BRIP-1 germline mutation and its role in colon cancer: presentation of two case reports and review of literature.

BACKGROUND: Hereditary colon cancer is characterized by the inheritance of an abnormal gene mutation which predisposes to malignancy. Recent advances in genomic medicine have identified mutations in "novel" genes as conferring an increased risk of colorectal cancer. Mutations in the BRIP1 gene (BRCA1 Interacting Protein C- terminal helicase 1) are known to increase the risk of ovarian and breast cancers, but this genes association with colon cancer has not been previously reported. CASE PRESENTATION: We describe two patients with colon cancer whose tumor tissue were found to harbor BRIP1 mutations on analysis by next-generation sequencing. These patients were confirmed by analysis of lymphocytes to carry the mutation in the germline as well. CONCLUSIONS: These case reports highlight a previously unreported association of BRIP1 germline mutations with colon cancer predisposition.

Chemotherapeutic and targeted biological agents for metastatic bladder cancer: a comprehensive review.

The American Cancer Society estimates that 73 510 new cases of bladder cancer will be diagnosed and 15 000 deaths will result this year. The paper summarizes the clinical evidence for the use of platinum-based, non-platinum-based and new targeted biological agents, while reporting the future directions in the treatment of metastatic bladder cancer. For cisplatin-base regimens, the combination of methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) has been the mainstream treatment for both advanced and metastatic bladder cancers. It showed significant improvement in the complete response rate and overall survival time in comparison with single-agent cisplatin. For cisplatin-ineligible patients, namely patients with renal impairment, symptomatic cardiac disease and poor performance status, alternative therapies consisting of paclitaxel, gemcitabine and carboplatin were shown to be of benefit. Pemetrexed and vinflunine have also shown effectiveness, with small but demonstrable overall survival benefits. Gemcitabine-based doublet therapies (combined with paclitaxel, docetaxel, irinotecan, oxaliplatin or epirubicin) have all been shown to be effective and well-tolerated. Several new targeted therapies, such as gefetinib, sorafenib and lapatinib, have received attention in recent years; however, their effectiveness as single agents in a relapse setting have not been optimal and more studies are warranted.

Rapid Room-Temperature Aerosol Dehydration Versus Spray Drying: A Novel Paradigm in Biopharmaceutical Drying Technologies.

To ensure the high quality of biopharmaceutical products, it is imperative to implement specialized unit operations that effectively safeguard the structural integrity of large molecules. While lyophilization has long been a reliable process, spray drying has recently garnered attention for its particle engineering capabilities for the pulmonary route of administration. However, maintaining the integrity of biologics during spray drying remains a challenge. To address this issue, we explored a novel dehydration system based on aerosol-assisted room-temperature drying of biological formulations recently developed at Princeton University, called Rapid Room-Temperature Aerosol Dehydration. We compared the quality attributes of the bulk powder of biopharmaceutical products manufactured using this drying technology with that of traditional spray drying. For all the fragment antigen-binding formulations tested, in terms of protein degradation and aerosol performance, we were able to achieve a better product quality using this drying technology compared to the spray drying technique. We also highlight areas for improvement in future prototypes and prospective commercial versions of the system. Overall, the offered dehydration system holds potential for improving the quality and diversity of biopharmaceutical products and may pave the way for more efficient and effective production methods in the biopharma industry.

Unusual sites of hepatocellular carcinoma metastasis: Case report.

Hepatocellular carcinoma is an increasingly frequent cause of cancer-related death. The majority of patients with hepatocellular carcinoma are asymptomatic. In rare cases, patients may present with symptoms of extrahepatic metastases. Early identification can lead to timely treatment and prevent poor outcomes. We report three cases of patients with hepatocellular carcinoma with unusual sites of metastasis, including clival, mandible, and cardiac involvement.

Digital ischaemia and necrosis from oxaliplatin.

Oxaliplatin is a chemotherapeutic agent used in a variety of malignancies such as colorectal cancer and pancreatic cancer. It is a platinum derivative that results in direct cell cytotoxicity with resultant cell death. The most common side effects often noted are neurotoxicity, nausea, vomiting, diarrhoea, hepatotoxicity and myelosuppression. Oxaliplatin induced digital ischaemia and necrosis is a rare side effect that was observed in our patient. In general, digital ischaemia is a rare vascular disorder that is often associated with autoimmune disease. A patient with digital ischaemia due to oxaliplatin will be described in this case report.

A Case of a Rare Parathyroid Hormone (PTH)-Producing Neuroendocrine Tumor.

