentation. We are herein to report two cases of SARS-CoV-2 induced rhabdomyolysis with an initial presentation of weakness and elevated creatinine kinase (CK). Both patients had no respiratory symptoms, they only complained of generalized weakness and were found to have elevated CK. Routine chest X-ray showed bilateral infiltrates in both cases and subsequently reverse-transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 was positive. To the best of our knowledge, there was only one literature to date documented SARS-CoV-2 induced rhabdomyolysis as a late complication of COVID-19 patient. Our cases showed that elevated CK and rhabdomyolysis can be the sole initial presentation of patients with COVID-19 and total CK should be ordered in every patient on admission.

Coronavirus disease 2019 (COVID-19) and ischemic colitis: An under-recognized complication.

COVID-19 has spread worldwide, with more than 2.5 million cases and over 80,000 deaths reported by the end of April 2020. In addition to pulmonary symptoms, gastrointestinal symptoms have been increasingly recognized as part of the disease spectrum. COVID-19-associated coagulopathy has recently emerged as a major component of the disease, leading to high morbidity and mortality. Ischemic colitis has been reported to be associated with a hypercoagulable state. To our knowledge, there have not been any case reports of COVID-19 associated with ischemic colitis. Herein, we present the first case of a probable association of COVID-19 with ischemic colitis in a patient with a hypercoagulable state.

Real-world experience of patients with sickle cell disease treated with crizanlizumab.

In 2019, crizanlizumab was approved by the Food and Drug Administration (FDA) to reduce the rate of vaso-occlusive crisis in patients with sickle cell disease (SCD). We aimed to study the real-world effectiveness of crizanlizumab in our comprehensive sickle cell center. This was a retrospective cohort analysis of patients with SCD who received at least two consecutive doses of crizanlizumab. Clinically significant improvement was captured using the patient global impression of change scale (PGI-C). As of December 2022, there were 18 patients eligible for analysis with a median age of 30.5 years. Eight patients had the HbSS genotype, 7 HbSC, and 3 HbSB null genotype. Median duration of exposure to crizanlizumab was 53.6 weeks, and 16 (88.9%) patients received crizanlizumab for ≥26 weeks. Crizanlizumab was very well tolerated with no serious adverse events (grade ≥3) related to treatment. There was no significant difference in laboratory parameters. There was a remarkable improvement in patients' subjective response to crizanlizumab infusion. The median PGI-C score of our patients was 5, signifying moderately better with slight but noticeable changes. The morphine equivalent daily doses (MEDD) were lower after crizanlizumab infusion. MEDD prior to crizanlizumab was 90; after ≥2 consecutive crizanlizumab doses, it was 60. There was also a reduction in the hospital admissions, emergency, and urgent care visit for acute pain crisis in 6 (28%) patients. This study shows that crizanlizumab was associated with improvement in patients' response, both directly and indirectly related to the reduction of opioids used, which is consistent with results from the SUSTAIN trial.

Complete Pathologic Response With Pembrolizumab and Enfortumab Vedotin in Urothelial Carcinoma of the Upper Urinary Tract.

Urothelial carcinoma of the upper urinary tract (UTUC) presents a significant clinical challenge, often requiring aggressive surgical intervention for optimal management. We present a case of an 84-year-old woman with recurrent high-grade papillary UTUC of the left renal pelvis, refractory to prior endourologic interventions, who underwent neoadjuvant treatment with pembrolizumab and enfortumab vedotin (Pembro/EV) due to contraindications to cisplatin therapy. Following a favorable response to neoadjuvant therapy, the patient underwent laparoscopic left radical nephroureterectomy, achieving a pathologic complete response. We discuss the utility of Pembro/EV in the perioperative management of patients with UTUC, particularly in those ineligible for cisplatin-based therapy. In addition, we highlight the potential role of somatic mutation testing and the integration of novel therapeutic agents such as olaparib in personalized treatment strategies for UTUC. This case underscores the importance of exploring innovative treatment approaches and optimizing patient selection for kidney preservation strategies in the management of UTUC. Further research and clinical trials are warranted to elucidate the full therapeutic potential of Pembro/EV and other emerging therapies in this setting.

Belzutifan, HIF-2α Inhibitor, and Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-of-Function Mutation.

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift and sustained response, underscoring the potential role of belzutifan as a viable option in second or subsequent lines of therapy for individuals with somatic VHL mutations. Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

Promising Response of Olaparib in Patient With Germline ATM-Mutated Metastatic Gastric Cancer.

