Severe Thrombocytopenia in Infective Endocarditis.

Thrombocytopenia can be seen in about 20-25% of patients with bacterial infective endocarditis (IE). Platelets have a major role in the pathogenesis of endocarditis, and they are also sensitive monitors of systemic host response to bacteremia. Thrombocytopenia on presentation of patients with IE identifies higher risk groups and carries higher mortality risk. The presence of thrombocytopenia is an independent prognosticator of poor outcomes in IE. We present a case of a 40-year-old male with the history of injection drug use who was diagnosed with IE and was found to have severe thrombocytopenia on admission was treated with intravenous antibiotics, which dramatically improved his platelet counts as well without any need for plasmapheresis or platelet transfusions.

HALT-D: a randomized open-label phase II study of crofelemer for the prevention of chemotherapy-induced diarrhea in patients with HER2-positive breast cancer receiving trastuzumab, pertuzumab, and a taxane.

PURPOSE: To assess whether crofelemer would prevent chemotherapy-induced diarrhea (CID) diarrhea in patients with HER2-positive, any-stage breast cancer receiving trastuzumab (H), pertuzumab (P), and a taxane (T; docetaxel or paclitaxel), with/without carboplatin (C; always combined with docetaxel rather than paclitaxel). METHODS: Patients scheduled to receive ≥ 3 consecutive TCHP/THP cycles were randomized to crofelemer 125 mg orally twice daily during chemotherapy cycles 1 and 2 or no scheduled prophylactic medication (control). All received standard breakthrough antidiarrheal medication (BTAD) as needed. The primary endpoint was incidence of any-grade CID for ≥ 2 consecutive days. Secondary endpoints were incidence of all-grade and grade 3/4 CID by cycle/stratum; time to onset and duration of CID; stool consistency; use of BTAD; and quality of life (Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea [FACIT-D] score). RESULTS: Fifty-one patients were randomized to crofelemer (n = 26) or control (n = 25). There was no statistically significant difference between arms for the primary endpoint; however, incidence of grade ≥ 2 CID was reduced with crofelemer vs control (19.2% vs 24.0% in cycle 1; 8.0% vs 39.1%, in cycle 2). Patients receiving crofelemer were 1.8 times more likely to see their diarrhea resolved and had less frequent watery diarrhea. CONCLUSION: Despite the choice of primary endpoint being insensitive, crofelemer reduced the incidence and severity of CID in patients with HER2-positive breast cancer receiving P-based therapy. These data are supportive of further testing of crofelemer in CID. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02910219, prospectively registered September 21, 2016.

Hematologic safety of palbociclib in combination with endocrine therapy in patients with benign ethnic neutropenia and advanced breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, are approved to treat hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) and are associated with hematologic toxicity. African American women, who are underrepresented in CDK4/6 inhibitor clinical trials, may experience worse neutropenia because of benign ethnic neutropenia. The authors specifically investigated the hematologic safety of palbociclib in African American women with HR-positive/HER2-negative ABC. METHODS: PALINA was a single-arm, open-label, investigator-initiated study of palbociclib (125 mg daily; 21 days on and 7 days off) plus endocrine therapy (ET) in African American women who had HR-positive/HER2-negative ABC and a baseline absolute neutrophil count ≥1000/mm3 (ClinicalTrials.gov identifier NCT02692755). The primary outcome was the proportion of patients who completed 12 months of therapy without experiencing febrile neutropenia or treatment discontinuation because of neutropenia. Single nucleotide polymorphism analysis was used to assess Duffy polymorphism status. RESULTS: Thirty-five patients received ≥1 dose of palbociclib plus ET; 19 had a Duffy null polymorphism (cytosine/cytosine). There were no reports of febrile neutropenia or permanent study discontinuation because of neutropenia. Significantly more patients with the Duffy null versus the wild-type variant had grade 3 and 4 neutropenia (72.2% vs 23.1%; P = .029) and required a palbociclib dose reduction (55.6% vs 7.7%; P = .008). Patients with the Duffy null versus the wild-type variant had lower overall relative dose intensity (mean ± SD, 81.89% ± 15.87 and 95.67% ± 5.89, respectively; P = .0026) and a lower clinical benefit rate (66.7% and 84.6%, respectively). CONCLUSIONS: These findings suggest that palbociclib is well tolerated in African American women with HR-positive/HER2-negative ABC. Duffy null status may affect the incidence of grade 3 neutropenia, dose intensity, and possibly clinical benefit.

