Improved long-term survival after resection of colorectal liver metastases following staging with FDG positron emission tomography.

BACKGROUND AND OBJECTIVES: Actual long-term survival of patients with colorectal liver metastases staged by PET CT has not been reported. Objectives were to investigate whether PET CT staging results in actual improved long-term survival, to examine outcome in patients with 'equivocal' PET CT scans, and those excluded from hepatectomy by PET CT. METHODS: A retrospective analysis of patients undergoing hepatectomy for colorectal liver metastases between March 1998 and September 2008. RESULTS: Overall 5- and 10-year survival was 44.8% and 23.9%. PET CT staging resulted in management changes in 23% of patients. PET CT staged patients showed significantly better survival than those staged by CT alone at 3 years (79.8% vs. 54.1%) and at 5 years (54.1% vs. 37.3%) with median survivals of 6.4 years versus 3.9 years (log rank P = 0.018). Patients with equivocal PET CT scans showed worse median survival than those with favourable PET CT (log rank P = 0.002), but may include a subpopulation whose prognosis trends towards a more favourable outcome than those excluded from liver resection by PET CT, whose median survival remains limited to 21 months. CONCLUSIONS: Staging of patients with colorectal liver metastases by PET CT is associated with significantly improved actual long-term survival, and provides valuable prognostic information which guides surgical and oncological treatments.

Randomized controlled trial of forward-planned intensity modulated radiotherapy for early breast cancer: interim results at 2 years.

PURPOSE: This single-center randomized trial was designed to investigate whether intensity-modulated radiotherapy (IMRT) reduces late toxicity in patients with early-stage breast cancer. METHODS AND MATERIALS: The standard tangential plans of 1,145 nonselected patients were analyzed. The patients with inhomogeneous plans were randomized to a simple method of forward-planned IMRT or standard radiotherapy (RT). The primary endpoint was serial photographic assessment of breast shrinkage. RESULTS: At 2 years, no significant difference was found in the development of any photographically assessed breast shrinkage between the patients randomized to the interventional or control group (odds ratio, 1.51; 95% confidence interval, 0.83-1.58; p = .41). The patients in the control group were more likely to develop telangiectasia than those in the IMRT group (odds ratio, 1.68; 95% confidence interval 1.13-2.40; p = .009). Poor baseline surgical cosmesis resulted in poor overall cosmesis at 2 years after RT. In patients who had good surgical cosmesis, those randomized to IMRT were less likely to deteriorate to a moderate or poor overall cosmesis than those in the control group (odds ratio, 0.63; 95% confidence interval, 0.39-1.03, p = .061). CONCLUSIONS: IMRT can lead to a significant reduction in telangiectasia at comparatively early follow-up of only 2 years after RT completion. An important component of breast induration and shrinkage will actually result from the surgery and not from the RT. Surgical cosmesis is an important determinant of overall cosmesis and could partially mask the longer term benefits of IMRT at this early stage.

Long term outcome following repeat transsphenoidal surgery for recurrent endocrine-inactive pituitary adenomas.

It is widely accepted that the standard first-line treatment for most endocrine inactive pituitary macroadenomas (EIA) is surgery, usually via a transsphenoidal approach. What is less clear is what approach to take when these tumors recur, especially when this recurrence involves areas which are difficult to surgically remove tumor from, such as the suprasellar region or cavernous sinuses. We present long term follow-up for a series of 81 patients who underwent repeat surgery for recurrent non-secreting pituitary adenomas. We analyzed data collected from all adult patients undergoing their second microsurgical transsphenoidal resection of a histologically proven endocrine-inactive pituitary adenoma at the University of California at San Francisco between January 1970 and March 2001. Data for these patients were collected by review of medical records, mail, and/or telephone interviews. Visual function, anterior pituitary function, and tumor control rates were analyzed for the series. Records were available for a total of 81 recurrent EIA patients. The median time between their initial and repeat operations was 4.1 years. The mean tumor size was 2.2 +/- 0.2 cm. A total of 35/81 patients had greater than 5 years of follow-up. A total of 24/81 patients had greater than 10 years of follow-up. Over one half of these patients presented with visual disturbance, and we found that 39% of these patients experienced improved vision with a second surgery. More importantly, no one with normal vision suffered any appreciable decline in vision. Approximately, 35% of patients with pre-operative anterior pituitary dysfunction recovered function after surgery in our series; and no patient's function worsened. A total of 4/52 (8%) patients with greater than 2 years of post-op follow-up experienced a clinically meaningful tumor recurrence requiring additional treatment. Our data suggest that when performed by experienced transsphenoidal surgeons, durable tumor control can be obtained in these frequently locally aggressive tumors with acceptable rates of post-operative morbidity.

