MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC).

BACKGROUND: Pain symptoms in the upper abdomen and back are prevalent in 80% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC), where the current standard treatment is a systemic therapy consisting of at least doublet-chemotherapy for fit patients. Palliative low-dose radiotherapy is a well-established local treatment option but there is some evidence for a better and longer pain response after a dose-intensified radiotherapy of the primary pancreatic cancer (pPCa). Stereotactic body radiation therapy (SBRT) can deliver high radiation doses in few fractions, therefore reducing chemotherapy-free intervals. However, prospective data on pain control after SBRT of pPCa is very limited. Therefore, we aim to investigate the impact of SBRT on pain control in patients with mPDAC in a prospective trial. METHODS: This is a prospective, double-arm, randomized controlled, international multicenter study testing the added benefit of MR-guided adaptive SBRT of the pPca embedded between standard of care-chemotherapy (SoC-CT) cycles for pain control and prevention of pain in patients with mPDAC. 92 patients with histologically proven mPDAC and at least stable disease after initial 8 weeks of SoC-CT will be eligible for the trial and 1:1 randomized in 3 centers in Germany and Switzerland to either experimental arm A, receiving MR-guided SBRT of the pPCa with 5 × 6.6 Gy at 80% isodose with continuation of SoC-CT thereafter, or control arm B, continuing SoC-CT without SBRT. Daily MR-guided plan adaptation intents to achieve good target coverage, while simultaneously minimizing dose to organs at risk. Patients will be followed up for minimum 6 and maximum of 18 months. The primary endpoint of the study is the "mean cumulative pain index" rated every 4 weeks until death or end of study using numeric rating scale. DISCUSSION: An adequate long-term control of pain symptoms in patients with mPDAC is an unmet clinical need. Despite improvements in systemic treatment, local complications due to pPCa remain a clinical challenge. We hypothesize that patients with mPDAC will benefit from a local treatment of the pPCa by MR-guided SBRT in terms of a durable pain control with a simultaneously favorable safe toxicity profile translating into an improvement of quality-of-life. TRIAL REGISTRATION: German Registry for Clinical Trials (DRKS): DRKS00025801. Meanwhile the study is also registered at ClinicalTrials.gov with the Identifier: NCT05114213.

Intrafractional stability of MR-guided online adaptive SBRT for prostate cancer.

BACKGROUND: MR-guided online adaptive stereotactic body radiation therapy (SBRT) for prostate cancer aims to reduce toxicity by full compensation of interfractional uncertainties. However, the process of online adaptation currently takes approximately 45 min during which intrafractional movements remain unaccounted for. This study aims to analyze the dosimetric benefit of online adaptation and to evaluate its robustness over the duration of one treatment fraction. METHODS: Baseline MR-scans at a MR-linear accelerator were acquired for ten healthy male volunteers for generation of mock-prostate SBRT plans with a dose prescription of 5 × 7.25 Gy. On a separate day, online MR-guided adaptation (ViewRay® MRIdian) was performed, and thereafter MR images were acquired every 15 min for 1 h to assess the stability of the adapted plan. RESULTS: A dosimetric benefit of online MR-guided adaptive re-planning was observed in 90% of volunteers. The median D95CTV- and D95PTV-coverage was improved from 34.8 to 35.5 Gy and from 30.7 to 34.6 Gy, respectively. Improved target coverage was not associated with higher dose to the organs at risk, most importantly the rectum (median D1ccrectum baseline plan vs. adapted plan 33.3 Gy vs. 32.3 Gy). The benefit of online adaptation remained stable over 45 min for all volunteers. However, at 60 min, CTV-coverage was below a threshold of 32.5 Gy in 30% of volunteers (30.6 Gy, 32.0 Gy, 32.3 Gy). CONCLUSION: The dosimetric benefit of MR-guided online adaptation for prostate SBRT was robust over 45 min in all volunteers. However, intrafractional uncertainties became dosimetrically relevant at 60 min and we therefore recommend verification imaging before delivery of MR-guided online adapted SBRT.