A rare case of bilateral breast lobular carcinoma coexisting with primary breast follicular lymphoma.

CLINICAL PRACTICE POINTS ● Co-existence of breast cancer and lymphoma is a rare condition. A few cases of synchronous breast ductal carcinoma and lymphoma have been reported in the literature. However, to our knowledge this is the first case report of a bilateral breast lobular carcinoma co-presenting with follicular lymphoma. ● Little is known about the pathophysiology of synchronous cancers of different tumor types, especially solid tumors co-existing with hematologic malignancies. In-depth review of these cases can shed light on underlying mechanism leading to synchronous cancer development.

Autoimmune Myocarditis Caused by Immune Checkpoint Inhibitors Treated With Antithymocyte Globulin.

The immune checkpoint inhibitors have brought about a paradigm shift in the treatment of many cancers and are being used as the first line therapy in increasing number of aggressive malignancies, including metastatic melanoma. Their adverse effects, mostly mediated by an uncontrolled overactivation of the immune system, may compromise the therapeutic benefit. Combination immune checkpoint therapies in particular, have higher therapeutic efficacy, but have also been associated with a higher incidence of severe immune-related adverse effects including autoimmune lymphocytic myocarditis. Recent clinical reports of this rare and life threatening condition indicated rapid progression of severe hemodynamic and electrical instability, with or without acute decompensated heart failure, reduced ejection fraction and shock, pointing to the need for early recognition, diagnosis and prompt management. Current guidelines for management of other immune-related adverse effects recommend high-dose glucocorticoids, with consideration of immunomodulators, such as infliximab in patients with severe colitis. However, knowledge about the treatment approaches in immune-related myocarditis remains extremely scarce. Here we report a case of severe, steroid refractory, lymphocytic myocarditis that occurred after the first cycle of combination immunotherapy with the programmed cell death protein-1 inhibitor, nivolumab, and the cytotoxic T-lymphocyte-associated protein 4 blocker, ipilimumab, for metastatic melanoma. We discuss treatment approaches including the role for transvenous pacemaker, advanced heart failure support, and interdisciplinary decision making.

PALINA: A phase II safety study of palbociclib in combination with letrozole or fulvestrant in African American women with hormone receptor positive HER2 negative advanced breast cancer.

Palbociclib has been shown to be a highly effective therapy in hormone receptor positive metastatic breast cancer when used in combination with letrozole or fulvestrant. Grade 3/4 neutropenia is a common side effect although febrile neutropenia is relatively uncommon. Insufficient data exist to describe the hematological safety of palbociclib in African American women (AAW) known to have a high incidence of benign ethnic neutropenia (BEN). PALOMA 1, 2 and 3, the initial phase II/III studies that led to the U.S. Food and Drug Administration (FDA) approval of palbociclib in metastatic breast cancer, only included participants with baseline absolute neutrophil count (ANC) of 1500/mm3 or higher. African American women (AAW) were underrepresented in the PALOMA trials and this may be partially explained by strict requirements for minimal ANC ≥1500/mm3. The ANC of 1500/mm3 for initiation of treatment in those with BEN has been previously challenged. In this study, we propose to lower the ANC cutoff for enrollment to 1000/mm3. PALINA (NCT02692755) is a phase II, single arm, multicenter clinical trial that will enroll 35 patients. The primary endpoint is to assess the proportion of patients who complete therapy without the development of febrile neutropenia or treatment discontinuation due to neutropenia. The secondary endpoints include number of patients who required dose delays or dose reductions in palbociclib attributed to neutropenia, rate of grade 3/4 neutropenia, clinical benefit rate at 24 weeks, the association between metabolite and exosomal signature with disease response and the association between baseline ANC prior to cancer diagnosis and the Duffy Null polymorphism (SNP rs2814778) with hematological safety. PALINA will provide important information about the hematologic safety of palbociclib in AAW with advanced breast cancer.

