A phase Ib feasibility trial of response adapted neoadjuvant therapy in gastric cancer (RANT-GC).

Current guidelines recommend neoadjuvant (NAC) and/or adjuvant chemotherapy for locally advanced gastric cancers (LAGCs). However, the choice and duration of NAC regimen is standardized, rather than personalized to biologic response, despite the availability of several different classes of agents for the treatment of gastric cancer (GC). The current trial will use a tumor-informed ctDNA assay (Signatera™) and monitor response to NAC. Based on ctDNA kinetics, the treatment regimen is modified. This is a prospective single center, single-arm, open-label study in clinical stage IB-III GC. ctDNA is measured at baseline and repeated every 8 weeks. Imaging is performed at the same intervals. The primary end point is the feasibility of this approach, defined as percentage of patients completing gastrectomy.

Flattening filter free beam energy selection and its impact in multitarget intracranial stereotactic radiosurgery treatments.

Extensive work has been done on the characteristics, dosimetry, and efficacy of flattening filter free (FFF) beams in radiosurgery. However, no study has addressed the dosimetric impact of FFF beam energy selection on treatment plan quality. This study aims to present a systematic dosimetric comparison of plan quality between 10 FFF vs 6 FFF beams in intracranial stereotactic radiosurgery (SRS) treatments using volumetric modulated arc therapy (VMAT). The dosimetric evaluation is based on radiation therapy oncology group (RTOG) dose conformity (CIRTOG) and gradient (GIRTOG) indices, and irradiated normal brain tissue volume. Thirty-five VMAT-based intracranial SRS treatments to multiple brain metastases using a 2.5 mm multileaf collimator (MLC) and 10 MV FFF beam were replanned with a 6 MV FFF and same MLC. The replans incorporated the same arc arrangement, planning target volume (PTV) and organs at risk structures, PTV coverage and prescription isodose normalization. The 6 MV FFF had a sharper dose fall-off compared to the 10 MV FFF (GIRTOG-10 FFF = 4.70, GIRTOG-6 FFF = 4.56; p < 0.05) and comparable conformity index (CIRTOG-10 FFF = 1.11, CIRTOG-6 FFF = 1.10; p = 0.9). On average, the irradiated normal brain tissue volume was 11% lower with 6 MV FFF compared to 10 MV FFF (p < 0.05). However, this difference was diminished for large target volumes and increased number of targets treated. The main dosimetric improvement of a 6 MV FFF over a 10 MV FFF beam is the sharper dose fall-off which directly correlates with less normal brain tissue volume irradiation.

The dosimetric impact of image guided radiation therapy by intratumoral fiducial markers.

PURPOSE: Pancreatic fiducials have proven superior over other isocenter localization surrogates, including anatomical landmarks and intratumoral or adjacent stents. The more clinically relevant dosimetric impact of image guided radiation therapy (IGRT) using intratumoral fiducial markers versus bony anatomy has not yet been described and is therefore the focus of the current study. METHODS AND MATERIALS: Using daily orthogonal kV or cone beam computed tomography (CBCT) images and positional and dosimetric data were analyzed for 12 consecutive patients treated with fiducial based IGRT and volumetric modulated arc therapy to the intact pancreas. The shifts from fiducial to bone (ΔFid-Bone) required to realign the daily fiducial-matched pretreatment images (kV, CBCTs) to the planning computed tomography (CT) using bony anatomic landmarks were recorded. The isocenter was then shifted by (ΔFid-Bone) for 5 evenly spaced treatments, and the dosimetric impact of ΔFid-Bone was calculated for planning target volume coverage (PTV50.4 and PTV47.9) and organs at risk (liver, kidney, and stomach/duodenum). RESULTS: The ΔFid-Bone were greatest in the superoinferior direction (ΔFid-Bone anteroposterior, 2.7 ± 3.0; left-right, 2.8 ± 2.8; superoinferior, 6.3 ± 7.9 mm; mean ± standard deviation; P = .03). PTV50.4 coverage was reduced by 13% (fiducial plan 95 ± 2.0 vs bone plan 82 ± 12%; P = .005; range, 5%-52%; >5% loss in all; and >10% loss in 42% of patients), and to a lesser degree for PTV47.9 (difference, -8%; range, 1%-30%; fiducial plan 100 ± 0.3% vs bone plan 92 ± 7.6%; P = .003; with reductions of >5% in 66% and >10% in 33% of patients). The dosimetric impact of ΔFid-Bone on the organs at risk was not significant. Positional shifts for kV- and CBCT-based realignments were nearly identical. CONCLUSION: Compared with matching by fiducial markers, IGRT matched by bony anatomy substantially reduces the PTV50.4 and PTV47.9 coverage, supporting the use of intratumoral pancreatic markers for improved targeting in IGRT for pancreatic cancer.

Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results.

PURPOSE: The purpose of this study was to determine locoregional control (LRC), disease-free survival (DFS), and toxicity of high-dose-rate interstitial brachytherapy (HDR-ISBT) in the treatment of locally advanced cervical cancer. METHODS AND MATERIALS: Between March 1996 and May 2009, 116 patients with cervical cancer were treated. Of these, 106 (91%) patients had advanced disease (International Federation of Gynecology and Obstetrics stage IIB-IVA). Ten patients had stage IB, 48 had stage II, 51 had stage III, and 7 had stage IVA disease. All patients were treated with a combination of external beam radiation therapy (EBRT) to the pelvis (5040 cGy) and 2 applications of HDR-ISBT to a dose of 3600 cGy to the implanted volume. Sixty-one percent of patients also received interstitial hyperthermia, and 94 (81%) patients received chemotherapy. RESULTS: Clinical LRC was achieved in 99 (85.3%) patients. Three-year DFS rates were 59%, 67%, 71%, and 57% for patients with stage IB, II, III, and IVA disease, respectively. The 5-year DFS and overall survival rates for the entire group were 60% and 44%, respectively. Acute and late toxicities were within acceptable limits. CONCLUSIONS: Locally advanced cervical cancer patients for whom intracavitary BT is unsuitable can achieve excellent LRC and OS with a combination of EBRT and HDR-ISBT.

The use of RapidArc volumetric-modulated arc therapy to deliver stereotactic radiosurgery and stereotactic body radiotherapy to intracranial and extracranial targets.

Twenty-three targets in 16 patients treated with stereotactic radiosurgery (SRS) or stereotactic body radiotherapy (SBRT) were analyzed in terms of dosimetric homogeneity, target conformity, organ-at-risk (OAR) sparing, monitor unit (MU) usage, and beam-on time per fraction using RapidArc volumetric-modulated arc therapy (VMAT) vs. multifield sliding-window intensity-modulated radiation therapy (IMRT). Patients underwent computed tomography simulation with site-specific immobilization. Magnetic resonance imaging fusion and optical tracking were incorporated as clinically indicated. Treatment planning was performed using Eclipse v8.6 to generate sliding-window IMRT and 1-arc and 2-arc RapidArc plans. Dosimetric parameters used for target analysis were RTOG conformity index (CI(RTOG)), homogeneity index (HI(RTOG)), inverse Paddick Conformity Index (PCI), D(mean) and D5-D95. OAR sparing was analyzed in terms of D(max) and D(mean). Treatment delivery was evaluated based on measured beam-on times delivered on a Varian Trilogy linear accelerator and recorded MU values. Dosimetric conformity, homogeneity, and OAR sparing were comparable between IMRT, 1-arc RapidArc and 2-arc RapidArc plans. Mean beam-on times ± SD for IMRT and 1-arc and 2-arc treatments were 10.5 ± 7.3, 2.6 ± 1.6, and 3.0 ± 1.1 minutes, respectively. Mean MUs were 3041, 1774, and 1676 for IMRT, 1-, and 2-arc plans, respectively. Although dosimetric conformity, homogeneity, and OAR sparing were similar between these techniques, SRS and SBRT fractions treated with RapidArc were delivered with substantially less beam-on time and fewer MUs than IMRT. The rapid delivery of SRS and SBRT with RapidArc improved workflow on the linac with these otherwise time-consuming treatments and limited the potential for intrafraction organ and patient motion, which can cause significant dosimetric errors. These clinically important advantages make image-guided RapidArc useful in the delivery of SRS and SBRT to intracranial and extracranial targets.