A randomised controlled trial of forward-planned radiotherapy (IMRT) for early breast cancer: baseline characteristics and dosimetry results.

BACKGROUND AND PURPOSE: This large trial was designed to investigate whether correction of dose inhomogeneities using intensity-modulated radiotherapy (IMRT) reduces late toxicity and improves quality of life in patients with early breast cancer. This paper reports baseline characteristics of trial participants and dosimetry results. MATERIALS AND METHODS: Standard tangential plans of 1145 trials were analysed. Patients with inhomogeneous plans, defined by ICRU recommendations, were randomised to forward-planned IMRT or standard radiotherapy. RESULTS: Twenty-nine percentage of patients had adequate dosimetry with standard 2D radiotherapy. In the randomised patients, the decreases in mean volumes receiving greater than 107% (Vol>107) and less than 95% (Vol<95) of the prescribed dose in the IMRT compared with the control group were 34.0 cm(3) (95% CI 26.4-41.6; P<0.0001) and 48.1 cm(3) (95% CI 34.4-61.9; P<0.0001), respectively. In this study, 90% of patients who had a breast separation greater > or = 21 cm had Vol>107>2 cm(3) on standard radiotherapy plans. CONCLUSION: This large trial, in which patients with all breast sizes were eligible, confirmed that breast dosimetry can be significantly improved with a simple method of forward-planned IMRT and has little impact on radiotherapy resources. It is shown that patients with larger breasts are more likely to have dose inhomogeneities and breast separation gives some indication of this likelihood. Photographic assessment of patients at 2 years after radiotherapy, as the next part of this randomised controlled trial, will show whether these results for IMRT translate into improved cosmetic outcome in patients with early breast cancer. This would provide impetus for the widespread adoption of 3D planning and IMRT.

Incidence of severe capsular contracture following implant-based immediate breast reconstruction with or without postoperative chest wall radiotherapy using 40 Gray in 15 fractions.

PURPOSE: To determine the incidence of capsular contracture (CC) requiring revisional surgery in patients receiving postoperative radiotherapy (RT) or no RT following mastectomy and immediate breast reconstruction. MATERIAL AND METHODS: One hundred and seventy-eight immediate breast reconstructions performed at the Cambridge Breast Unit between 1.1.2001 and 31.12.2005 were identified. RT was delivered using a standard UK scheme of 40 Gray in 15 fractions over 3 weeks. The influence of hormones and chemotherapy as well as postoperative RT on time to development of severe CC after implant-based reconstruction was explored in univariate and multivariate analysis. RESULTS: One hundred and ten patients had implant-based reconstructions with a median follow-up of 51 months. In the RT group (41 patients), there were 8 patients with severe CC requiring revisional surgery, a crude rate of 19.5%, with actuarial rates of 0%, 5%, 5%, 21%, 30% and 30% at 1, 2, 3, 4, 5 and 6 years follow-up. In the unirradiated group, there were no cases of severe CC. This difference is highly significant (p<0.001). Hormones and chemotherapy were not significantly associated with severe CC. CONCLUSIONS: This series showed a significantly higher rate of severe CC with postoperative RT. This finding has important clinical implications, when counselling patients for immediate breast reconstruction.

Pre-operative dopamine agonist therapy improves post-operative tumor control following prolactinoma resection.

OBJECTIVE: Normalization of serum prolactin concentrations in patients with prolactinomas is an accepted endpoint of therapy. Clinical signs and symptoms of hyperprolactinemia are usually resolved when prolactin levels are lowered to within the normal range. While most patients are treated with dopamine agonist drugs, some patients require surgical resection of their tumors. We sought to determine whether preoperative treatment with dopamine agonists alters the outcome of surgical intervention. METHODS AND RESULTS: We present an analysis of 253 patients with prolactinomas treated surgically during the period of time when dopamine agonist therapy was first introduced and prior to its widespread use as first-line therapy. We compared both short- and long-term outcomes of patients treated with dopamine agonists prior to surgery with those undergoing surgery as their initial treatment modality. Our data showed that that patients treated with dopamine agonists prior to surgery experienced greater reductions in prolactin levels, had lower prolactin levels, were more likely to have normal prolactin levels at long term follow-up, and were less likely to require additional therapy to control their prolactin levels. CONCLUSION: Our study provides strong evidence suggesting that, regardless of initial prolactin level, preoperative dopamine agonist therapy is not detrimental. In fact, pretreatment with dopamine agonist drugs, possibly by inducing tumor regression, seemed to improve the surgeon's ability to resect a greater percentage of the tumor and led to better control of the prolactin level.