BACKGROUND Neuroendocrine neoplasms are commonly seen in association with hormone production, and clinical signs that arise from these hormonal effects often manifest as the first presentation of malignancy. The excess production of parathyroid hormone (PTH) in particular, however, is primarily sporadic (80-85%) in clinical settings. In the context of malignancy, hyperparathyroidism manifestations arise most frequently from non-neuroendocrine pulmonary tumors through a ligand mimicker, parathyroid hormone-related peptide (PHrP). Excess PTH or PTHrP production has been very rarely described in association with gastrointestinal tumors and almost never described as a primary paraneoplastic syndrome from a neuroendocrine tumor (NET) alone. CASE REPORT We present a patient with a prior surgically resected carcinoid tumor who later presented with an elevated parathyroid hormone level, hypercalcemia, and clinical manifestations of primary hyperparathyroidism. She was found to have a low-grade, recurrent neuroendocrine tumor on resection of a parathyroid mass suspected to be a productive adenoma. Despite no longer having parathyroid glands given the extent of resection, her PTH level remained elevated and was rising. Further investigation via repeat sestamibi nuclear scan excluded the possibility of exogenous parathyroid tissue, and subsequent dotatate positron emission tomography/computed tomography (PET/CT) revealed the source of the PTH production: multiple sites of metastatic neuroendocrine tumors producing native PTH. CONCLUSIONS This case highlights the rare possibility of NETs to secrete PTH and the importance of considering early staging with dotatate PET/CT to evaluate the extent of disease. Additionally, our case reveals the importance of considering NET as an alternative etiology for refractory hypercalcemia.

Dramatic prostate-specific antigen response with activated hemicellulose compound in metastatic castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an incurable disease with limited treatment options. Herbal supplements are unconventional treatments for a variety of diseases. Active hemicellulose compound (AHCC) is a Japanese supplement discovered by hybridizing several mushrooms used in traditional healing for the purpose of maintaining 'super immunity'. We report on a 66-year-old gentleman with CRPC with an excellent serologic response to AHCC. This case hypothesizes that AHCC may have potential activity against CRPC.

Testicular lymphoma: an update for clinicians.

Testicular lymphoma is a lethal disease with a median survival of approximately 12 to 24 months. It is the most common testicular malignancy in men older than 60 years of age. Testicular lymphoma has a predilection for widespread dissemination to unusual sites, including the central nervous system, contralateral testis, Waldeyer's ring, skin, and lung. Doxorubicin based chemotherapy with prophylactic intrathecal chemotherapy and radiation to the contralateral testis seems most promising. This review article will focus on the presentation, pathology, patterns of relapse and challenges in improving the outcome of this disease.

Multidisciplinary Cancer Care Model: A Positive Association Between Oncology Nurse Navigation and Improved Outcomes for Patients With Cancer.

BACKGROUND: Patients with cancer often experience prominent deficiencies in cancer care in the immediate period following initial cancer diagnosis. OBJECTIVES: This article aims to determine whether the inclusion of a gastrointestinal (GI) oncology nurse navigator (ONN) on the multidisciplinary cancer care team is associated with improved quality of care for patients. METHODS: This retrospective study compared randomly selected patients with GI cancer with and without an ONN. Two endpoints, the time from diagnosis to treatment and the average number of missed appointments, were evaluated through a review of healthcare records using the Epic electronic health records system. FINDINGS: Patients with an ONN had a shorter time lapse between diagnosis and treatment commencement (p < 0.001). In this group, the average time spent between initial diagnosis and the start of treatment was 15.15 days, compared to 42.93 days for patients who were not part of the multidisciplinary cancer care model.

Phase I dose escalation study of vinorelbine and topotecan combination chemotherapy in patients with recurrent lung cancer.

BACKGROUND: A platinum doublet is the current standard treatment for good performance status patients with advanced non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (SCLC) with good performance status. However, platinum-based treatment may be associated with significant toxicities, therefore alternative platinum-free combinations should be investigated. Topotecan is a topoisomerase I inhibitor that exerts its cytotoxic effect through stabilization of the topoisomerase I-DNA complex. Preclinical data suggests synergy between topoisomerase I inhibitors and mitotic spindle poisons. Considerable hematologic toxicities have been reported with topotecan dosed for 5 consecutive days in combination with vinorelbine. Therefore, the aim of this study was to evaluate the optimal dosage and the maximal tolerated dose (MTD) of topotecan and vinorelbine in patients with relapsed or refractory non-small cell or small cell lung cancer administered on an alternate dosing schedule. METHODS: From February, 2004 to March, 2007 eighteen patients with advanced or recurrent NSCLC or SCLC previously treated with chemotherapy were enrolled. Patients were heavily pretreated with 22% having received at least 3 prior lines of chemotherapy. Vinorelbine was administered at a fixed dose (20 mg/m2) and topotecan at escalating doses (2, 2.5, 3, 3.5, and 4 mg/m2) on days 1 and 8 every 21 days. RESULTS: The MTD was not reached in any of the 5 cohorts, with only one dose limiting toxicity (DLT) occurring in cohort 4. Non-hematological toxicities were manageable. One patient had a partial response with four patients (27%) achieving stable disease. The median progression-free and overall survival for all patients, were 2.7 months (95% CI: 1.6, 9.1) and 10.5 months (95% CI: 4.2, 22.7), respectively. CONCLUSION: Vinorelbine and topotecan administered on days 1 and 8 every 21 days is well tolerated without any DLT seen with previously investigated topotecan schedules. This doublet provides a potentially active non-platinum containing doublet for the treatment of patients with advanced SCLC and NSCLC. Vinorelbine and topotecan should therefore be investigated in subsequent phase II studies at a dose of 20 mg/m2 and 4 mg/m2, respectively. TRIAL REGISTRATION NUMBER: NCT00287963.

