Splenectomy outcomes in immune cytopenias: Treatment outcomes and determinants of response.

BACKGROUND: Splenectomy is commonly used to treat refractory immune-mediated cytopenia, but there are no established factors that are associated with response to the procedure. OBJECTIVES: A cohort study was conducted to evaluate the hematologic and surgical outcomes of splenectomy in adult patients with immune cytopenias and identify preoperative factors associated with response. METHODS: Data from the Cleveland Clinic Foundation for 1824 patients aged over 18 who underwent splenectomy from 2002 to 2020 were analyzed. RESULTS: The study found that the most common indications for splenectomy were immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia, with a median age of 55 years and median time from diagnosis to splenectomy of 11 months. Hematologic response rates were 74% overall, with relapse in 12% of cases. Postsplenectomy discordant diagnoses were present in 13% of patients, associated with higher relapse rates. Surgery-related complications occurred in 12% of cases, whereas only 3% of patients died from disease complications. On univariate analysis, preoperative factors associated with splenectomy treatment failure were ≥3 lines of pharmacologic treatment, whereas isolated thrombocytopenia, primary ITP, and age ≤40 years had a strong association with response. The multivariable regression confirmed that treatment failure with multiple lines of medical therapy was associated with the failure to respond to splenectomy. CONCLUSION: Overall, the study demonstrates that splenectomy is an effective treatment option for immune-mediated cytopenias with a low complication rate.

New approaches to idiopathic neutropenia in the era of clonal hematopoiesis.

Isolated chronic idiopathic neutropenia (CIN) is a rare disease with multiple contributing etiologies that must be ruled out before establishing a diagnosis. We studied clinical and molecular data of 238 consecutive adult patients with CIN. Autoimmune neutropenia was present in 28% of our cohort. In contrast, T cell-mediated neutropenia was the main underlying pathological mechanism among patients with T cell expansions, such as T-cell large granular lymphocytic leukemia (T-LGL) and T cell clonopathy of undetermined significance, found in 37% and 8% of cases, respectively. Patients with neutropenia also had hypogammaglobulinemia (6%) and/or monoclonal gammopathy of undetermined significance (5%). NGS application has further broadened the spectrum of causes of CIN by including manifestations of clonal hematopoiesis, present in 12% of cases. TET2 (3%), TP53 (2%), and IDH1/IDH2 (2%) mutations were the most commonly found and were enriched in cases with T-LGL. We show that these clinico-molecular associations can be simultaneously present, complicating a proper diagnostic distinction within the broader entity of seemingly idiopathic neutropenia of autoimmune origin. Identification of etiologic culprits may also guide rational selection of therapies.

Novel Scheme for Defining the Clinical Implications of TP53 Mutations in Myeloid Neoplasia.

Background: TP53 mutations ( TP53 MT ) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. Methods: We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model to properly resolve the allelic configuration of TP53 MT and assess prognosis more precisely. Results: Overall, TP53 MT were found in 1010 patients. Following the traditional criteria, 36% of cases were classified as single hits while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53 MT . Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. These results were recapitulated by single-cell DNA studies, which unveiled the biallelic nature of previously considered monoallelic cases. Conclusion: Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.

Novel scheme for defining the clinical implications of TP53 mutations in myeloid neoplasia.

BACKGROUND: TP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. METHODS: We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model by identifying an optimal VAF cutoff using a statistically robust strategy of sampling-based regression on survival data to accurately classify the TP53 allelic configuration and assess prognosis more precisely. RESULTS: Overall, TP53MT were found in 1010 patients. Following the traditional criteria, 36% of the cases were classified as single hits, while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53MT. Interestingly, our method was able to upstage 192 out of 352 (54.5%) traditionally single hit lesions into a probable biallelic category. Such classification was further substantiated by a survival-based model built after re-categorization. Among cases traditionally considered monoallelic, the overall survival of those with probable monoallelic mutations was similar to the one of wild-type patients and was better than that of patients with a biallelic configuration. As a result, patients with certain biallelic hits, regardless of the disease subtype (AML or MDS), had a similar prognosis. Similar results were observed when the model was applied to an external cohort. In addition, single-cell DNA studies unveiled the biallelic nature of previously considered monoallelic cases. CONCLUSION: Our novel approach more accurately resolves TP53 genomic configuration and uncovers genetic mosaicism for the use in the clinical setting to improve prognostic evaluation.