Long-term recurrence and mortality after surgery and adjuvant radiotherapy for nonfunctional pituitary adenomas.

OBJECT: Long-term outcomes following surgery for nonfunctional pituitary adenomas (NFPAs) are unclear. The role of adjuvant radiation therapy is therefore controversial because it is associated with higher tumor control but also carries known long-term morbidity. The authors' aim was to determine predictors of recurrence and overall survival and to define patient subgroups that may benefit from radiotherapy. METHODS: The authors performed a retrospective cohort analysis of 663 patients who underwent surgery between 1975 and 1995 for treatment of primary NFPAs. The main outcome measures were disease progression after surgery, defined by clinical and/or imaging criteria, and all-cause mortality. RESULTS: Over a median clinical follow-up of 8.4 years, there were 64 (9.7%) recurrences after treatment, with a median time to recurrence of 5.6 years. The 5-, 10-, and 15-year recurrence-free probabilities were 0.93, 0.87, and 0.81, respectively. Multivariate Cox proportional hazard regression analysis identified the following predictors as associated with increased recurrence: cavernous sinus invasion (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.5-6.4; p < 0.001) and subtotal resection (STR) without radiotherapy (HR 3.6, 95% CI 1.4-14; p = 0.01). Using time-to-event estimates to adjust for differences in follow-up between groups, radiotherapy was found to reduce tumor recurrence in only those patients who received an STR (p < 0.001, log-rank test) but not gross-total resection (GTR; p = 0.63, log-rank test). Median follow-up for overall survival was 14.0 years. The 5-, 10-, 15- and 20-year overall survival estimates were 0.91, 0.81, 0.69, and 0.55, respectively. Within the study cohort and in age- and sex-adjusted comparison with the general US population, increased relative mortality was observed in patients who underwent radiotherapy or STR. CONCLUSIONS: Cavernous sinus invasion is an important prognostic variable for long-term control of NFPAs. Radiotherapy results in long-term tumor control for patients who undergo STR but does not affect recurrence rates and may increase the risk of death after GTR. Given the risks associated with radiotherapy, there is no role for its routine application in patients who have undergone GTR of their NFPA. In all patients, long-term monitoring is required.

Pediatric intracranial aneurysms: durability of treatment following microsurgical and endovascular management.

OBJECT: Longer life expectancies and differences in the underlying disease in children with aneurysms raise important issues concerning the choice of microsurgical or endovascular therapy. The authors reviewed their experience at one institution regarding patients treated between 1977 and 2003, focusing on the issue of treatment durability. METHODS: Forty-three aneurysms in 32 pediatric patients were identified. The patients ranged in age from 2 months to 18 years (mean 11.7 years). Only seven patients (22%) presented with subarachnoid hemorrhage, and in nine patients (28%) significant medical comorbidities were present. Aneurysm locations included the internal carotid artery (13 lesions), middle cerebral artery (11 lesions), and the basilar artery/vertebrobasilar junction (six lesions). Of the 43 lesions, 17 (40%) were giant aneurysms and 22 (51%) exhibited fusiform/dolichoectatic morphological features. Thirteen patients underwent microsurgery, 16 endovascular treatment, and three observation. Complete aneurysm obliteration rates were 94 and 82% in the microsurgical and endovascular groups, respectively. There were no deaths in either group, and neurological morbidity rates were comparable. Over time, 14% of endovascularly treated aneurysms recurred, and in 19% of these patients de novo aneurysms developed (mean follow-up duration 5.7 years). In contrast, there were no recurrences in the microsurgically treated aneurysms and only one de novo aneurysm (6%). CONCLUSIONS: Both microsurgical and endovascular therapies can be conducted safely to treat pediatric aneurysms. Microsurgery may be more efficacious in completely eliminating the aneurysm and its effects more durable over the extended lifetime of these patients. Parental biases toward nonoperative therapy should be thoroughly addressed before ultimately selecting a treatment strategy.

Transsphenoidal microsurgery for Cushing's disease: initial outcome and long-term results.