Bortezomib in combination with celecoxib in patients with advanced solid tumors: a phase I trial.

BACKGROUND: COX-2 inhibitors, such as celecoxib, and ubiquitin-proteasome pathway inhibitors, such as bortezomib, can down-regulate NF-kappaB, a transcription factor implicated in tumor growth. The objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of bortezomib in combination with celecoxib in patients with advanced solid tumors. METHODS: Patients received escalating doses of bortezomib either on a weekly schedule (days 1, 8, 15, 22, and 29 repeated every 42 days) or on a twice-weekly administration schedule (days 1, 4, 8, and 11 repeated every 21 days), in combination with escalating doses of celecoxib twice daily throughout the study period from 200 mg to 400 mg twice daily. RESULTS: No dose-limiting toxicity was observed during the study period. Two patients had stable disease lasting for four and five months each, and sixteen patients developed progressive disease. CONCLUSION: The combination of bortezomib and celecoxib was well tolerated, without dose limiting toxicities observed throughout the dosing ranges tested, and will be studied further at the highest dose levels investigated. TRIAL REGISTRATION NUMBER: NCT00290680.

A rare case of clear cell adenocarcinoma of the bladder with unique pathological features.

Clear cell adenocarcinomas of the urinary bladder are rare tumors with an unknown histogenesis. Since these tumors appear histologically similar to clear cell tumors of the female genital tract, a mullerian histogenesis has been proposed. Several publications have examined the immunohistochemical properties of clear cell adenocarcinomas to improve understanding of the cause and pathogenesis of this tumor. While specific criteria for a diagnosis of clear cell adenocarcinoma have not been defined, there are consistent staining patterns suggested for characterization. We present an important case of clear cell adenocarcinoma of the bladder with a unique staining pattern. We review the literature and discuss the differential diagnosis and various theories concerning the origin of this rare tumor.

Use of low molecular weight heparin and aminocaproic acid in chronic DIC associated with prostate cancer--a case report.

Disseminated Intravascular Coagulopathy (DIC) is the most common coagulopathy in patients with prostate cancer. Though rare, it could be fatal without treatment. Literature suggests that there is significant activation of fibrinolytic pathway. Pathophysiology of DIC in patients with prostate cancer is not completely understood. We present here a case of chronic DIC in a patient with metastatic androgen independent prostate cancer. His DIC was managed successfully with a combination of aminocaproic acid and low weight molecular heparin. The use of low molecular weight heparin may make management of chronic DIC in prostate cancer more feasible in an out patient setting.

Sacral epithelioid angiosarcoma associated with a bleeding diathesis and spinal epidural hematoma: case report.

Epithelioid angiosarcoma of bone is a rare, high-grade lesion that is highly vascular and can be associated with a bleeding diathesis. An association has been reported in angiosarcomas in other locations with coagulopathy from tumor-related disseminated intravascular coagulopathy and fibrinolysis. The authors report the case of a rare occurrence of a primary sacral epithelioid angiosarcoma associated with a large epidural hematoma and a severe bleeding diathesis. A 25-year-old woman presented with weakness, fatigue, neck and low-back pain, and progressive left S-1 radiculopathy. Imaging studies revealed a large ventral epidural hematoma extending from the sacral region rostrally to C-2 and a vascular tumor located in the sacrum. The patient underwent a sacral laminectomy, complicated by postoperative bleeding from the wound, and required massive transfusions. Ultimately, multimodal therapy was required to obtain hemostasis, including the use of endovascular embolization, radiation therapy, and an infusion of epsilon-aminocaproic acid with heparin. This case represents the first report of a primary epithelioid angiosarcoma in the sacrum and emphasizes that the coagulopathy seen in angiosarcoma is also a feature of this epithelioid variant.

Primary mediastinal large B-cell lymphoma in an HIV-infected patient.

