Novel Pharmacological Treatment Options of Steroid-Refractory Graft-versus-Host Disease.

Background: Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplant. The mainstay of treatment is corticosteroids, which are ineffective in 30-50% of cases. Steroid-refractory GVHD (SR-GVHD) confers a poor prognosis, with high mortality rates despite appropriate therapy. While there is no reliable treatment for SR-GVHD, a variety of novel therapeutic options are slowly emerging and have yet to be examined simultaneously. Objectives: This review evaluates the potential of novel therapeutic options, as well as their efficacy and safety, for the treatment of SR-GVHD. Study Design. The literature search was conducted in PubMed, Cochrane, and Embase, employing MeSH terms and keywords. The studies had to be prospective phases 1, 2, or 3. We excluded retrospective and nonoriginal studies. Results: While the only approved drug for acute GVHD is ruxolitinib with an impressive overall response rate of 73.2% and a complete response of 56.3%, several monoclonal antibodies and other agents are currently under investigation, offering promising results. These include anti-CD2, anti-CD147, IL-2 antagonist, a mixture of anti-CD3 and anti-CD7 antibodies, anti-CD25, monoclonal antibody to a4b7 on T-cells, anti-CD26, pentostatin, sirolimus, denileukin diftitox, infliximab, itacitinib, and alpha-1 antitripsin. However, the toxicities associated with these novel drugs need further investigation. For chronic GVHD, approved options include ruxolitinib with an ORR of up to 62%, ibrutinib with an ORR of up to 77%, and belumosudil with an ORR of up to 77%. Meanwhile, emerging treatments include tyrosine kinase inhibitors such as nilotinib, rituximab, and low-dose IL-2, as well as axatilimab and pomalidomide. Conclusion: While their efficacy needs to be better evaluated through large-scale, multicenter, randomized clinical trials, these novel agents show potential and could provide a better alternative for SR-GVHD treatment in the future.

Identifying at risk populations amongst breast cancer survivors and their common symptoms and concerns.

PURPOSE: The survival rate amongst breast cancer survivors (BCS) have been increasing, with a 5-year survival rate of almost 90%. These women face many quality of life (QOL) issues either due to either cancer itself or the complex treatment regimen. Our retrospective analysis aims to identify at risk populations among the BCS and their most common concerns. METHODS: This is a single-institution, retrospective, descriptive analysis of patients who were seen at our Breast Cancer Survivorship Program from October 2016 to May 2021. Patients completed a comprehensive survey which assessed self-reported symptoms, their concerns and degree of worry and recovery to baseline. The descriptive analysis on the patient characteristics included age, cancer stage and treatment type. The bivariate analysis included the relationship between the patient characteristics and their outcomes. Analysis of group differences was completed with Chi-square test. When the expected frequencies were five or less, Fisher exact test was used. Logistic regression models were developed to identify significant predictors for outcomes. RESULTS: 902 patients (age 26-94; median 64) were evaluated. Majority of women had stage 1 breast cancer. The most common self-reported concerns affecting the patients were fatigue (34%), insomnia (33%), hot flashes (26%), night sweats (23%), pain (22%), trouble concentrating (19%), and neuropathy (21%). Though 13% of BCS felt isolated at least 50% of their time, the majority of patients (91%) reported having a positive outlook and felt that they have a sense of purpose (89%). Younger patients were more likely to worry about their cancer more than 50% of the time (p < 0.0001). Patients that were less likely to return back to at least 50% of their pre-treatment baseline were younger (age ≤ 45) (p = 0.0280), had higher stage breast cancer (Stage 2-4) (p = 0.0061), and had chemotherapy either alone or as part of their multi-modality treatment (p < 0.0001). CONCLUSION: According to our study, younger patients, those with higher stage breast cancer and survivors who had chemotherapy may experience significant QOL issues. Fortunately, majority of BCS report a positive and optimistic outlook post treatment. Identifying common concerns after treatments and vulnerable populations are especially important to deliver quality care and to optimize interventions. IMPLICATIONS FOR CANCER SURVIVORS: Our study identified the most common self-reported concerns affecting BCS. In addition, our results suggest that younger patients, patients with higher stage breast cancer and survivors who had chemotherapy were more likely to have QOL issues. Despite this, our study showed, the majority of BCS reported positive outlooks and emotions.