Untreated Cushing's disease and the resultant chronically elevated glucocorticoid levels lead to severe metabolic disturbances, including diabetes mellitus, obesity, hypertension, muscle wasting, and osteoporosis. Although transsphenoidal resection has become the standard of care for Cushing's disease with high initial success rates, little information is available on the long-term morbidity and mortality of patients in remission compared with patients with recurrent or persistent Cushing's disease after such treatment. We therefore conducted a retrospective study of 289 patients with Cushing's disease who underwent transsphenoidal microsurgery for an ACTH-secreting adenoma at a tertiary care center exclusively by one surgeon (C.B.W.). Postoperative remission was achieved in 82% (n = 236) of patients, with best initial remission rates observed in patients with grade I (86%) and II (83%) or stage 0 (88%), A (94%), and B (100%) tumors. Male gender, larger tumor size, and higher stage predicted poorer initial outcome. Long-term follow-up was obtained on 178 patients, with a median follow-up time of 11.1 yr (range, 0.6-24.1 yr). Thirteen of 150 (9%) of patients in initial remission developed recurrent disease, and 12 patients underwent additional treatment. At last follow-up, only two of these patients had active disease. However, of the 28 patients with initial persistent disease who had follow-up greater than 6 months, 10 patients continued to have active disease at last follow-up. Although overall survival rates in patients with initial remission did not differ significantly from expected compared with the general population based on age and sex distribution, patients with initial persistent disease had a significant increase in mortality compared with the expected mortality. Thus, successful treatment of Cushing's disease is associated with normal long-term survival. These results suggest that patients with persistent Cushing's disease require early and aggressive intervention to attempt to prevent this excess mortality.

Cavernous and inferior petrosal sinus sampling in the evaluation of ACTH-dependent Cushing's syndrome.

OBJECTIVE: Central venous sampling (CVS) is used frequently in the evaluation of ACTH-dependent Cushing's syndrome. However, several controversies exist including the diagnostic accuracy, the sampling site of choice (cavernous sinus vs. inferior petrosal sinus) and the use of lateralization data in tumour localization. We have analysed our experience with CVS to address these controversies. DESIGN: We retrospectively reviewed CVS data in patients with ACTH-dependent Cushing's syndrome, in whom cavernous sinus sampling (CSS), inferior petrosal sinus sampling (IPSS) and IPSS after administration of ovine corticotrophin releasing hormone (oCRH) were performed. PATIENTS: Data on 95 patients were analysed, including 79 patients with suspected Cushing's disease (CD) and 16 patients with suspected ectopic ACTH syndrome (EAS). RESULTS: For the differential diagnosis of ACTH-dependent Cushing's syndrome, the diagnostic accuracy of IPSS after oCRH stimulation was 97% compared to 86% for CSS. While no single sampling site was perfect in diagnostic accuracy, sampling both CS and IPS achieved a combined diagnostic accuracy of 100%. Lateralization data predicted tumour location in 62-68% of the patients with various central venous drainage patterns and in 77-80% of the patients with symmetrical drainage. CSS was not significantly superior to IPSS in tumour lateralization. In patients with suspected CD based on CVS and in whom an adenoma was not found on magnetic resonance imaging (MRI) and not located by the surgeon intraoperatively, hemihypophysectomy based on lateralization data was successful in only 10 of the 18 patients (56%) with various central venous drainage patterns and in 5 of 10 patients with symmetrical drainage. CONCLUSION: CVS is a powerful method for differentiating CD from the EAS. CSS without oCRH was not superior to IPSS after oCRH stimulation; however, we achieved a 100% diagnostic accuracy if at least two sites were sampled. Tumour localization by CVS did not accurately predict the tumour site at surgery and should not be used to guide surgical resection.

Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial.

To determine the safety and evaluate the efficacy of repeated administration of virus-producing cells (GLI 328) containing the herpes simplex virus thymidine-kinase gene followed by ganciclovir treatment in adults with recurrent glioblastoma multiforme, we conducted a phase I/II multi-institutional trial. Eligible patients underwent surgical resection of tumor, followed by injections of vector producing cells (VPC) into the brain adjacent to the cavity. An Ommaya reservoir placed after surgery was used to inject a further dose of VPC seven days after surgery, followed seven days later by ganciclovir. Further gene therapy was given at 28-day intervals for up to a total of five cycles. Toxicity and anti-tumor effect were assessed. Of 30 patients who enrolled in the study, 16 experienced serious adverse events possibly related to the experimental therapy. Laboratory testing, including polymerase chain reaction analysis to detect replication-competent retrovirus in peripheral blood lymphocytes and tissues, as well as co-cultivation bioassays, were negative. Before receiving ganciclovir, 37% of the patients showed evidence of transduced peripheral blood leukocytes, but only 12% showed a persistence of transduced cells at the end of the first cycle of ganciclovir. Median survival was 8.4 months. Twenty percent of the patients (n = 6) survived more than 12 months from the date of study entry. This treatment modality is feasible and appears to have some evidence of efficacy. Toxicity may be related in part to the method of gene delivery.

Predictive model for pain recurrence after posterior fossa surgery for trigeminal neuralgia.

