Identification of AKAP-4 as a new cancer/testis antigen for detection and immunotherapy of prostate cancer.

BACKGROUND: Prostate cancer (PC) is the second most common cancer in older men, after skin cancer. PC is difficult to diagnose because the prostate-specific antigen screening method is associated with many false positives. In addition there is a need to develop new and more effective treatments. Among presently available new treatments, immunotherapy is a promising approach. We investigated the expression of the cancer/testis antigen, AKAP-4, in PC patients to evaluate the possibility of exploiting AKAP-4 as a target for immunotherapy. METHODS: We analyzed normal prostate tissues, 15 patients with PC and the LnCAP PC cell line by immunohistochemistry. We tested AKAP-4 immunogenicity through indirect ELISA on sera from patients and healthy subjects, and we generated in vitro AKAP-4-specific cytotoxic lymphocytes from peripheral blood mononuclear cells. RESULTS: AKAP-4 was shown both at the cytoplasmic and surface levels of the LnCAP PC cell line. AKAP-4 was also highly expressed in PC cells from patients. We detected specific anti-AKAP-4 circulating immunoglobulins in AKAP-4 positive subjects. Using recombinant AKAP-4 loaded autologous dendritic cells, we generated AKAP-4-specific and HLA-I-restricted cytotoxic T lymphocytes able to kill PC cells in vitro. Further characterization indicated a Th-1 skewing in the cytokine secretion profile of these cells. CONCLUSIONS: We demonstrate the aberrant expression of AKAP-4 in PC, which will potentially be developed as a biomarker in PC. We provide evidence that AKAP-4 is a potential target for PC adoptive immunotherapy or anti-tumor vaccination.

Risk of Infection Associated With Ibrutinib in Patients With B-Cell Malignancies: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

INTRODUCTION: B-cell malignancies confer an increased risk of infection due to associated immune defects. Conflicting evidence exists on the risk of infection in patients receiving ibrutinib. We conducted a systematic review and meta-analysis to estimate relative risk of infection with ibrutinib in B-cell malignancies. METHODS: A systematic search of Embase, Medline, Web of Science, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, European Union Clinical Trials Register, and ClinicalTrials.gov was performed through January 15, 2019, to identify randomized controlled trials comparing ibrutinib with other agents or placebo in B-cell malignancies. We pooled point estimates using the Der Simonian and Laird random-effects model. Statistical analyses were performed by Stata/SE 15.1. RESULTS: Seven studies randomizing 2167 patients were included in the final analysis. Treatment duration in studies ranged from 9.4 to 38.7 months. Ibrutinib was associated with a significantly increased risk of infection (any grade and grade 3-5) in patients with B-cell malignancies [pooled risk ratio (RR) = 1.34, 95% confidence interval [CI], 1.06-1.69, P = .015; and RR = 1.35, 95% CI, 1.05-1.74, P = .018, respectively]. In patients with chronic lymphocytic leukemia, a significantly increased risk of grade 3-5 infection was noted in the ibrutinib group [pooled RR = 1.24, 95% CI, 1.02-1.50, P = .028]. Incidences of pneumonia and upper respiratory tract infection were not significantly different between groups. CONCLUSION: Our meta-analysis found that ibrutinib was associated with significantly higher risk of infections in patients with B-cell malignancies. Occurrence of major individual subtypes was not different between groups, possibly as a result of inconsistent reporting across studies.

The pituitary tumor transforming gene 1 (PTTG-1): an immunological target for multiple myeloma.

BACKGROUND: Multiple Myeloma is a cancer of B plasma cells, which produce non-specific antibodies and proliferate uncontrolled. Due to the potential relapse and non-specificity of current treatments, immunotherapy promises to be more specific and may induce long-term immunity in patients. The pituitary tumor transforming gene 1 (PTTG-1) has been shown to be a novel oncogene, expressed in the testis, thymus, colon, lung and placenta (undetectable in most other tissues). Furthermore, it is over expressed in many tumors such as the pituitary adenoma, breast, gastrointestinal cancers, leukemia, lymphoma, and lung cancer and it seems to be associated with tumorigenesis, angiogenesis and cancer progression. The purpose was to investigate the presence/rate of expression of PTTG-1 in multiple myeloma patients. METHODS: We analyzed the PTTG-1 expression at the transcriptional and the protein level, by PCR, immunocytochemical methods, Dot-blot and ELISA performed on patient's sera in 19 multiple myeloma patients, 6 different multiple myeloma cell lines and in normal human tissue. RESULTS: We did not find PTTG-1 presence in the normal human tissue panel, but PTTG-1 mRNA was detectable in 12 of the 19 patients, giving evidence of a 63% rate of expression (data confirmed by ELISA). Four of the 6 investigated cell lines (66.6%) were positive for PTTG-1. Investigations of protein expression gave evidence of 26.3% cytoplasmic expression and 16% surface expression in the plasma cells of multiple myeloma patients. Protein presence was also confirmed by Dot-blot in both cell lines and patients. CONCLUSION: We established PTTG-1's presence at both the transcriptional and protein levels. These data suggest that PTTG-1 is aberrantly expressed in multiple myeloma plasma cells, is highly immunogenic and is a suitable target for immunotherapy of multiple myeloma.

