William W. Wong

PROTEOLYTIC ACTIVATION OF PROTEIN KINASE C DELTA BY AN ICE-LIKE PROTEASE IN APOPTOTIC CELLS

These studies demonstrate that treatment of human U‐937 cells with ionizing radiation (IR) is associated with activation of a cytoplasmic myelin basic protein (MBP) kinase. Characterization of the kinase by gel filtration and in‐gel kinase assays support activation of a 40 kDa protein. Substrate and inhibitor studies further support the induction of protein kinase C (PKC)‐like activity. The results of N‐terminal amino acid sequencing of the purified protein demonstrate identity of the kinase with an internal region of PKC delta. Immunoblot analysis was used to confirm proteolytic cleavage of intact 78 kDa PKC delta in control cells to the 40 kDa C‐terminal fragment after IR exposure. The finding that both IR‐induced proteolytic activation of PKC delta and endonucleolytic DNA fragmentation are blocked by Bcl‐2 and Bcl‐xL supports an association with physiological cell death (PCD). Moreover, cleavage of PKC delta occurs adjacent to aspartic acid at a site (QDN) similar to that involved in proteolytic activation of interleukin‐1 beta converting enzyme (ICE). The specific tetrapeptide ICE inhibitor (YVAD) blocked both proteolytic activation of PKC delta and internucleosomal DNA fragmentation in IR‐treated cells. These findings demonstrate that PCD is associated with proteolytic activation of PKC delta by an ICE‐like protease.

The results of radiotherapy for ependymomas: the Mayo Clinic experience.

PURPOSE This analysis was performed to examine the outcome of patients with histologically confirmed ependymomas of the brain or spinal cord who received postoperative radiotherapy. METHODS AND MATERIALS Eighty patients with histologically confirmed ependymomas were evaluated retrospectively. All were treated with various combinations of surgery, radiotherapy (RT), and chemotherapy. Follow-up ranged from 5 to 30 years (median 10.4 years). RESULTS The 5- and 10-year survival rates for the entire study group were 79% and 73%, respectively. Patients with low-grade (1 and 2 of 4) tumors had a 5-year survival rate of 87% as compared to 27% for those with high-grade (3 and 4 of 4) tumors (p < 0.0001). Patients with tumors of the spine had a 5-year survival rate of 97% as compared to 68% for those with infratentorial tumors, and 62% for those with supratentorial tumors (p = 0.03). Patients with myxopapillary ependymomas of the spine had a 5-year survival rate of 100% as compared with 76% for patients with other histological subtypes of ependymoma (p = 0.02). Multivariate analysis revealed that the survival rate was independently associated with tumor grade (p = 0.0007) and histological subtype (p = 0.02). Twenty-eight patients (35%) experienced local failure and 10 patients (13%) developed leptomeningeal seeding. The 5-year leptomeningeal failure rate was 10% in patients with low-grade tumors as compared to 41% for patients with high grade tumors (p = 0.01). CONCLUSION Patients with low-grade tumors, especially those with myxopapillary subtypes, have high 5-year survival rates when treated with post-operative radiotherapy. High grade ependymomas are associated with a much poorer outcome. New forms of therapy are required to improve the outcome of patients with high-grade ependymomas.

Conservative surgery and adjuvant radiation therapy in the management of adult soft tissue sarcoma of the extremities: Clinical and radiobiological results

