Phase II trial of SM-88, a cancer metabolism based therapy, in non-metastatic biochemical recurrent prostate cancer.

Background Androgen deprivation therapy (ADT) is a standard treatment for high-risk biochemically-recurrent, non-metastatic prostate cancer (BRPC) but is not curative and associated with toxicity. Racemetyrosine (SM-88) is an amino-acid analogue used with methoxsalen, phenytoin, and sirolimus (MPS) to enhance SM-88 activity. Method A phase 1b/2, open-label trial in BRPC and rising PSA. Patients were given daily SM-88 (230 mg BID), methoxsalen (10 mg), phenytoin (50 mg), and sirolimus (0.5 mg)). Outcome measures included changes in PSA, circulating tumor cells (CTCs) and imaging. Results 34 subjects were screened, 23 treated and 21 remained on study for ≥12 weeks. The median PSA was 6.4 ng/ml (range 1.7-80.1); doubling-time 6.2 months (range 1.4-36.6) and baseline testosterone 319.1 ng/ml (range 2.5-913.7). Median duration of therapy was 6.5 months (2.6-14.0). CTCs (median 48.5 cells/4 ml (range 15-268) at baseline) decreased a median of 65.3% in 18 of 19 patients. For patients who achieved an absolute CTC nadir count of <10 cells/4 ml (n = 10), disease control was 100% i.e. no metastases or PSA progression, while on trial (p = 0.005). PSA fell by ≥50% in 4.3% (1 subject). No patients developed metastatic disease while on treatment (metastases free survival =100%). There were no treatment-related adverse events (AEs) and quality of life was unchanged from baseline on the EORTC QLQ-C30 and QLQ-PR25. Testosterone levels rose slightly on SM-88 and were unrelated to efficacy or toxicity. Conclusions Use of SM-88 was associated with disease control while maintaining QOL. SM-88 may delay the need for ADT and the associated hormonal side effects. Larger trials are planned.Trial registration number, date of registration - NCT02796898, June 13, 2016.

Pre-clinical and clinical evaluation of estramustine, docetaxel and thalidomide combination in androgen-independent prostate cancer.

OBJECTIVE: To evaluate the combination of docetaxel plus estramustine (which prolongs survival in patients with androgen-independent prostate cancer, AIPC), and thalidomide (that also adds to docetaxel activity), both pre-clinically and clinically in AIPC. PATIENTS, MATERIALS AND METHODS: In the pre-clinical evaluation we injected PC3 cells subcutaneously into severely combined immunodeficient mice and started treatment after the tumour volume reached 50 mm3. We also evaluated the combination using luciferase-labelled PC3M-luc-C6 cells in nude mice. We enrolled 20 patients with metastatic progressive AIPC into a phase II clinical trial to evaluate this combination. Docetaxel (30 mg/m2) was administered every week, for 3 of 4 weeks. The dose of thalidomide was 200 mg/day and estramustine was given three times a day at 1, 2, 3, 8, 9, 10, 15, 16 and 17 days. RESULTS: In the mice, thalidomide with docetaxel plus estramustine reduced tumour volume by 88% at 17 days vs the control treatment (p=0.001). The combination of docetaxel, estramustine and thalidomide nearly eradicated the signal from the luciferase-expressing PC3M cells in the metastasis model. Clinically, the progression-free time was 7.2 months with this combination; 18 of 20 patients had a decline of half or more in prostate-specific antigen level and two of 10 patients with soft-tissue lesions had a partial response on computed tomography. There were 24 grade 3 and two grade 4 complications associated with this combination. There was a statistically significant association between overall survival and the CYP1B1*3 genotype (P=0.013). CONCLUSION: Docetaxel-based chemotherapy is now regarded as a standard regimen for metastatic AIPC. The combination of estramustine, docetaxel and thalidomide is an advantageous treatment in pre-clinical models of prostate cancer and is a safe, tolerable and active regimen in patients with AIPC.

Polymorphism in the hypoxia-inducible factor 1alpha gene may confer susceptibility to androgen-independent prostate cancer.