Pure Squamous Cell Carcinoma of the Gallbladder Masquerading as a Hepatic Mass.

Gallbladder (GB) carcinomas are adenocarcinomas (AC) in the majority of cases. Adenosquamous carcinoma (ASC) and pure squamous cell carcinoma (SCC) of the gallbladder are rarely encountered and comprise 1-3% of gallbladder cancer cases.  Pure squamous cell carcinoma of the gallbladder is rarer with less than 1% of the incidence. Most of the published literature is based on case reports and case series. The survival rates of ASC and SCC of the gallbladder are significantly lower (mean of five months) compared to the AC of the gallbladder (mean survival of 11.4 months). Most of these lesions are advanced at presentation, rendering them unresectable and resulting in a poor prognosis. However, if the lesions are diagnosed at an early stage, they could potentially be resectable. We report one such rare case of pure SCC GB presenting as a hepatic mass. The patient subsequently underwent resection of the gallbladder and liver mass with complete recovery and is currently planned for chemotherapy and radiation treatment.

Acquired hemophilia: a case report of 2 patients with acquired factor VIII inhibitor treated with rituximab plus a short course of steroid and review of the literature.

Acquired hemophilia is an unusual disorder in which nonhemophiliac patients develop autoantibodies (inhibitor) against the factor VIII coagulation protein. Factor VIII inhibitor leads to life-threatening bleeding disorders classically described as new onset of diffuse bruising and prolonged partial thromboplastin time in elderly patients. Treatment is focused in the control of the acute bleeding episode and the long-term suppression of the autoantibody. Several immunosuppressive combinations have been described; however, these treatments are also associated with serious side effects that are difficult to tolerate, especially in older and debilitated patients. New treatment modalities explore the elimination of the autoantibody production by targeting B-cells with rituximab, an anti CD-20 monoclonal antibody that has shown success in a multitude of autoimmune processes. This report presents 2 patients successfully treated with rituximab and a short tapering course of steroids and focuses our discussion in the analysis of different treatment approaches available for these patients' population.

Giant-cell tumor of bone with pathological evidence of blood vessel invasion.

Giant cell tumor of bone is a rare but aggressive benign tumor that arises at the end of long tubular bones. The tumor rarely metastasizes; however, we report a case in which a giant cell tumor of bone presented with progressive pulmonary metastases. There has been no clear pathologic evidence of the definitive cause or route of metastasis. In our case, the primary tumor site was located in the left femur with pathological evidence of blood vessel invasion. The histological and pathological features of this entity are discussed in this letter to the editor.

Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: case report and review of the literature.

A 36-year-old woman was hospitalized for preoperative chemotherapy for osteosarcoma. She received intravenous fluids for 12 hours for volume expansion, then methotrexate 24 g (12 g/m2) over 6 hours. This was followed by intravenous leucovorin 200 mg over 1 hour. Two hours after the methotrexate infusion the patient developed chest pain and bradycardia. An electrocardiogram revealed sinus pauses, and telemetry recordings indicated a 4-beat run of ventricular tachycardia. A cardiac work-up consisting of cardiac enzyme level determination, two-dimensional echocardiography, and an adenosine technetium-99m tetrofosmin stress test was negative for structural and ischemic heart disease. The patient recovered without treatment and, approximately 2 weeks later, received a second course of methotrexate at half the dose without complication. One month later the patient received treatment with doxorubicin and cisplatin; 2 days later she died unexpectedly at home. Clinicians should be aware that high-dose methotrexate can cause cardiac symptoms and arrhythmias in previously healthy adults. This complication warrants attention and needs additional clinical investigation.

Maxillary sinus inflammatory myofibroblastic tumors: a review and case report.

An inflammatory myofibroblastic tumor (IMT) is an immunohistochemically diverse entity demonstrating neoplastic and nonneoplastic qualities. Although IMTs can arise in any area of the body, lesions arising in certain sites, namely, the nasal cavity, paranasal sinuses, and pterygopalatine fossa, demonstrate a heightened neoplastic and invasive potential. Despite case specific complete tumor regression and disease remission in response to pharmacotherapeutics, a subset of IMTs remain resistant to all forms of therapy. We present such a case, a 34-year-old female patient, with a highly resistant, maxillary sinus IMT. Her refractory, ALK-1 negative IMT has not responded well to novel therapies reported in current literature. This case suggests the role of zonal expressivity within a single lesion as a probable mechanism for its highly resistant nature and should promote determination of each IMT's cytogenetic profile to provide more effective targeted therapy. Paper includes a literature review of all maxillary sinus IMTs from 1985 to 2014 along with their immunohistochemical staining, treatments, and outcomes.