Adverse events of immune checkpoint therapy alone versus when combined with vascular endothelial growth factor inhibitors: a pooled meta-analysis of 1735 patients.

Background: Combining immune checkpoint therapy (ICT) and vascular endothelial growth factor inhibitors (VEGFi) may result in increased treatment-related and immune-related adverse events (TRAEs and irAEs) compared to ICT alone. This metanalysis was conducted to identify prospective phase II or III clinical studies that evaluated the toxicity profile of ICT + VEGFi compared to ICT alone. Methods: A systematic search was performed across all cancer types and major databases until August 10, 2022, and screening was done by two independent investigators. Inclusion criteria included phase 2 or 3 studies with at least one arm of patients treated with combination therapy and one arm treated with monotherapy. Adverse event data were pooled using a restricted maximum likelihood fixed effects model, and heterogeneity using Cochran's Q (chi-square) test. Results: 7 out of 9366 studies met the inclusion criteria, and 808 and 927 patients were treated with ICT monotherapy and a combination of ICT with VEGFi, respectively. Only one study reported irAEs, so the analysis was restricted to TRAEs. The total number of TRAEs was significantly higher in the ICT + VEGFi group (RR:1.49; 95% CI 1.37 -1.62; p=1.5×10-21), and more frequent treatment withdrawals were attributed to TRAEs (RR:3.10; 95% CI 1.12-8.59; p=0.029). The highest TRAE effect size increases noted for rash (RR 6.50; 95% CI 3.76 - 11.25; p=2.1×10-11), hypertension (RR:6.07; 95% CI 3.69-10.00; p=1.3×10-12), hypothyroidism (RR:5.02; 95% CI 3.08 - 8.19; p=8.9×10-11), and diarrhea (RR:4.94; 95% CI 3.21-7.62; p=3.8×10-13). Other significantly more frequent TRAEs included nausea, anemia, anorexia, and proteinuria. Conclusion: Combination therapy with ICT and VEGFi carries a higher risk of certain TRAEs, such as rash, hypertension, hypothyroidism, diarrhea, nausea, anorexia, and proteinuria, compared to ICT monotherapy. More granular details on the cause of AEs, particularly irAEs, should be provided in future trials of such regimens.

Cryptococcus neoformans Presenting as a Lung Mass in an Immunocompromised Patient.

BACKGROUND Pulmonary cryptococcosis is an uncommon infection mainly affecting immunocompromised individuals. Presentation of cryptococcal disease ranges from asymptomatic pulmonary colonization to severe pneumonia. It can progress to acute respiratory failure and life-threatening meningoencephalitis. CASE REPORT A 55-year-old woman with a history of a kidney transplant, on immunosuppressive therapy, presented to the hospital with persistent low-grade fever, headache, weight loss, and fatigue for 2 weeks. On arrival, she was tachycardic, normotensive, and saturating 99% on room air. Her chest X-ray showed right middle lung opacity measuring 1.9×2.8 cm. She was admitted and started on broad-spectrum antibiotics for suspected pneumonia. Her chest computed tomography (CT) scan showed a 3.0×1.7 cm hypo-dense opacity at the right upper lobe. Overnight, she developed a severe headache and neck stiffness. Her serum cryptococcal antigen and cerebrospinal fluid culture results were positive. The patient was started on intravenous liposomal amphotericin B plus flucytosine. A CT-guided lung biopsy was performed to rule out malignancy. Cultures came back positive for Cryptococcus neoformans. She completed a 2-week course of amphotericin and flucytosine and was switched to oral fluconazole to complete an 8-week course. CONCLUSIONS Prompt diagnosis and effective management of the cryptococcal disease can decrease morbidity and mortality. Diagnosis requires CT-guided lung biopsy, with culture growing mucoid colonies of Cryptococcus neoformans. Antifungal therapy with intravenous liposomal amphotericin B plus flucytosine is the mainstay of treatment. Clinicians should be aware of the various presentations of pulmonary cryptococcosis, especially in immunocompromised patients.