PURPOSE The outcome of adult patients with soft tissue sarcoma of the extremities treated with conservative surgery and adjuvant irradiation was evaluated to (a) determine the appropriate treatment volume and radiation dosage in the postoperative setting, and (b) correlate in vitro radiobiological parameters obtained prior to therapy with clinical outcome. METHODS AND MATERIALS Sixty-four consecutive adult patients with soft tissue sarcoma of the extremities (40 lower, 24 upper) who underwent conservative surgery and adjuvant irradiation 7 preoperative, 50 postoperative, 7 perioperative) between 1978 and 1991 were reviewed. The initial radiation field margin surrounding the tumor bed/scar was retrospectively analyzed in all postoperative patients. Initial field margins were < 5 cm in 12 patients, 5-9.9 cm in 32 and > or = 10 cm in 6. Patients with negative pathological margins were initially treated with traditional postoperative doses (64-66 Gy); however, in later years the postoperative dose was reduced to 60 Gy. Thirteen cell lines were established prior to definite therapy, and radiobiological parameters (multitarget and linear-quadratic) were obtained and correlated with outcome. RESULTS Postoperative patients treated with an initial field margin of < 5 cm had a 5-year local control of 30.4% vs. 93.2% in patients treated with an initial margin of > or = 5 cm (p = 0.0003). Five-year local control rates were similar in patients treated with initial field margins of 5-9.9 cm (91.6%) compared with those treated with > or = 10 cm margins (100%) (p = 0.49). While postoperative patients receiving < 60 Gy had a worse local control than those receiving > or = 60 Gy (p = 0.08), no difference was seen in local control between patients receiving less than traditional postoperative doses (60-63.9 Gy) (74.4% vs. those receiving 64-66 Gy (87.0%) (p = 0.5). The local control of patients treated in the later years of the study, with strict attention to surgical and radiotherapeutic technique, was 87.6%. Severe late sequelae were more frequent in patients treated with doses > or = 63 Gy compared to patients treated with lower doses (23.1% vs. 0%) (p < 0.05). Mean values for Do, alpha, beta, D, n and SF2 obtained from the 13 cell lines were 115.7, 0.66, 0.029, 2.15, 0.262, respectively. Four of the 13 cell lines established prior to therapy ultimately failed locally. The radiobiological parameters of these cell lines were similar to the other nine cell lines in terms of radiosensitivity. CONCLUSIONS Our data confirm the importance of maintaining an initial field margin of at least 5 cm around the tumor bed/scar in the postoperative setting. No benefit was seen with the use of margins > or = 10 cm. In addition, patients undergoing wide local excision with negative margins can be treated with lower than traditional postoperative doses (60 Gy) without compromising local control and with fewer chronic sequelae. Finally, it does not appear that inherent tumor cell sensitivity is a major determinant of local failure following radiation therapy and conservative surgery in soft tissue sarcoma.

TIME-DOSE RELATIONSHIP FOR LOCAL TUMOR CONTROL FOLLOWING ALTERNATE WEEK CONCOMITANT RADIATION AND CHEMOTHERAPY OF ADVANCED HEAD AND NECK CANCER

PURPOSE To analyze the time-dose relationship for local control of disease in patients with advanced head and neck neoplasms enrolled in two sequential Phase I dose escalation studies in which concomitant chemotherapy and radiotherapy were delivered on an alternate week schedule (i.e., 1 week of concomitant therapy alternated with 1 week of rest). METHODS AND MATERIALS From 1986-1988, 65 patients were enrolled in two Phase I clinical trials. In trial one, 5-fluorouracil and hydroxyurea were administered concomitantly with radiation on an alternate week schedule (39 pts). In trial two, cisplatin was added to 5-fluorouracil and hydroxyurea (26 pts). Fifty-seven patients were evaluable for local control, including 26 patients who had failed prior local therapy and were retreated (group A), and 31 patients who had received no prior local therapy (group B). The median dose of RT and the median duration of therapy were 59.7 Gy and 12 weeks for group A, and 70.2 Gy and 14 weeks for group B, respectively. The biological effective dose of radiation therapy (RT) was calculated using the equation based on the linear quadratic model as proposed by J. Fowler. Univariate and multivariate logistic regression analyses were performed to evaluate prognostic factors for local control. RESULTS Six of 26 patients in group A and 30 of 31 patients in group B had local control of disease. The 2-year Kaplan-Meier local failure rates were 84% for group A and 4% for group B, respectively. Despite the doubling of treatment duration compared to conventional daily radiotherapy and the low biological equivalent dose calculated (median biological equivalent dose for patients with local control of disease were 50.3 Gy and 48.8 Gy in groups A and B, respectively), local control was achieved in 5/17 patients in group A and 30/31 patients in group B who received RT dose of 59.4 Gy or higher. In multivariate logistic regression analysis, the only significant predictor for local control of disease was RT dose (p = 0.004). Treatment duration, chemotherapy dose intensities, age, and performance status were not significant variables. Decreasing the RT dose by 10 Gy would increase the rate of local failure by 24%. CONCLUSION Our data suggest that prolongation of treatment duration to twice the normal duration of conventional once-a-day radiotherapy does not result in loss of local control when aggressive cell-cycle specific chemotherapy is given concomitantly with radiotherapy. The usual time-dose relationship based on RT alone does not appear to be applicable when concomitant chemotherapy is added. The clinical significance of biological equivalent dose calculation based on radiotherapy alone is unclear when chemotherapy is given with radiation.