BACKGROUND: Surgical exploration of the posterior fossa is the definitive treatment for trigeminal neuralgia refractory to medication, but predictors of its success in effecting long-term pain relief have not been established. OBJECTIVE: To develop a model that allows stratification of patients' risk of postoperative recurrence of pain based on pretreatment factors. METHODS: We reviewed the records of 420 consecutive patients who underwent posterior fossa exploration by one of us (C.B.W.) for the treatment of idiopathic trigeminal neuralgia. The primary outcome measure was recurrence of trigeminal pain. The predictive value of preoperative and intraoperative factors was evaluated. Multivariate analysis revealed the statistically significant predictors of pain recurrence, permitting creation of a risk model for recurrence of pain. RESULTS: After surgery, trigeminal pain had lessened in 98% of patients and completely resolved in 87%. There were no perioperative deaths. After a mean follow-up of 56.3 months, 93% of patients reported significant pain improvement and 72% continued to have no pain. The estimated likelihood of pain recurrence at 8 years was 34%. Significant predictors of eventual recurrence of pain were age younger than 53 years at the time of surgery, symptoms lasting longer than 11(1/2) years, female sex, and pain on the left side in men. These factors were weighted and incorporated into a risk model that revealed 4-year pain-free survival of 89% +/- 4% for the low-risk group, 80% +/- 4% for the moderate-risk group, and 58% +/- 6% for the high-risk group (data are mean +/- SD). CONCLUSIONS: We developed a predictive model that stratifies the risk for eventual recurrence of pain after posterior fossa exploration for trigeminal neuralgia. This information may be useful in counseling patients regarding treatment.

Magnetic source imaging demonstrates altered cortical distribution of function in patients with arteriovenous malformations.

OBJECTIVE: Arteriovenous malformations (AVMs) can be treated successfully, but treatment can pose unacceptable risks if the AVM is located in eloquent cortex. Because AVMs are developmental lesions, the location of primary cortical function may be deranged. We used magnetic source imaging (MSI) to identify the central sulcus and to determine whether primary cortical function was shifted in a set of 30 patients. We correlated these findings with outcome after treatment. METHODS: We retrospectively analyzed the clinical data of 30 patients with AVMs who underwent MSI. Nonparametric statistical comparisons were made to correlate the proximity of AVMs to primary cortex and somatosensory shift to outcome at 12 months. RESULTS: Using MSI, 14 patients (47%) were found to have AVMs involving primary cortex, and 10 patients (33%) were found to have shift in the somatosensory homunculus. Primary cortical involvement was neither required nor sufficient to cause shift (Mann-Whitney U test, z = -0.02, P = 0.31). Patients with AVMs involving primary cortex fared worse after treatment than did patients with AVMs that spared primary cortex (Mann-Whitney U test, z = -2.3, P = 0.02). The presence or absence of shift did not correlate with outcome after treatment (Mann-Whitney U test, z = -0.18, P = 0.48). CONCLUSION: MSI showed that some patients with AVMs have abnormal cortical distribution of function. The involvement of primary cortex correlated with worse outcome after treatment. Our results suggest that preoperative functional imaging may help to better estimate treatment risks and ultimately to guide therapeutic planning.

Delayed surgical resection reduces intraoperative blood loss for embolized meningiomas.

OBJECTIVE: Embolization before surgical resection of tumors has been demonstrated to reduce intraoperative blood loss, but the optimal time that should elapse between embolization and tumor resection has not been established. We evaluated whether immediate surgical resection (< or =24 h) after embolization or delayed surgical resection (>24 h) was more effective in minimizing intraoperative blood loss. METHODS: We retrospectively analyzed the records for 50 patients with meningiomas who underwent preoperative embolization between 1993 and 1999. We divided the patients into two groups, i.e., those who underwent surgical resection of their meningiomas < or =24 hours after embolization and those who underwent surgery more than 24 hours after embolization. The extent of embolization, intraoperative blood loss, duration of surgery, and length of the hospital stay were compared for the two groups. Postoperative pathological specimens were examined for assessment of the extent of vascularity and necrosis caused by embolization. RESULTS: Intraoperative blood loss was greater for the immediate group than for the delayed group (29% with blood loss of >1000 ml [median, 475 ml] versus 0% with blood loss of >700 ml [median, 337.5 ml]; P = 0.01). There were no statistically significant differences between the groups with respect to tumor volume, extent of embolization, degree of devascularization, necrosis, duration of surgery, or length of the hospital stay. CONCLUSION: Contrary to previous studies that emphasized a need for tumor removal immediately after embolization, to prevent revascularization, surgical resection of meningiomas should be delayed more than 24 hours after embolization, because there is less intraoperative blood loss.