Milk-Alkali Syndrome: How Electronic Medical Record Open Notes Helped to Rule Out Cancer.

BACKGROUND Milk-alkali syndrome is caused by excessive consumption of calcium and absorbable alkali and typically presents as a triad of hypercalcemia, acute renal failure, and metabolic alkalosis. In the era of histamine receptor blockers and proton pump inhibitors, the incidence of milk-alkali syndrome has decreased. However, the disease has not been eliminated, due to existing calcium-containing therapies. Here, we present a case of severe milk-alkali syndrome with a challenging initial diagnosis. CASE REPORT We present the case of a 64-year-old man who came to the hospital with encephalopathy. Serologic evaluation revealed acute renal failure, severe hypercalcemia, and metabolic alkalosis. He underwent volume resuscitation, with the initiation of calcitonin. Despite our efforts, the patient developed anuria and proceeded to intermittent hemodialysis. His workup was unrevealing, including an appropriately suppressed parathyroid hormone level, low vitamin D, and normal serum protein electrophoresis and angiotensin converting enzyme levels. Considering his persistent encephalopathy, the team was unable to obtain information from the patient regarding his calcium intake. However, at home, the patient's significant other read his progress notes in the electronic medical record and reported that he consumed at least 1 bottle of calcium carbonate (Tums) every week. Once the encephalopathy resolved, the patient confirmed this information. CONCLUSIONS The search for malignancy in the setting of hypercalcemia was ceased because of the family's at-home electronic medical record use and reporting of Tums overuse. Milk-alkali syndrome, although a rarity, should not be forgotten as a cause of hypercalcemia.

Secretory Carcinoma of the Breast Mimicking Invasive Ductal Carcinoma: A Case Report.

BACKGROUND Secretory breast carcinoma (SBC), an extremely rare malignancy, is related to a chromosomal translocation which leads to an ETV6-NTRK3 fusion mutation. SBC is characterized by eosinophilic secretions and is usually triple-negative, with a small number of patients demonstrating ER-positivity of the tumors. Diagnosis can be challenging and requires genomic testing for confirmation. CASE REPORT A 40-year-old woman presented with a breast mass found on mammography. She underwent an ultrasound-guided biopsy of the tumor. Initial pathology evaluation revealed features consistent with invasive ductal carcinoma. The immunochemistry report described an ER-positive, PR-negative, and HER2-negative tumor. The specimen was sent for oncotype scoring, which was not performed due to the specimen not meeting the criteria for invasive ductal carcinoma and displaying pathological features of SBC. A fluorescent in situ hybridization (FISH) study revealed ETV6 translocation, consistent with the diagnosis of SBC. The patient underwent lumpectomy followed by adjuvant radiotherapy and endocrine therapy. She remains in complete remission 3 years after treatment. CONCLUSIONS Accurately diagnosing SBC is of extreme importance as it has an indolent clinical course, but has a favorable prognosis if detected early. Due to nonspecific imaging findings, pathology evaluation with immunohistochemical staining followed by genomic testing is required. Our case highlights the challenges associated with SBC diagnosis requiring genomic testing due to equivocal pathological findings, along with increasing incidence of SBT in adults. There are no established guidelines for SBC management. The mainstay of treatment is partial or total mastectomy. Data on the benefits of adjuvant endocrine therapy, chemotherapy, and radiotherapy are inconclusive.