Rectal Cancer in the Eye: A Case Report of Orbital Metastasis.

Orbital metastasis from colorectal cancer is extremely rare. In this case report, we describe a 48-year-old woman who presented with recurrent severe headaches and new onset constipation with no known history of cancer. After vigilant workup, imaging, and biopsies, she was diagnosed with orbital metastasis from a primary rectal carcinoma. She was started on chemotherapy and radiation therapy. Her chemotherapy regimen consisted of FLOX (leucovorin + fluorouracil + oxaliplatin), along with panitumumab, which she tolerated well. She received chemotherapy for seven months before she lost her battle with cancer.

Video intervention increases participation of black breast cancer patients in therapeutic trials.

There is a striking racial and ethnic disparity in incidence and mortality of cancer yet minorities remain markedly underrepresented in clinical trials. This pilot study set out to determine the impact of a 15-min culturally tailored educational video on three outcomes relating to clinical trials: likely participation, attitudes (assessed based on six barriers), and actual enrollment. Breast cancer patients with Stage I-III, if diagnosed within previous 6 months, or metastatic disease who self-identified as black or African American were invited to participate. The primary outcome measure was the decision to participate in a therapeutic clinical trial after the intervention. Patients' intention to enroll on a therapeutic clinical trial and the change in attitudes toward clinical trials were measured by the previously developed Attitudes and Intention to Enroll in Therapeutic Clinical Trials (AIET) questionnaire. Of the 200 patients that participated, 39 (19.5%) patients signed consent to participate in a therapeutic clinical trial; 27 (13.5%) patients enrolled, resulting in a 7.5% increase from our baseline comparison of 6% clinical trial enrollment rate in black cancer patients (p < .001). Pre-test versus post-test assessment demonstrated the proportion of patients expressing likelihood to enroll in a therapeutic trial following the intervention increased by 14% (p < .001). Among 31 AIET items, 25 (81%) showed statistically significant and positive change post-intervention. The findings suggest the promising utility of a culturally tailored video intervention for improving black patients' attitudes regarding clinical trial participation and resultant enrollment. Future efforts should continue to target facilitators of population-specific recruitment, enrollment, and retention in therapeutic and non-therapeutic clinical trials.

Cardiovascular Complications Associated With Novel Cancer Immunotherapies.

OPINION STATEMENT: Immune therapies represent a quantum leap in the fight against cancer. Recently approved immune checkpoint inhibitors that target receptors involved in immune escape of cancer cells (including cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death protein ligand-1 (PD-L1) are increasingly being used for therapeutic benefit in a number of cancers. The robust anti-cancer activity of these agents has been accompanied by the recognition of new adverse effects, often due to the over activation of immune system, that may limit their therapeutic benefit and adversely impact outcomes. Combination treatments in particular, such as approaches using two targeted immunotherapy agents, have higher risk of adverse effects. Our review focuses on the approved checkpoint inhibitor therapies and their potential for cardiovascular toxicity. While very few cases of autoimmune cardiotoxicity and myocarditis have been reported in clinical trials, severe, life-threatening episodes of heart failure and hemodynamic compromise associated with the use of immune checkpoint inhibitors have recently been reported in the literature. Early recognition, diagnosis, and management of autoimmune myocarditis represent an important clinical challenge with no current guidelines available for prevention, identification, and treatment of this serious condition. This area of cardio-oncology is evolving rapidly as more drugs in this class are being discovered and pending approval. There is a need for future studies focused on prospective identification of biomarkers and clinical standards for treatment and long-term follow-up of cardiovascular toxicity to successfully continue the treatment of cancer while preventing the adverse outcomes with novel immune therapies.

Docetaxel Alone or in Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial.