Acute and chronic results of adjuvant radiotherapy after mastectomy and Transverse Rectus Abdominis Myocutaneous (TRAM) flap reconstruction for breast cancer.

A retrospective review of the treatment of 15 breast cancer patients who received postoperative radiotherapy after a mastectomy and transverse rectus abdominis myocutaneous (TRAM) flap breast reconstruction was undertaken to determine the effects of postoperative irradiation on flap viability and cosmesis. Fourteen patients had pedicle TRAM flaps, and one patient had a free TRAM flap. Surgical complications, acute and chronic side effects of radiotherapy, and cosmetic outcome were evaluated. The median interval between the TRAM flap procedure and radiotherapy was 7 months. The median total radiation dose was 60 Gy. All patients underwent three-dimensional radiotherapy treatment planning to determine the optimal dose distribution. Mild erythema developed in 9 patients (60%), moderate erythema developed in 2 (13%), and severe erythema developed in 1 (7%). Dry desquamation developed in 6 patients (40%), whereas moist desquamation developed in none. At median follow-up of 26.4 months, only 2 (13%) of the 15 patients had fat necrosis within the TRAM flap that was not present before radiotherapy. Fourteen patients (93%) retained their flap, and 13 patients (87%) rated their cosmetic outcome as “good” to “excellent.” We conclude that TRAM flaps can be irradiated with few complications and acceptable cosmetic results.

Prognostic indicators in node-negative early stage breast cancer

With the increasing availability of screening mammography, more women are diagnosed as having breast cancers at an early, node-negative stage. The majority of these patients would be cured with total mastectomy or breast conservation treatment. However, about 30% of the patients would have recurrence of disease in distant sites. In recent randomized clinical trials, adjuvant systemic therapy has been shown to reduce the rate of recurrence in these patients. Proper selection of patients for adjuvant therapy is necessary to avoid exposing many patients with low risk of recurrence to treatments for whom the benefit is not justified by the toxicity and the cost. In this article, we review the clinical and pathologic prognostic factors in early stage, node-negative breast cancer patients, including tumor size, nuclear and histologic grades, estrogen and progesterone receptors, menopausal status, proliferative rate, HER-2/neu oncogene amplification, and cathepsin D level. Favorable prognostic factors include tumor size less than or equal to 2 cm, low nuclear and histologic grades, low S-phase fraction, diploid state, low cathepsin-D level, and positive estrogen and progesterone receptor status. The value of HER-2/neu oncogene overexpression is controversial, and further studies are needed to define its role as a prognostic factor in patients with node-negative breast cancer. Based on these prognostic factors, it is possible to identify subsets of patients who have a low risk of recurrence and would not benefit significantly from adjuvant systemic therapy.

Metastatic prostate carcinoma mimicking meningioma: case report and review of the literature.

Background:Intracranial dural-based lesions can be due to benign or malignant processes. Imaging characteristics cannot always discern between different pathologic conditions. A thorough clinical evaluation may reveal likely diagnostic possibilities. However, in certain cases, the etiology of the underlying lesion may require biopsy or resection to appropriately treat the patient. Review Summary:We report the case of a large dural-based adenocarcinoma of the prostate clinically and radiographically mimicking a meningioma. We review the history and physical evaluation of the patient and subsequent treatment and response. We discuss the implications of dural-based intracranial lesions in patients with prostate cancer and review the literature of dural metastases, including the pathogenesis, tumor types, and clinical presentations. Conclusion:The differential diagnosis of dural-based lesions in the brain varies from incidental and benign to symptomatic and malignant. Careful vigilance in patients with a history of cancer and presenting with new symptoms or imaging evidence of dural-based lesions is critically important to provide timely intervention.

Development of a treatment planning protocol for prostate treatments using intensity modulated radiotherapy.