A randomized, controlled, double-blind study of light emitting diode photomodulation for the prevention of radiation dermatitis in patients with breast cancer.

BACKGROUND AND OBJECTIVES: Radiation dermatitis occurs in a majority of patients with breast cancer who receive radiation therapy (RT), causes significant pain, and may necessitate treatment delay. Light emitting diode (LED) photomodulation has been reported to minimize radiation dermatitis. This study sought to further evaluate the efficacy of LED photomodulation in lessening radiation dermatitis. MATERIALS & METHODS: After surgery, patients with breast cancer received LED photomodulation or sham treatments in conjunction with three-dimensional conformal RT. Reactions were evaluated using standardized photographs graded according to National Cancer Institute criteria. RESULTS: In the LED treatment group (n=18), no patients had grade 0 reactions, six (33.3%) had grade 1 reactions, 12 (66.7%) had grade 2 reactions, and none had a grade 3 reaction. In the sham treatment group (n=15), one (6.6%) patient had a grade 0 reaction, four (26.7%) had grade 1 reactions, 9 (60.0%) had grade 2 reactions, and one (6.7%) had a grade 3 reaction. Two (11.1%) patients in the LED treatment group and one (6.7%) in the control group had to interrupt treatment. Differences between groups were not statistically significant. CONCLUSION: LED photomodulation did not reduce the incidence of radiation-induced skin reactions or interruptions in therapy. .

Mapping the first stages of mesoderm commitment during differentiation of human embryonic stem cells.

Our understanding of how mesodermal tissue is formed has been limited by the absence of specific and reliable markers of early mesoderm commitment. We report that mesoderm commitment from human embryonic stem cells (hESCs) is initiated by epithelial-to-mesenchymal transition (EMT) as shown by gene expression profiling and by reciprocal changes in expression of the cell surface proteins, EpCAM/CD326 and NCAM/CD56. Molecular and functional assays reveal that the earliest CD326-CD56+ cells, generated from hESCs in the presence of activin A, BMP4, VEGF, and FGF2, represent a multipotent mesoderm-committed progenitor population. CD326-CD56+ progenitors are unique in their ability to generate all mesodermal lineages including hematopoietic, endothelial, mesenchymal (bone, cartilage, fat, fibroblast), smooth muscle, and cardiomyocytes, while lacking the pluripotency of hESCs. CD326-CD56+ cells are the precursors of previously reported, more lineage-restricted mesodermal progenitors. These findings present a unique approach to study how germ layer specification is regulated and offer a promising target for tissue engineering.

A feasibility study of topotecan with standard-dose cisplatin and concurrent primary radiation therapy in locally advanced cervical cancer.

OBJECTIVES: Topotecan improves response rate (RR), progression-free survival (PFS) and overall survival (OS) when added to cisplatin in treating metastatic and recurrent cervical cancer. The objective of this study was to assess the feasibility of adding weekly topotecan to cisplatin in patients with primary, locally advanced carcinoma of the cervix receiving pelvic irradiation. METHODS: Patients with primary, previously untreated, histologically confirmed invasive squamous cell, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, stages IB2-IVA were treated with external beam pelvic radiotherapy (45 Gy), intracavitary low dose rate brachytherapy (40 Gy) and a parametrial boost (5.4-9 Gy) with overall treatment time not to exceed 8 weeks. Concurrent chemotherapy was IV cisplatin 40 mg/m(2)plus IV topotecan 2 mg/m(2) on days 1, 8, 15, 22, 29 and once during parametrial boost for 6 cycles. Patients were monitored with history, physical examination, tumor measurement and laboratory evaluation before entering the study, before each cycle of chemotherapy, at study termination and every three months thereafter. RESULTS: The study met its accrual goal of 12 patients. With a median follow-up of 22 months, eleven patients completed treatment and ten are in long term follow up without evidence of recurrent disease. The 12th patient developed progressive disease during therapy. All patients completed at least 4 cycles of chemotherapy, with the majority (82%) completing 5 or more. Grade 2 or higher neutropenia delayed treatment in 54% of cycles. The median treatment delay was 1.5 cycles (range: 1 to 5 cycles). Median treatment time was 59 days (range 46 to 81 days). The complete RR was 92% (95% confidence interval, 55%-100%). CONCLUSIONS: The addition of weekly topotecan to cisplatin at this dose and schedule during pelvic irradiation for locally advanced cervical cancer appears to be feasible. Based on this primary treatment data and the activity of cisplatin-topotecan in the recurrent disease setting, phase II and III studies of this combination are warranted.