The hypoxia-inducible factor 1alpha (HIF-1alpha) plays a major role in cancer progression. The role of this transcription factor in prostate cancer development and its transition to a metastatic and androgen refractory state remains to be elucidated. Previous reports have identified the existence of single nucleotide polymorphisms (SNPs) in the oxygen-dependent degradation domain of the HIF-1alpha gene in renal cell carcinoma, head and neck squamous cell carcinoma, and androgen-independent prostate cancer (AIPC). Studies in prostate cancer, however, are variable and limited in the number of cases assessed. Herein we further investigate these SNPs, specifically C1772T (which results in an amino acid change from proline 582 to serine) and G1790A (alanine 588 to threonine). The frequency of these polymorphisms was evaluated in a population of individuals with metastatic AIPC and compared to a set of healthy control subjects. The distribution of HIF-1alpha genotypes for C1772T in 196 AIPC patients was 161 C/C (82.1%), 29 C/T (14.8%), and 6 T/T (3.1%). The genotype distribution in 196 controls was 179 C/C (91.3%), 14 C/T (7.1%), and 3 T/T (1.5%). Our results demonstrate a significant difference in genotype distribution between AIPC patients and control subjects only for the C1772T polymorphism (p = 0.024). The association of the incidence of the polymorphism with overall survival was determined to be not statistically significant (p = 0.93) by the Mantel-Haenszel (log-rank) test. These results suggest that the C1772T polymorphism in HIF-1alpha may confer susceptibility to AIPC and contribute to the progression or metastasis of this disease.

Novel therapeutic strategies in prostate cancer.

Prostate cancer is the most common noncutaneous cancer in American men and the second most common cause of death. It is estimated that in 2003, 220,900 new cases will be diagnosed and 28,900 men will die from the disease.1 Hormonal therapy via surgical or chemical castration is the mainstay of treatment for metastatic prostate cancer. While this is quite effective initially, with time patients become refractory to this treatment and may require additional therapy. There have been a substantial number of novel agents that have been developed in the last 10 years that show promise in the treatment of patients with prostate cancer, when used alone or when combined with current approaches (Table 1).

Group B streptococcal endocarditis in obstetric and gynecologic practice.

BACKGROUND: We describe a case and review ten other instances of group B streptococcal endocarditis in the setting of obstetric and gynecologic practice reported since the last review in 1985. CASE: Abortion remains a common antecedent event, but in contrast to earlier reports, most patients did not have underlying valvular disease, the tricuspid valve was most often involved, and mortality was low. Patients with tricuspid valve infection tended to have a subacute course, whereas those with aortic or mitral involvement typically had a more acute, fulminant course. CONCLUSION: Despite an improvement in mortality, morbidity remains high, with 8 of 11 patients having clinically significant emboli.

The role for intravenous immunoglobulin in the treatment of West Nile virus encephalitis.

Intravenous immunoglobulin (IVIG) with high titers to West Nile virus was used as an adjuvant therapy for a patient with West Nile virus encephalitis that did not respond to supportive care. We present this case report and review the evidence supporting the use of high-titer IVIG.

The combination of antiangiogenic and cytotoxic agents in the treatment of prostate cancer.

Metastatic prostate cancer is one of the leading causes of cancer death in men. Although initially responsive to hormone therapy, it eventually progresses in almost all patients. For this reason, there has been a search for novel agents to use in the fight against androgen-independent prostate cancer. Antiangiogenesis is a relatively new antitumor strategy that has been employed in the treatments of many malignancies. As prostate cancer is likely dependent on angiogenesis for its growth and progression, it would logically serve as a good target for this modality. Initially met with great enthusiasm, antiangiogenic drugs have seen only limited success when used as single agents. This has been attributed to many possible etiologies including lack of cytotoxicity and use in situations of large tumor burden. In order to overcome these problems, many investigators are combining antiangiogenic agents with more traditional cytotoxic chemotherapy regimens in hope of augmenting the effects of either drug alone. This article will review the background of angiogenesis inhibition and the use of such combinations in metastatic prostate cancer.

Pericardial disease in the oncology patient.

Malignant pericardial disease is a serious and common problem seen in patients with cancer. It is usually due to metastatic spread of the underlying malignancy or a complication of radiation therapy. The patient may have a mild, subtle presentation, as is often seen in the early stages of pericardial effusion, or may experience dramatic hemodynamic compromise, as is seen with cardiac tamponade and constrictive pericarditis. There are many treatment options available that range from simple drainage to thoracic surgery. It is essential that the treating physician choose a treatment plan in the context of the cancer stage and the patient's prognosis. This article discusses the incidence, pathophysiology, clinical presentation, diagnosis, and treatment options in the various types of malignant pericardial disease.