HIV-related non-Hodgkin lymphoma is well documented in the literature. We report a case of an HIV-infected patient who presents with primary mediastinal large B-cell lymphoma. On review of the literature, this appears to be the first documented case of this subtype of large B-cell non-Hodgkin lymphoma seen in an HIV-infected patient. Our patient received CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone) chemotherapy with granulocyte colony-stimulating factor support but unfortunately died a few days later.

Secondary hormonal manipulations in the management of advanced prostate cancer.

Prostate cancer is a heterogeneous disease and clinical outcomes vary considerably after failure of primary androgen ablation. With the development of new therapeutics the management of patients with androgen independent prostate cancer has changed considerably over the last few years. Multiple secondary hormonal manipulations are available and may lead to prolonged periods of clinical response. These maneuvers include the use of oral antiandrogens, antiandrogen withdrawal, ketoconazole, aminoglutethimide, corticosteroids and use of estrogenic compounds. This article reviews the clinical activity of these agents in management of patients with advanced prostate cancer.

Long-term complications of chemotherapy for germ cell tumours.

Testicular cancer is the most common solid tumour among young males aged 15-35 years. Cisplatin-based combination chemotherapy has changed the outlook of this disease. Disseminated testicular cancer, once uniformly fatal, now has a cure rate of more than 80% with combination chemotherapy. Systematic randomised trials have shown that cisplatin, etoposide and bleomycin (PEB) combination chemotherapy remains the mainstay of treatment. While there is a high cure rate with chemotherapy in patients with this disease, some long-term complications from chemotherapy have now been recognised, including secondary leukaemia, therapy-related solid tumours, nephrotoxicity, neurotoxicity, pulmonary toxicity, vascular toxicity and infertility. Etoposide, a DNA topoisomerase II inhibitor, is a significant risk factor for developing leukaemia; the risk appears to be correlated with the total dose given. Patients receiving cisplatin-based combination chemotherapy for testicular cancer also appear to have a higher relative risk for developing second non-germ cell malignancies; the greatest risks for therapy-related solid tumours were seen with a combination of radiation therapy plus chemotherapy. Long-term vascular toxicities associated with chemotherapy include Raynaud's phenomenon, acute myocardial infarction and cerebrovascular events. Bleomycin is thought to be the most important drug in the pathogenesis of Raynaud's phenomenon, while cisplatin is the most likely agent involved in myocardial infarction. Peripheral neuropathy is the most common form of neurotoxicity observed with cisplatin-based chemotherapy. Risk factors for the development of neural damage include a high cumulative dose of cisplatin, the use of vinblastine and the concomitant development of Raynaud's phenomenon. Cisplatin is also well known to cause significant nephrotoxicity. Approximately 25% of patients present with azoospermia after undergoing combination chemotherapy with a follow up of 2-5 years. Physician awareness of complications associated with chemotherapy is vital to maximise efficacy, minimise toxicity, and preserve quality of life after treatment. Sperm cryopreservation should be considered for patients who desire children. Close monitoring during therapy allows for the early diagnosis of complications, and close follow up of patients after the completion of therapy is necessary to monitor for relapse and development of long-term complications such as myelodysplastic syndrome and leukaemia. Despite these complications, given the potential for cure rates in this young group of patients, the benefits far outweigh the risks.

The evolving role of cytoreductive surgery for metastatic renal cell carcinoma.

Metastatic renal cell carcinoma is a devastating disease associated with poor survival. Immunotherapy is the mainstay of treatment, but response rates are low. The role of cytoreductive surgery in the presence of metastatic disease is evolving. From both retrospective and recently published randomized clinical trials, it is now apparent that among patients with metastatic renal cell carcinoma and good performance status, cytoreductive surgery followed by immunotherapy improves survival. However, this approach is likely to be detrimental in patients with poor performance status. Clinical trials of novel agents remain a priority in this disease.

Transitional cell carcinoma of the bladder producing parathyroid hormone-related protein (PTHrP).

Hypercalcemia associated with transitional cell carcinoma (TCC) is rarely encountered. We report a case of TCC of bladder with documented production of parathyroid hormone related protein (PTHrP). Our patient had a rapidly progressive course and died 2 months after radical cystectomy. Literature suggests that these patients present with advanced stage and carry a poor prognosis. The histopathologic features, treatment and prognosis associated with this rare paraneoplastic syndrome are reviewed.

Isolated late recurrence of renal cell carcinoma in the inferior vena cava.

The occurrence of an isolated late recurrence of renal cell carcinoma within the inferior vena cava (IVC) is a rare event. We present a case of a 55-year-old patient with recurrence in the IVC more than 3 years following her initial nephrectomy. The asymptomatic presentation of this patient with recurrent disease emphasizes the importance of close, long-term surveillance.