Molecular patterns identify distinct subclasses of myeloid neoplasia.

Genomic mutations drive the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia. While morphological and clinical features have dominated the classical criteria for diagnosis and classification, incorporation of molecular data can illuminate functional pathobiology. Here we show that unsupervised machine learning can identify functional objective molecular clusters, irrespective of anamnestic clinico-morphological features, despite the complexity of the molecular alterations in myeloid neoplasia. Our approach reflects disease evolution, informed classification, prognostication, and molecular interactions. We apply machine learning methods on 3588 patients with myelodysplastic syndromes and secondary acute myeloid leukemia to identify 14 molecularly distinct clusters. Remarkably, our model shows clinical implications in terms of overall survival and response to treatment even after adjusting to the molecular international prognostic scoring system (IPSS-M). In addition, the model is validated on an external cohort of 412 patients. Our subclassification model is available via a web-based open-access resource ( https://drmz.shinyapps.io/mds_latent ).

Spermatic Cord Liposarcoma: A Case Report and Review of the Literature on the Role of Radiotherapy and Chemotherapy in Preventing Locoregional Recurrence.

Spermatic cord cancer is a rare entity. Among malignant tumors of the spermatic cord, liposarcomas are the most common type, often presenting as painless slow-growing masses usually in the fifth and sixth decades of life; they can be misdiagnosed as inguinal hernia or hydrocele. Radical orchiectomy with wide local soft tissue resection is an accepted standard of care for spermatic cord liposarcoma and has been curative in some cases. There is no definitive role for other treatment modalities such as chemotherapy, retroperitoneal lymph node dissection (RPLND), and radiotherapy. We present a case of liposarcoma of the spermatic cord managed with radical orchiectomy, wide local excision, and was followed up without disease recurrence. We also engage in a review of the literature on the role of systemic chemotherapy and radiotherapy in preventing locoregional recurrence after primary surgery. A combination of surgery and postoperative radiotherapy is effective in preventing locoregional spread. Data from case reports support this strategy in certain histologic subtypes or when margins are positive after primary surgery. A follow-up period of up to a decade after surgery is recommended.

A Rare Case of Emphysematous Gastritis Secondary to Chemotherapy.

Emphysematous gastritis is a rare medical condition characterized by the presence of intra-mural air in the stomach associated with portal venous air tracking to a variable degree. There are no established guidelines favoring surgery over medical management. We present a case of a 64-year-old Caucasian male with a history of stage four colon adenocarcinoma with peritoneal carcinomatosis, malignant ascites, and liver metastasis status post-three cycles of chemotherapy who presented to the emergency room with complaints of generalized abdominal pain, nausea, non-bilious vomiting, and melena stools. He was managed conservatively as a case of sepsis secondary to emphysematous gastritis and made a full recovery. To our knowledge, this is the first reported case of emphysematous gastritis in an adult with colon cancer. Although we cannot establish a causal link between his chemotherapy regimen and emphysematous gastritis, the combined effect of an immunosuppressive state caused by advanced malignancy and cytotoxic effects of chemotherapy are the probable risk factors in our patient. We described the possible mechanisms of mucosal disruption by fluorouracil and bevacizumab in our case. Despite historically having a poor prognosis, emphysematous gastritis can be managed conservatively on a case-by-case basis. Clinicians should be aware that chemotherapy can be a predisposing factor to developing this rare condition.

A Review of the Impact of Smoking on Inhaled Insulin: Would You Stop Smoking if Insulin Can Be Inhaled?

