Donor Cell Leukemia Following Allogeneic Hematopoietic Stem Cell Transplantation.

Approximately 25,000 allogeneic transplants are performed annually worldwide; a figure that has steadily increased over the past three decades. The study of transplant recipient survivorship has become a cogent topic and post-transplant donor cell pathology warrants further study. Donor cell leukemia (DCL) is a rare but serious complication of allogeneic stem cell transplantation (SCT) where the recipient develops a form leukemia originating from the donor cells used for transplantation. Detection of abnormalities predicting donor cell pathology might inform donor selection, and the design of survivorship programs for early detection of these abnormalities might allow therapeutic intervention earlier in the disease course. We present four recipients of allogeneic hematopoietic stem cell transplant (HSCT) from our institution who developed donor cell abnormalities allogeneic SCT, highlighting their clinical characteristics and challenges.

Immunotherapy in the Management of Esophagogastric Cancer: A Practical Review.

Recent data support incorporation of immune checkpoint inhibitors into the treatment armamentarium for esophageal, gastroesophageal junction, and gastric (esophagogastric) cancer. This practical review focuses on clinical trials that influenced US Food and Drug Administration approvals and treatment guidelines in esophagogastric cancer, including the impact of location, stage, histology, human epidermal growth factor receptor 2 status, and PD-(L)1 expression on these guidelines. The role of immunotherapy in the locally advanced and metastatic setting is constantly expanding. Over the next few years, the many ongoing trials exploring immunotherapy are anticipated to bring new treatment regimens into the frontline setting with the potential to improve survival in patients with advanced disease.

Long-term outcomes by response to neoadjuvant chemotherapy or chemoradiation in patients with resected pancreatic adenocarcinoma.

BACKGROUND: Response of pancreatic adenocarcinoma to neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) may be associated with prognosis, but long-term outcomes based on response to neoadjuvant therapy have not been well evaluated to date. METHODS: The National Cancer Database was queried for patients with pancreatic adenocarcinoma receiving nCT/nCRT. To evaluate response to nCT/nCRT, comparisons were made from cT and cN stage to the respective post-neoadjuvant therapy ypT and ypN stages. Based on these comparisons, patients were classified as responders, progressors, or non-responders. Statistical analyses included estimation of survival using Kaplan-Meier analysis, as well as multivariable Cox proportional hazards modeling. RESULTS: Of 2,028 patients, 30% had a response, 32% progressed, and 38% had no response; 1% of patients experienced pathologic complete response (pCR). Responders were more likely to have received multi-agent chemotherapy (P=0.0001) as well as radiotherapy (RT) (P=0.02) in the neoadjuvant setting. Response to nCT/nCRT was also associated with a higher R0 resection rate (P=0.02). At a median follow-up of 49 months, median overall survival (OS) was higher in responders than non-responders or progressors (29.9 vs. 24.3 vs. 22.2 months, P<0.001). The mean OS for patients experiencing pCR was 55.5 months. On multivariable analysis, treatment response was independently associated with OS (P=0.02). CONCLUSIONS: Response to nCT/nCRT independently predicts long-term outcomes following resection of pancreatic adenocarcinoma; higher rates of treatment response were observed for patients receiving neoadjuvant RT as well as neoadjuvant multi-agent chemotherapy. These results may have implications on strategies to improve response rates.

Rare presentation of cryptococcal meningitis in an immunocompetent patient.

Cryptococcal meningitis is an opportunistic infection predominantly affecting immunocompromised patients but rarely can affect the immunocompetent. We describe a 53-year-old Caucasian man who presented complaining of a 2-week history of severe bilateral eye pain and diplopia. His only known risk factor was that he lived in a horse farm and recently shot bats and pigeons in his barn. He visited an outside hospital during this time without a diagnosis established. After further deliberation, we obtained a lumbar puncture (LP) which revealed an opening pressure (OP) of 27 cm H2O. Cerebrospinal fluid (CSF) and fungal cultures confirmed the presence of Cryptococcus neoformans The patient was diagnosed with C. neoformans-mediated meningoencephalitis and was initiated on the appropriate induction anti-fungal therapy. This case emphasises the need for clinicians to remain vigilant and consider cryptococcal meningitis in immunocompetent individuals even when classic symptoms of meningitis are absent.

Aggressive Disease and Rare Sequelae in a Unique Case of Atypical Hemolytic Uremic Syndrome Secondary to Adult Onset Still's Disease.

Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) which generally presents as a triad of thrombocytopenia, hemolytic anemia and renal failure. We present the case of a 69-year-old woman with ongoing fevers, arthralgias, diffuse rash and pharyngitis for 3 months. Investigation revealed an elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin; however, autoimmune and infectious studies were unremarkable, raising the suspicion for adult onset Still's disease (AOSD). Before out patient therapy could be initiated, she presented to our emergency room (ER) with a grand mal seizure and persistence of her initial triad of fevers, arthralgias and rash. Evaluation revealed non-immune hemolytic anemia, thrombocytopenia, and abnormal renal function consistent with TMA and the patient was subsequently started on plasmapheresis, hemodialysis and corticosteroid therapy. ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)-13 activity was 38%, ruling out thrombotic thrombocytopenic purpura (TTP). A kidney biopsy demonstrated glomerular changes of TMA and a diagnosis of secondary aHUS triggered by AOSD was established. The patient was treated with eculizumab and high dose steroids with improvement in her laboratory values, eventually becoming hemodialysis-independent. This case highlights the clinical urgency in the prompt recognition of AOSD, a potent inflammatory disorder, which when co-existing with a complement- dysregulatory defect, can significantly augment TMA disease severity.

Postsymptomatic restoration of SMN rescues the disease phenotype in a mouse model of severe spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a common neuromuscular disorder in humans. In fact, it is the most frequently inherited cause of infant mortality, being the result of mutations in the survival of motor neuron 1 (SMN1) gene that reduce levels of SMN protein. Restoring levels of SMN protein in individuals with SMA is perceived to be a viable therapeutic option, but the efficacy of such a strategy once symptoms are apparent has not been determined. We have generated mice harboring an inducible Smn rescue allele and used them in a model of SMA to investigate the effects of turning on SMN expression at different time points during the course of the disease. Restoring SMN protein even after disease onset was sufficient to reverse neuromuscular pathology and effect robust rescue of the SMA phenotype. Importantly, our findings also indicated that there was a therapeutic window of opportunity from P4 through P8 defined by the extent of neuromuscular synapse pathology and the ability of motor neurons to respond to SMN induction, following which restoration of the protein to the organism failed to produce therapeutic benefit. Nevertheless, our results suggest that even in severe SMA, timely reinstatement of the SMN protein may halt the progression of the disease and serve as an effective postsymptomatic treatment.