Treatment of Hepatic Epithelioid Hemangioendothelioma: Finding Uses for Thalidomide in a New Era of Medicine.

Hepatic epithelioid hemangioendothelioma (HEH) is extremely rare, occurring in 1 to 2 per 100,000, with chemotherapy options not well defined. Our case involved a 49-year-old female who had hepatic masses and metastasis to the lungs with a liver biopsy revealing HEH. After developing a rash from sorafenib, thalidomide was started with the progression of disease stabilized. Resection is only an option in 10% of the cases; therefore, chemotherapy is the only line of treatment. Newer chemotherapy alternatives are targeting angiogenesis via the vascular endothelial growth factor. Thalidomide was first used as an antiemetic, but, sadly, soon linked to phocomelia birth defects. Given the mechanism of action against angiogenesis, thalidomide has a valid role in vascular tumors. In conclusion, the use of thalidomide as chemotherapy is novel and promising, especially in the setting of a rare vascular liver tumor such as HEH.

Fatal Clostridium septicum infection in a patient with a hematological malignancy.

A 49-year-old woman with acute myeloid transformation of myelodysplastic syndrome was admitted with mild erythema and pain in the right thigh and left forearm. She was doing well and had been discharged the previous day after consolidation chemotherapy. Examination showed only mild erythema and tenderness of the right thigh. She was started on broad-spectrum antibiotics. Discoloration progressed rapidly, and within hours the right femoral and left brachial pulses were not palpable. She was taken to the operating room for a suspicion of embolic arterial occlusion. Surgical incision, however, revealed extensive necrosis of the tissues with the presence of gas. Her relatives did not want her to undergo amputation. The patient developed refractory hypotension and died within 15 hours of presentation. Blood samples later tested positive for Clostridium septicum. This case is presented to create awareness about the subtle presentation and rapid progression of this infection, which can lead to death in less than 24 hours.

Management of hand-foot syndrome induced by capecitabine.

INTRODUCTION: Capecitabine (Xeloda) is a systemic prodrug of 5-fluorouracil (5-FU), which is administered in an oral formulation. Hand-foot syndrome (HFS) has proven to be a chronic dose-limiting toxicity of capecitabine, leading to significant morbidity in patients receiving this agent. The purpose of this review is to define the pathophysiology, risk factors, incidence and management of capecitabine-induced HFS. METHODS: Literature for this review article was collected from the following databases: PubMed, CINAHL, and the proceedings of the American Society of Clinical Oncology (ASCO) confined to the years 1995-2006. The following key terms were used in the search: hand-foot syndrome, palmar-plantar erythrodysesthesia, capecitabine, Xeloda, colorectal cancer, and metastatic breast cancer. RESULTS: HFS associated with capecitabine is a serious dose-limiting toxicity. Incidence of grade 3/4 toxicity is of extreme significance, and introduces the need for dose reductions and/or interruptions in capecitabine therapy. Drug-related therapies studied include topical emollients and creams, systemic and topical corticosteroids, nicotine patch, vitamin E, pyridoxine, and COX-2 inhibitors. However, due to the lack of randomized, controlled trials with these therapies, the current mainstay of treatment for the management of this toxicity is interruption of therapy and, if necessary, dose reduction. CONCLUSION: Treatment interruption or dose reduction remain the only methods shown to effectively manage HFS, but supportive measures to reduce pain and discomfort and prevent secondary infection are very important. Many other prophylactic and treatment strategies have been investigated, with pyridoxine and COX-2 inhibitors being the most promising in case reports and retrospective studies; therefore, prospective, randomized, controlled trials are needed to prove their efficacy.

A review of clinical experience with paclitaxel extravasations.

Paclitaxel is a novel anti-neoplastic with a wide spectrum of activity in various malignant tumors. Extravasation of chemotherapy drugs is a widely feared adverse event in oncology patients. A Medline search between 1966 and October 2002 was conducted to identify case reports related to paclitaxel extravasation, as well as a bibliography screening of identified papers. The goal of this work is to summarize the available reports of paclitaxel extravasation and assess its vesicant potential. Additionally, management strategies for extravasation events due to paclitaxel are assessed.

Nasopharyngeal carcinoma metastasis to the pituitary gland: a case report and literature review.

While nasopharyngeal carcinoma (NPC) commonly invades the skull base, true central nervous system metastasis is a rare phenomenon. We report a case of NPC metastasis to the pituitary gland and review the literature for similar events. Eight months after his definitive radiation therapy, our patient presented with symptoms of optic chiasm compression and panhypopituitarism. Medical imaging revealed a pituitary mass but demonstrated no evidence of skull base erosion or direct intracranial extension. Subsequent biopsy of the pituitary lesion was confirmed as NPC in origin with Epstein-Barr virus-encoded RNA in-situ hybridization studies. The patient was treated with high dose chemotherapy followed by autologous stem cell transplant, which produced short-term symptomatic relief and at least a 7 month survival.