Gastric cancer ranks as the fifth leading cause of global cancer incidences, exhibiting varied prevalence influenced by geographical, ethnic, and lifestyle factors, as well as Helicobacter pylori infection. The ATM gene on chromosome 11q22 is vital for genomic stability as an initiator of the DNA damage response, and mutations in this gene have been associated with various cancers. Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown efficacy in cancers with homologous recombination repair deficiencies, notably in those with ATM mutations. Here, we present a case of a 66-year-old patient with germline ATM-mutated metastatic gastric cancer with very high CA 19-9 (48 000 units/mL) who demonstrated an exceptional response to the addition of olaparib to chemo-immunotherapy and subsequent olaparib maintenance monotherapy for 12 months. CA 19-9 was maintained at low level for 18 months. Despite the failure of a phase II clinical trial on olaparib in gastric cancer (NCT01063517) to meet its primary endpoint, intriguing findings emerged in the subset of ATM-mutated patients, who exhibited notable improvements in overall survival. Our case underscores the potential clinical utility of olaparib in germline ATM-mutated gastric cancer and emphasizes the need for further exploration through larger clinical trials. Ongoing research and clinical trials are essential for optimizing the use of PARP inhibitors, identifying biomarkers, and advancing personalized treatment strategies for gastric cancer.

Non-Hodgkin lymphoma mortality disparities across different sexes, races, and geographic locations.

Non-Hodgkin lymphoma (NHL) is one of the most common hematological cancers in the United States. The mortality rate of NHL in the United States is the sixth highest among all cancers. Our cross-sectional study aims to examine the trends and disparity in NHL mortality. We analyzed death certificate data from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) United States to determine the NHL mortality trends among the U.S. population aged ≥15 years. NHL (ICD-10 C82-85) was listed as the underlying cause of death. Age-adjusted mortality rates (AAMRs) per 100,000 individuals and joinpoint trend analysis were performed to determine the average annual percent change (AAPC) in AAMR trends. From 1999 to 2020, NHL accounted for 457,143 deaths in the United States, of which 54% are men and 46% are women. The NHL AAMR decreased significantly from 10.59 to 6.21 per 100,000 individuals with an AAPC of -2.55. Men had a higher AAMR than women (10.10 vs 6.29 per 100,000 individuals). Whites recorded the highest AAMR (8.43 per 100,000 individuals), followed by Hispanics (6.32 per 100,000 individuals), Blacks (5.71 per 100,000 individuals), American Indians (5.31 per 100,000 individuals), and Asians (5.10 per 100,000 individuals). Those who lived in the Midwest and the rural areas had the highest AAMR at 8.60 and 8.35 per 100,000 individuals respectively. Despite the declining NHL mortality rate, this study calls for targeted intervention to improve outcomes for susceptible individuals affected by NHL.

A Review of the Current Approach and Treatment Landscape for Stage III Non-Small Cell Lung Cancer.

The therapeutic landscape of the management of stage III non-small cell lung cancer (NSCLC) has drastically evolved with the incorporation of immunotherapy and targeted therapy. Stage III NSCLC accounts for one-third of the cases and the treatment strategy of these locally advanced presentations are diverse, ranging from surgical to non-surgical options; with the incorporation of chemo-immunotherapy, radiation, and targeted therapies wherever applicable. The staging of this disease has also changed, and it is essential to have a strong multidisciplinary approach to do justice to patient care. In this article, we aim to navigate the nuanced approaches in the diagnosis and treatment of stage III NSCLC and expand on the evolution of the management of this disease.

Genomic profiling and sites of metastasis in non-small cell lung cancer.

Background: We investigated the biological predisposition to site of metastasis in patients with NSCLC based on their molecular profiling and program death ligand PD-L1 status. We sought to identify any association between metastatic site and molecular profile in NSCLC patients. Methods: This was a retrospective analysis of patients with stage IV NSCLC who were newly diagnosed from January 2014 to June 2022. Clinical characteristics, pathology, molecular reports, and imaging were retrieved and analyzed. Results: A total of 143 patients were included in the study. Median age was 65 years, with an equal number of men (n=71) and women (n=72). The most common histology was adenocarcinoma (81.8%). At least one genetic mutation was discovered in 100 patients. Mutations with a targetable drug were found in 86 patients. The most common mutations were TP53 (25.2%), EGFR (24.5%), KRAS/NRAS (20.3%), and CDKN2A/2B (7.7%). Patients with any mutation were significantly more likely to have metastatic disease to the brain (57% vs. 37%, p=0.03), but there was no difference in metastatic disease to bone (34% vs. 26%, p=0.32). Patients without a discoverable mutation were significantly more likely to have metastatic disease to other sites (e.g., adrenal gland 91% vs. liver 66%, p=0.002). There was no difference in progression-free survival (PFS) or overall survival (OS) between those with versus without mutations. Median PFS and OS were significantly longer in patients with an EGFR mutation than those with KRAS/NRAS or TP53 mutations. Patients with PD-L1 >1% or TP53 were significantly more likely to have metastatic disease to organs other than bone or brain (p=0.047 and p=0.023, respectively). We identified four prognostic groups in metastatic NSCLC. Patients with PD-L1 <1% and no actionable mutations have the poorest prognosis, with median survival of around 20 months. Conclusion: Patients with mutations discoverable on NGS are more likely to have metastatic disease to the brain. KRAS/NRAS in particular has a predilection to metastasize to the brain and bone. PD-L1 expression and a TP53 mutation, on the other hand, tend to lead to metastasis of NSCLC to organs other than brain or bone. These results need to be corroborated in larger prospective studies.