Endoscopic ultrasound delivery of an antitumor agent to treat a case of pancreatic cancer.

BACKGROUND: A 72-year-old white male presented to a University Digestive Disease Center with epigastric pain and weight loss. A CT scan suggested that the patient had a mass in his pancreas and he was referred for further diagnostic work-up, staging and treatment. INVESTIGATIONS: Endoscopic ultrasound (EUS), EUS-guided fine-needle aspiration. DIAGNOSIS: Locally advanced, unresectable adenocarcinoma of the pancreas. MANAGEMENT: Opioid analgesics and EUS-guided celiac neurolysis (transgastric injection of bupivacaine and alcohol on both sides of the celiac artery) for pain relief. Five once-weekly intratumoral injections of TNFerade (GenVec, Inc., Gaithersburg, MD) by EUS-guided fine needle injection, in combination with chemoradiation (5 FU/XRT), as part of a multicenter clinical trial. Repeat fine-needle aspiration followed by surgical resection of the tumor.

NMDA receptor antagonist MK-801 infused into the insular cortex prevents the attenuation of gustatory neophobia in rats.

Gustatory neophobia dissipates with repeated exposures to an initially novel taste solution. The aim of the present study was to determine whether NMDA receptors in the insular cortex are involved in this experience-dependent process. Results showed that acute microinfusion of MK-801 into the insular cortex prevented the attenuation of gustatory neophobia indicating that this process is an NMDA receptor-dependent phenomenon.

Use of Yttrium-90 TheraSphere for the treatment of unresectable hepatocellular carcinoma.

This is a retrospective analysis of a new treatment modality, intra-arterial administration of Yttrium-90 TheraSphere, for unresectable hepatocellular carcinoma (HCC). Patients with HCC not amenable to surgical treatment who had satisfactory physiological function without comorbid disease or significant pulmonary shunting were eligible for treatment. Patients were categorized into complete, partial, or no response based on serum alpha-fetoprotein (AFP) levels and CT or MRI imaging. Fourteen patients were considered candidates for treatment. Three patients were excluded due to significant hepatopulmonary shunting. Eleven patients were treated with TheraSphere. One patient (9%) had a complete response, eight patients (78%) had a partial response, and two patients (18%) showed no response. Partial and complete responders with AFP-associated HCC demonstrated a median decrease in AFP levels of 79 per cent at 73 days. No patients developed liver toxicity nor died due to treatment. Five patients (45%) died of progressive disease at a median of 7 months post-treatment. Six patients (54%) were alive at a median of 11 months (range, 9 to 20 months). Okuda stage 2 and 3 patients showed a median survival of 11 months and 7 months, respectively. Yttrium-90 TheraSphere treatment for unresectable hepatocellular carcinoma is well tolerated and appears to extend survival.

Intensity-modulated radiation therapy for the spine at the University of California, Irvine.