IMPORTANCE: Previous phase 1 and 2 trials of PANVAC, a poxviral-based cancer vaccine, have suggested clinical efficacy in some patients with breast, ovarian, and colorectal cancer and have shown evidence of immunologic activity. Preclinical data have shown that docetaxel can modify tumor phenotype, making tumor cells more amenable to T cell-mediated killing. OBJECTIVE: The goal of this study was to determine if the treatment combination of docetaxel and PANVAC improves clinical outcomes in patients with metastatic breast cancer compared with docetaxel treatment alone. DESIGN, SETTING, AND PARTICIPANTS: Between May 2006 and February 2012, this open-label, phase 2 randomized clinical trial enrolled 48 patients with metastatic breast cancer of all subtypes, without limitation on other lines of previous therapy, to receive treatment with either docetaxel with PANVAC (arm A) or docetaxel alone (arm B). Final clinical data were collected on September 16, 2013. All patients were treated at either the National Cancer Institute or the Department of Breast Medical Oncology, MD Anderson Cancer Center. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS), using a phase 2.5 statistical design, with the intent of identifying a trend toward benefit (defined as 1-sided P≤.10) to guide a larger trial design. Secondary end points included safety and immunologic correlative studies. RESULTS: Forty-eight participants were enrolled: 25 were randomized to the combination treatment arm A, and 23 to arm B. No patient remained in the study at the time of the final analysis. Patient and tumor characteristics were well matched. Analysis of adverse events in both treatment arms demonstrated very little difference between the 2 groups. In the combination treatment arm (arm A), statistically significant increases were noted in the frequency of grades 1 and 2 edema (P=.02, likely related to greater median number of docetaxel cycles) and injection-site reactions (P<.001). In the final data analysis, median PFS was 7.9 months in arm A vs 3.9 months in arm B (hazard ratio, 0.65 [95% CI, 0.34-1.14]; P=.09). CONCLUSIONS AND RELEVANCE: The results suggest that the combination of PANVAC with docetaxel in metastatic breast cancer may provide a clinical benefit. This study was hypothesis generating and provides both rationale and statistical assumptions for a larger definitive randomized study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00179309.

Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

BACKGROUND: Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80. METHODS: We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×10(8) plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×10(9) plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984. FINDINGS: We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%. INTERPRETATION: The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC. FUNDING: US National Institutes of Health.

Hemolytic uremic syndrome and Clostridium difficile colitis.

Hemolytic uremic syndrome (HUS) can be associated with different infectious etiologies, but the relationship between pseudomembranous colitis and HUS was first described in the 1970s in some childhood patients. There is very limited published literature on Clostridium difficile-associated HUS. We report a case of C. difficile-related HUS in an adult patient and provide a review of the literature.

A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer.

PURPOSE: PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients. EXPERIMENTAL DESIGN: Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated. RESULTS: These patients were heavily pretreated, with 21 of 26 patients having 3 or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1-37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remained on study for 37 months or more, with a significant drop in serum interleukin (IL)-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. For the ovarian cancer patients (n = 14), the median time to progression was 2 months (1-6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months. CONCLUSIONS: Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted.

A pilot safety trial investigating a vector-based vaccine targeting carcinoembryonic antigen in combination with radiotherapy in patients with gastrointestinal malignancies metastatic to the liver.

OBJECTIVE: Previous studies have demonstrated the ability of non-lethal doses of radiation to alter the phenotype of tumor cells to facilitate immune mediated killing. This pilot study evaluated the tolerability of a vector-based vaccine targeting carcinoembryonic antigen (CEA) in combination with radiation therapy in patients with gastrointestinal malignancies metastatic to the liver. METHODS: Patients enrolled had progressive CEA(+) tumors with metastatic liver lesions. Patients had received a median of three previous chemotherapy regimens, with a median of 2 months since their last chemotherapy regimen. Only 58% had metastatic disease limited to the liver. Vaccination commenced day 1 with biweekly boosters and split-course radiation (total 32 Gy) starting on day 21. Blood was collected at baseline and day 91 for immunological analysis. RESULTS/CONCLUSION: A total of 12 patients were enrolled. There were no grade 3 or greater toxicities or grade 2 or greater hepatic toxicities. Median time on-study was 3 months, with the longest time on treatment being 5 months (n = 2). Immunological analysis was limited to two patients; neither showed an increase above baseline in CEA-specific T cells post-therapy. CEA/TRICOM vaccination in combination with low-dose radiation therapy is safe. There was limited evidence of activity in this patient population.