High prevalence of diabetes and the need for tight glycemic control have been well established. With the invention of inhaled insulin, an alternate route has been explored and shows great promise. Inhaled insulin shows a similar physiologic response to subcutaneous insulin, with a faster onset of action, making it suitable for post-prandial hyperglycemia. This comes as a great relief, especially to those who are hesitant to use multiple injections in a day. Many factors affect insulin absorption, including device, particle size, airway patency. Another essential factor is smoking, which is prevalent among people with diabetes, as is in the non-diabetic population. Smoking increases the absorption of inhaled insulin, but it is not a straight fact, since acute smoking, passive smoking, chronic smoking - all have different effects on inhaled insulin. Furthermore, inhaled insulin is also affected by lung diseases. Most studies that have been conducted have included limited populations, thus questioning their generalisability. The studies from inception till 2020 have shown increased permeability of epithelial with acute smoking, change of epithelial layer back to normal after few weeks of smoking cessation, and reverting to chronic smoker levels with just one to two days of start in smoking. Data also suggests that smoking causes a reduction in insulin sensitivity, which could compensate for its increased absorption. Nicotine causes a decrease in the absorption of subcutaneous insulin, but its effect has not been seen on inhaled insulin. More studies, including diabetic smoker patients, need to be performed to give a specific set of variables. This would also add another reason to encourage smokers to quit smoking.

Impact of Snoring on the Cardiovascular System and its Treatment: Positive and Negative Effects of Continuous Positive Airway Pressure in Sleep Apnea.

Obstructive sleep apnea (OSA) is a common condition, and if not treated can be a significant risk factor for multiple comorbidities like hypertension (HTN), coronary artery disease (CAD), and congestive heart failure (CHF). The underlying pathophysiology involves coagulation and inflammatory pathways, including an overactive sympathetic nervous system. This ultimately causes hemodynamic changes and subclinical myocardial injuries. We reviewed the published literature about the impact of continuous positive airway pressure (CPAP) when used as a mode of treatment to reduce the OSA effects on cardiomyocytes. We found that the results were mixed, including both ill and good effects. The cardiac markers like N-terminal pro-brain natriuretic peptide (NT-proBNP) and atrial natriuretic peptide (ANP) were reduced, implying the decrease in the incidence of heart failure with CPAP treatment in a few of the studies. They also proved a significant decrease in harmful cardiovascular (CV) outcomes, while others concluded that CPAP therapy might be stressful on the heart, causing an elevation in cardiac troponin T levels. However, the impact on inflammatory markers is still indeterminate and needs more research in future.

Current Trends Featuring the Bridge Between Stroke and End-Stage Renal Disease: A Review.

The relationship between end-stage renal disease (ESRD) and cerebral stroke is graded and cumulative, having a significant impact on morbidity and mortality. Ischemic stroke is more prevalent than hemorrhagic stroke and both stroke types have modifiable and non-modifiable risk factors. The presence of risk factors such as hypertension, diabetes, and atrial fibrillation (AF) before stroke occurrence in dialysis patients has a significant impact on the outcomes such as a discharge to rehabilitation, in-hospital mortality with the worst prognosis when compared to the general population. ESRD patients with either peritoneal or hemodialysis (HD) are at increased risk of stroke than the general population, with a high mortality rate at the commencement of dialysis and gradually decreases. Primary and secondary prevention of risk factors plays a significant role in this susceptible population and helps to mitigate better treatment and outcomes. Our review article focuses on the mechanisms, outcomes, treatment, and preventive aspects of stroke in the ESRD population.

Biologic Therapies in Sarcoidosis and Uveitis: A Review.

Sarcoidosis and uveitis are chronic inflammatory conditions with potentially debilitating effects on quality of life. Steroids form the mainstay standard therapy in both conditions. Biologic agents are considered to be appropriate alternatives for treatment in steroid-refractory sarcoidosis and uveitis due to the role of tumor necrosis factor (TNF) in mediating the inflammatory cascade seen in both conditions. We performed a thorough literature search using PubMed to compare the extent of use, efficacy, and safety profile of individual anti-TNF agents in the management of these conditions. Our review consists of two systematic reviews with meta-analysis, thirteen observational studies, and fifteen case series/reports. Infliximab had the widest range of organ-system usage in extra-pulmonary sarcoidosis but is equivalent to adalimumab in terms of efficacy. In uveitis, adalimumab was found to be the most efficacious agent for maintaining disease remission in adults and children with chronic non-infectious uveitis. Etanercept was neither used widely, nor was it efficacious in the management of either condition. In terms of safety profile, biologic agents were found to be well tolerated and have a similar safety profile. More randomized clinical trials are needed to inform evidence-based use of biologic agents in these conditions.