Radiation treatment of malignant diseases of the spine poses unique challenges to the radiation oncology treatment team. Intensity-modulated radiation therapy (IMRT) offers the capability of delivering high doses to targets near the spine while respecting spinal cord tolerance. At the University of California, Irvine, 8 patients received a total of 10 courses to the spine for a variety of primary and metastatic malignant conditions. This paper discusses anatomical considerations, spinal cord radiation myelopathy, and treatment planning issues as it relates to the treatment of spinal cord lesions. Between October 1997 and August 2001, a total of 8 patients received 10 courses of IMRT for primary or metastatic disease of the spine. Cancers treated included metastatic lung, renal, adrenocortical cancers, and primary sarcomas and giant cell tumor. Five cases had 6 courses given for re-irradiation of symptomatic disease and 3 cases had 4 courses of IMRT as primary management of their spinal lesions. Although 3 courses were given postoperatively, these were for grossly residual disease. For the re-irradiation patients, the mean follow-up interval was 4 months. The local control was estimated at 14%. Of the patients treated with primary intent, the mean follow-up was 9 months and the local control rate 75%. No patients developed spinal cord complications.

Intensity-modulated radiotherapy for previously irradiated, recurrent head-and-neck cancer.

The purpose of this work is to evaluate our initial experience in treating previously irradiated, recurrent head-and-neck cancers using intensity-modulated radiotherapy (IMRT). Between July 1997 and September 1999, 12 patients with previously irradiated, locally recurrent head-and-neck cancers were treated with IMRT. These included cancers of the nasopharynx, oropharynx, hypopharynx, larynx, paranasal sinus, skin of the head-and-neck region, and malignant melanoma. Five of these 12 patients had received radiation as the primary treatment, with doses ranging from 66.0 to 126.0 Gy, and the remaining 7 patients had undergone definitive surgeries followed by an adjuvant course of radiation treatment, with doses ranging between 36.0 and 64.8 Gy. Recurrence after the initial course of radiation occurred in periods ranging from 4 to 35 months, with 11 of 12 cases recurring fully in the fields of previous irradiation. Recurrent tumors were treated with IMRT to total doses between 30 to 70 Gy (> 50 Gy in 10 cases) prescribed at the 75% to 92% isodose lines with daily fractions of 1.8 to 2 Gy. The results revealed that acute toxicities were acceptable except in 1 patient who died of aspiration pneumonia during the course of retreatment. There were 4 complete responders, 2 partial responders, and 2 patients with stable disease in the IMRT-treated volumes. Three patients received IMRT as adjuvant treatment following salvage surgery. At 4 to 16 months of follow-up, 7 patients were still alive, with 5 revealing no evidence of disease. In conclusion, this pilot study demonstrates that IMRT offers a viable mode of re-irradiation for recurrent head-and-neck cancers in previously irradiated sites. Longer follow-up time and a larger number of patients are needed to better define the therapeutic advantage of IMRT in recurrent, previously irradiated head-and-neck cancers.

Primary invasive vaginal cancer in the setting of the Mayer-Rokitansky-Kuster-Hauser syndrome.

BACKGROUND: The Mayer-Rokitansky-Kuster-Hauser syndrome occurs in 1 in 4000 to 5000 female births. Primary vaginal cancer constitutes less than 2% of all malignancies of the female genital tract. A report of the first case of the unlikely occurrence of both of these developments in the same patient is presented. CASE: A 34-year-old nulligravid Philippine woman with a history of Mayer-Rokitansky-Kuster-Hauser syndrome presented with a 5-month history of bleeding from a blind vaginal pouch. Vaginal biopsy identified a moderately differentiated endometrioid adenocarcinoma. Exploratory laparotomy, bilateral salpingo-oophorectomy, pelvic and iliac lymph node samplings, and excision of a mullerian remnant were performed with no evidence of disease. A FIGO Stage I vaginal cancer was assigned and pelvic irradiation was given. Disease recurred 4 months later and the patient underwent total pelvic exenteration. More than 1 year since the exenteration procedure, she is without evidence of disease. CONCLUSION: This is the first reported case of a primary vaginal cancer in a patient with Mayer-Rokitansky-Kuster-Hauser syndrome. It is a reminder that routine gynecologic examinations are still warranted as these patients are at risk for malignant changes in residual mullerian tissues.