We have developed a treatment planning protocol for intensity‐modulated radiation therapy of the prostate using commercially available inverse planning software. Treatment plans were developed for ten patients using the Corvus version 3.8 planning system, testing various prescription options, including tissue types, dose volume histogram values for the target and normal structures, beam arrangements, and number of intensity levels. All plans were scaled so that 95% of the clinical target volume received 75.6 Gy; mean doses to the prostate were typically 79 Gy. The reproducibility of the inverse planning algorithm was tested by repeating a set of the plans five times. Plans were deemed acceptable if they satisfied predefined dose constraints for the targets and critical organs. Figures of merit for target coverage, target dose uniformity, and organ sparing were used to rank acceptable plans. Certain systematic behaviors of the optimizer were noted: the high dose regions for both targets and critical organs were 5–10 Gy more than prescribed; reducing bladder and rectum tolerance increased the range of doses within the target; increasing the number of fields incrementally improved plan quality. A set of planning parameters was found that usually satisfied the minimum requirements. Repeating the optimization with different beam order produced similar but slightly different dose distributions, which was sometimes useful for finding acceptable solutions for difficult cases. The standard set of parameters serves as a useful starting point for individualized planning. PACS number(s): 87.53.–j, 87.90.+y

Statins and Metformin Use Is Associated with Lower PSA Levels in Prostate Cancer Patients Presenting for Radiation Therapy

Background A possible association between the level of prostate specific antigen (PSA) and the use of some commonly prescribed medications has been reported in recent studies. Most of these studies were carried out in general populations of men who were screened for prostate cancer using the PSA test. We reported on the association between the initial PSA level and the use of statins, metformin and alpha-blockers in patients who were diagnosed with prostate cancer and presented for radiation therapy. Methods Three hundred and eighty one patients treated between the years of 2000-2005 and 2009-2012 were included in this retrospective study. The information about statin, metformin and alpha-blockers use was recorded immediately prior to treatment. Differences in PSA levels prior to treatment by medication status were estimated using univa-riate and multivariate linear regression on log PSA values. Results Compared with men who were not on these medications, the PSA level at presentation was 20% lower for statin users (p = 0.002) and 33% lower for metformin users (p = 0.004). We did not observe statistically significant associations between the use of statins or metformin and cancer stage, National Comprehensive Cancer Network (NCCN) risk score, or therapy outcome. A statistically significant association between the NCCN risk score and the use of alpha-blockers was observed (p = 0.002). Conclusions We found that statins and metformin were associated with lower PSA levels in prostate cancer patients to an extent that could influence management decisions. We found no statistically significant associations between the use of these medications and treatment outcomes.

Choosing wisely after publication of level I evidence in breast cancer radiotherapy

Background Recent trials in early-stage breast cancer support hypofractionated whole-breast radiotherapy (WBRT) as part of breast-conserving therapy (BCT). Evidence also suggests that radiotherapy (RT) omission may be reasonable for some patients over 70 years. Among radiation-delivery techniques, intensity-modulated RT (IMRT) is more expensive than 3-dimensional conformal RT (3DCRT). Based on this evidence, in 2013, the American Society for Radiation Oncology (ASTRO) recommended hypofractionated schedules for women aged ≥50 years with early-stage breast cancer and avoiding routine use of IMRT for WBRT. To assess response to level I evidence and adherence to ASTRO recommendations, we evaluated the pattern of RT use for early-stage breast cancer at our National Comprehensive Cancer Network institution from 2006 to 2008 and 2011 to 2013 and compared the results with national trends. Methods Data from a prospective database were extracted to include patients treated with BCT, aged ≥50 years, with histologic findings of invasive ductal carcinoma, stage T1-T2N0M0, estrogen receptor-positive, and HER2 normal. We retrospectively reviewed the medical records and estimated costs based on 2016 Hospital Outpatient Prospective Payment System (technical fees) and Medicare Physician Fee Schedule (professional fees). Results Among 55 cases from 2006 to 2008, treatment regimens were 11% hypofractionated, 69% traditional schedule, and 20% RT omission (29% of patients were aged >70 years). Among 83 cases from 2011 to 2013, treatment regimens were 54% hypofractionated, 19% traditional schedule, and 27% RT omission (48% of patients were aged >70 years). 3DCRT was used for all WBRT treatments. Direct medical cost estimates were as follows: 15 fractions 3DCRT,