Effects of symptomatic and asymptomatic isolates of Blastocystis hominis on colorectal cancer cell line, HCT116.

The pathogenesis of Blastocystis hominis in human hosts has always been a matter of debate as it is present in both symptomatic and asymptomatic individuals. A recent report showed that B. hominis isolated from an asymptomatic individual could facilitate the proliferation and growth of existing cancer cells while having the potential to downregulate the host immune response. The present study investigated the differences between the effects of symptomatic and asymptomatic derived solubilized antigen of B. hominis (Blasto-Ag) on the cell viability and proliferation of colorectal cancer cells. Besides that, the gene expression of cytokine and nuclear transcriptional factors in response to the symptomatic and asymptomatic B. hominis antigen in HCT116 was also compared. In the current study, an increase in cell proliferation was observed in HCT116 cells which led to the speculation that B. hominis infection could facilitate the growth of colorectal cancer cells. In addition, a more significant upregulation of Th2 cytokines observed in HCT116 may lead to the postulation that symptomatic Blasto-Ag may have the potential in weakening the cellular immune response, allowing the progression of existing tumor cells. The upregulation of nuclear factor kappa light chain enhancer of activated B cells (NF-κB) was observed in HCT116 exposed to symptomatic Blasto-Ag, while asymptomatic Blasto-Ag exhibited an insignificant effect on NF-κB gene expression in HCT116. HCT116 cells exposed to symptomatic and asymptomatic Blasto-Ag caused a significant upregulation of CTSB which lead to the postulation that the Blasto-Ag may enhance the invasive and metastasis properties of colorectal cancer. In conclusion, antigen isolated from a symptomatic individual is more pathogenic as compared to asymptomatic isolates as it caused a more extensive inflammatory reaction as well as more enhanced proliferation of cancer cells.

Warm autoimmune haemolytic anaemia seen in association with primary sclerosing cholangitis in the setting of Klebsiella pneumoniae bacteraemia.

Warm autoimmune haemolytic anaemia mediated by warm agglutinins is a rare and heterogeneous disease which can be idiopathic or secondary to an underlying disease. Primary sclerosing cholangitis is a chronic autoimmune cholangiopathy that is very rarely associated with haemolytic anaemia. Infections can also act as triggers for immune haemolytic anaemia. Here, we report a case of a woman in her 50s with a history of primary sclerosing cholangitis and a positive direct antiglobulin test with no evidence of haemolysis who developed overt warm autoimmune haemolytic anaemia in the setting of cholangitis and Klebsiella pneumoniae bacteraemia. She was treated conservatively with appropriate antibiotics and cautious red blood cell transfusion with complete resolution of haemolysis; immunosuppression was avoided given sepsis on presentation. This case highlights a rare association of warm immune haemolytic anaemia in the setting of K. pneumoniae bacteraemia and the role of a tailored treatment approach to treat this heterogeneous disease.

A rare case of marijuana associated with ascending aorta thrombosis complicated with stroke and bilateral renal infarcts.

Ascending aortic is an uncommon site for arterial thrombosis and ascending aortic thrombosis is a very rare phenomenon with a high fatality rate. Marijuana is the most commonly used psychoactive drug in the United States and a few cases have been reported on the association of marijuana with vascular thromboembolism. However, the pathophysiology and exact mechanism are still not well studied. Herein, we present a case of a 44-year-old female with active marijuana use presented with ascending aortic thrombus associated with acute arterial occlusion of the right vertebral artery and bilateral renal artery. The unique part of this case is that the patient did not have the classical risk factors for vascular thromboembolic disease. The only risk factor was marijuana smoking. To our best knowledge, this is one of the unique cases of marijuana-associated with ascending aorta thrombosis.