Helicobacter pylori and its effects on human health and disease.

H. pylori is now a known cause of gastric and duodenal ulcers, noncardia gastric cancer and gastric MALT lymphoma. In addition, the role of this microorganism in causing or preventing a large number of other diseases has been investigated, some of which include esophageal cancer, functional dyspepsia, gastroesophageal reflux disease, asthma, cardiovascular diseases, iron deficiency anemia and idiopathic thrombotic purpura. This article reviews the evidence for these associations and provides suggestions for further research.

Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design.

Although docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer in 2004, additional therapies are still required. Prostate cancer is often slow-growing and expresses many tumor-associated antigens, making it a feasible target for immunotherapy. Several therapeutic cancer vaccines have been developed for prostate cancer, including antigen-presenting-cell-based, vector-based, and whole tumor cell vaccines. Initial trials demonstrated that vaccine approaches have limited toxicity. Clinical trials of targeted biologic therapies have demonstrated that patient selection is vital, and there is preliminary evidence that clinical parameters can be used to encompass metastatic prostate cancer patients who will more probably respond to vaccine treatment. In addition to appropriate patient selection, a successful clinical trial must have an appropriate primary endpoint as well. Three randomized, 'placebo'-controlled studies in metastatic castration-resistant prostate cancer have suggested a clinically significant survival advantage in spite of a lack of improvement in time to progression, implying that overall survival is the ideal endpoint for such trials. Careful examination of data from completed immunotherapy clinical trials in prostate cancer has identified appropriate patient populations and endpoints. Those principles need to be applied to future trial design to properly evaluate prostate cancer vaccines.

Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer.

Prostvac is a prostate cancer vaccine regimen consisting of a recombinant vaccinia vector as a primary vaccination, followed by multiple booster vaccinations employing a recombinant fowlpox vector. Both vectors contain the transgenes for prostate-specific antigen (PSA) and multiple T-cell co-stimulatory molecules (TRICOM). The PSA-TRICOM vaccines infect antigen-presenting cells (APCs) and generate proteins that are expressed on the surface of the APCs in an immune context. The interaction of these APCs with T cells initiates a targeted immune response and T cell-mediated tumor cell destruction. Preliminary clinical trials have indicated negligible toxicity, and Phase II trials have suggested a survival benefit after treatment with Prostvac, especially in patients with indolent disease characteristics. Preclinical and clinical data indicate that radiation, hormonal therapy, and chemotherapy may be combined with Prostvac to enhance the vaccine's efficacy. Additional strategies are in development to further enhance the clinical benefits of Prostvac, and a Phase III trial is being planned in metastatic castration-resistant prostate cancer.

Promising novel immunotherapies and combinations for prostate cancer.

The field of therapeutic cancer vaccines is currently in a state of active preclinical and clinical investigation, and certain novel therapies involving tumor immunotherapy have recently come to the forefront of prostate cancer research. While no therapeutic cancer vaccine has yet been approved by the US FDA, recent findings have demonstrated that new paradigms of combination therapies involving vaccines, employed in clinical trials with appropriate design and end points, may ultimately lead to cancer vaccines being used to treat various malignancies. Several characteristics of prostate cancer make it an ideal target for immunotherapy. Its relative indolence allows sufficient time to generate immune responses, which usually take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal tissue. This review focuses on the future of promising new vaccines and novel perspectives in the treatment of prostate cancer.

Cancer vaccines: current directions and perspectives in prostate cancer.

Numerous research groups are investigating the use of cancer vaccines as a potential therapeutic modality for various tumor types. The efficacy of cancer vaccines has improved because of advances in the characterization of tumor-associated antigens, the development of improved vaccine delivery systems, and the combination of vaccines with cytokines and other immunostimulants to enhance immune responses. Although cancer vaccines are under investigation for the treatment of various different tumor types, several characteristics of prostate cancer make it an ideal target for immunotherapy. The relative indolence of prostrate cancer allows sufficient time to generate immune responses, which usually take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal tissue. This review focuses on promising new strategies for combining vaccines with other therapeutic approaches, as well as novel perspectives in the treatment of prostate cancer.