Thrombotic Microangiopathy After Hematopoietic Stem Cell and Solid Organ Transplantation: A Review for Intensive Care Physicians.

Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies.

Successful treatment of lupus anticoagulant hypoprothrombinemia syndrome with rituximab.

Lupus anticoagulant-hypoprothrombinemia syndrome (LAHPS) is a rare acquired bleeding disorder secondary to development of antibodies against prothrombin protein, in the presence of antiphospholipid antibodies. We describe the case of a 13-year-old girl who presented with severe menorrhagia and symptomatic anemia. Labs indicated anemia, thrombocytopenia, elevated PT and aPTT, high-titer inhibitor on mixing studies, positive ANA and anti-dsDNA antibodies, along with a triple-positive antiphospholipid antibody panel. Given additional systemic manifestations, systemic lupus erythematosus was diagnosed. High dose steroids and hydroxychloroquine subsequently started. Her clinical course was complicated by femoral deep venous thrombosis and post renal biopsy retroperitoneal hematoma. Further workup revealed low prothrombin level and the diagnosis of lupus anticoagulant hypoprothrombinemia syndrome. In view of suboptimal response to initial immunosuppressive therapy, rituximab was added to her regimen, leading to an improvement in clinical symptoms and resolution of hypoprothrombinemia. She remains recurrence free 5 years from the event.

Non-Small Cell Lung Cancer Presenting as Anterior Nasal Mass and Epistaxis.

Lung malignancy presentation with an uncommon metastatic site is a diagnostic challenge and often associated with poor prognosis. Nasal cavity is a rare metastatic site for any type of lung cancer. We report an unusual case of poorly differentiated adenosquamous carcinoma of the lung with widespread metastasis presenting as a right vestibular nasal mass with epistaxis. A 76-year-old male patient with chronic obstructive pulmonary disease and 80 pack-year smoking history presented with spontaneous epistaxis. He reported a new rapidly growing right-sided nasal vestibular mass first noticed 2 weeks prior. Physical examination showed fleshy mass with crusting in right nasal vestibule along with a left nasal domus mass. Imaging revealed an ovoid mass in the right anterior nostril and a large mass in the right upper lobe of the lung (RULL) along with thoracic vertebral sclerotic metastasis and large left frontal lobe hemorrhagic lesion with severe vasogenic edema. Positron emission tomography scan showed large right upper lobe mass and suspected to be the primary malignancy along with widespread metastasis. Biopsy of the nasal lesion revealed poorly differentiated non-small cell carcinoma with squamous and glandular features. The diagnosis of very poorly differentiated adenosquamous carcinoma of the lung with widespread metastasis was made. In conclusion, unusual metastatic sites with unknown primary lesions require a thorough diagnostic workup involving biopsy and extensive imaging. Lung cancer with unusual metastatic sites is inherently aggressive and associated with poor prognosis. Multidisciplinary treatment modalities should be employed keeping in view the functional status and comorbidities of the patient.

PROMISE: a real-world clinical-genomic database to address knowledge gaps in prostate cancer.

PURPOSE: Prostate cancer is a heterogeneous disease with variable clinical outcomes. Despite numerous recent approvals of novel therapies, castration-resistant prostate cancer remains lethal. A "real-world" clinical-genomic database is urgently needed to enhance our characterization of advanced prostate cancer and further enable precision oncology. METHODS: The Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) is a consortium whose aims are to establish a repository of de-identified clinical and genomic patient data that are linked to patient outcomes. The consortium structure includes a (1) bio-informatics committee to standardize genomic data and provide quality control, (2) biostatistics committee to independently perform statistical analyses, (3) executive committee to review and select proposals of relevant questions for the consortium to address, (4) diversity/inclusion committee to address important clinical questions pertaining to racial disparities, and (5) patient advocacy committee to understand patient perspectives to improve patients' quality of care. RESULTS: The PROMISE consortium was formed by 16 academic institutions in early 2020 and a secure RedCap database was created. The first patient record was entered into the database in April 2020 and over 1000 records have been entered as of early 2021. Data entry is proceeding as planned with the goal to have over 2500 patient records by the end of 2021. CONCLUSIONS: The PROMISE consortium provides a powerful clinical-genomic platform to interrogate and address data gaps that have arisen with increased genomic testing in the clinical management of prostate cancer. The dataset incorporates data from patient populations that are often underrepresented in clinical trials, generates new hypotheses to direct further research, and addresses important clinical questions that are otherwise difficult to investigate in prospective studies.

Two Roads Diverge: Treatment Choice in Coexisting Severe Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria.

Aplastic anemia (AA) is a bone marrow failure syndrome of pancytopenia due to impaired hematopoiesis. It is strongly associated with paroxysmal nocturnal hemoglobinuria (PNH). Each condition can cause the other, or occur simultaneously. There are no guidelines for treating concomitant AA and PNH; immunosuppressive therapy (IST) or hematopoietic stem cell therapy (HSCT) is first-line for the former, and eculizumab is first-line for the latter. New studies suggest that treating AA/PNH together versus sequentially should depend on AA severity. We report the case of a previously healthy male (31-year-old, Nigerian immigrant) who developed jaundice, scleral icterus, easy fatigability, and epistaxis. He was diagnosed with AA on bone marrow biopsy and with PNH on flow cytometry. He initially underwent chemotherapy due to increased infection risk with eculizumab in a neutropenic patient; however, he showed minimal response and thus began eculizumab pending allogeneic stem cell transplant. There are no guidelines for treating patients with both AA and PNH, and clinical decision making is generally individualized based on disease severity. Only one prior publication reported simultaneous treatment with eculizumab and chemotherapy, due to stated concern for pancytopenia, especially neutropenia, being the most immediate cause of morbidity/mortality. This demonstrates the individualized decisions that must be made when treating simultaneous PNH and AA, and the importance of PNH/severe AA patients as a separate subpopulation.

Reflux and sex: what drives testing, what drives treatment?

Gastroesophageal reflux (GER) affects ∼10-20% of American adults. Although symptoms are equally common in men and women, we hypothesized that sex influences diagnostic and therapeutic approaches in patients with GER. PubMed database between 1997 and October 2011 was searched for English language studies describing symptoms, consultative visits, endoscopic findings, use and results of ambulatory pH study, and surgical therapy for GER. Using data from Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality, we determined the sex distribution for admissions and reflux surgery between 1997 and 2008. Studies on symptoms or consultative visits did not show sex-specific differences. Even though women are less likely to have esophagitis or Barrett's esophagus, endoscopic studies enrolled as many women as men, and women were more likely to undergo ambulatory pH studies with a female predominance in studies from the US. Surgical GER treatment is more commonly performed in men. However, studies from the US showed an equal sex distribution, with Nationwide Inpatient Sample data demonstrating an increase in women who accounted for 63% of the annual fundoplications in 2008. Despite less common or severe mucosal disease, women are more likely to undergo invasive diagnostic testing. In the US, women are also more likely to undergo antireflux surgery. These results suggest that healthcare-seeking behavior and socioeconomic factors rather than the biology of disease influence the clinical approaches to reflux disease.