Improving interinstitutional and intertechnology consistency of pulmonary SBRT by dose prescription to the mean internal target volume dose.

PURPOSE: Dose, fractionation, normalization and the dose profile inside the target volume vary substantially in pulmonary stereotactic body radiotherapy (SBRT) between different institutions and SBRT technologies. Published planning studies have shown large variations of the mean dose in planning target volume (PTV) and gross tumor volume (GTV) or internal target volume (ITV) when dose prescription is performed to the PTV covering isodose. This planning study investigated whether dose prescription to the mean dose of the ITV improves consistency in pulmonary SBRT dose distributions. MATERIALS AND METHODS: This was a multi-institutional planning study by the German Society of Radiation Oncology (DEGRO) working group Radiosurgery and Stereotactic Radiotherapy. CT images and structures of ITV, PTV and all relevant organs at risk (OAR) for two patients with early stage non-small cell lung cancer (NSCLC) were distributed to all participating institutions. Each institute created a treatment plan with the technique commonly used in the institute for lung SBRT. The specified dose fractionation was 3â€¯× 21.5 Gy normalized to the mean ITV dose. Additional dose objectives for target volumes and OAR were provided. RESULTS: In all, 52 plans from 25 institutions were included in this analysis: 8 robotic radiosurgery (RRS), 34 intensity-modulated (MOD), and 10 3D-conformal (3D) radiation therapy plans. The distribution of the mean dose in the PTV did not differ significantly between the two patients (median 56.9 Gy vs 56.6 Gy). There was only a small difference between the techniques, with RRS having the lowest mean PTV dose with a median of 55.9 Gy followed by MOD plans with 56.7 Gy and 3D plans with 57.4 Gy having the highest. For the different organs at risk no significant difference between the techniques could be found. CONCLUSIONS: This planning study pointed out that multiparameter dose prescription including normalization on the mean ITV dose in combination with detailed objectives for the PTV and ITV achieve consistent dose distributions for peripheral lung tumors in combination with an ITV concept between different delivery techniques and across institutions.

Outcomes for Patients with Residual Stage II/III Breast Cancer Following Neoadjuvant Chemotherapy (AFT-01).

INTRODUCTION: Pathologic complete response (pCR) after neoadjuvant chemotherapy has a demonstrated survival advantage; however, outcomes for non-pCR by receptor status are less understood. We sought to evaluate survival and distant recurrence by receptor status for patients with residual stage II/III breast cancer. METHODS: A stage-stratified random sample of 11,366 patients with stage II-III breast cancer in 2006-2007 was selected from 1217 facilities in the National Cancer Database for a Commission on Cancer Special Study. We identified patients with residual pathologic stage II/III cancer who received standard of care therapy based on receptor status. Distant recurrence and 5-year survival were abstracted and Kaplan-Meier curves were generated by receptor status. Multivariable Cox regression was used to estimate hazard ratios for death and distant recurrence. RESULTS: A total of 734 patients had residual disease; 58%, 28%, and 14% were ER or PR+/Her2neu-, ER and PR-/Her2neu-, and Her2neu+ (any ER/PR), respectively. ER and PR-/Her2neu- cancers had the poorest 5-year overall (52% vs. 82% for Her2neu+ and ER or PR+/Her2neu-, p < 0.0001) and distant recurrence-free survival (57% vs. 72% Her2neu+ and 77% ER or PR+/Her2neu, p < 0.0001). Cox regression models demonstrated a higher likelihood of distant recurrence and death for patients with ER and PR-/Her2neu- disease (HR 2.25, 95% CI 1.56-3.24 and HR 3.19, 95% CI 2.20-4.64 respectively) compared with ER or PR+/Her2neu-. CONCLUSIONS: Patients with residual ER and PR-/Her2neu- cancer have a significant risk of distant recurrence and mortality compared with other breast cancer types, supporting the consideration for additional adjuvant therapy and novel clinical trials in this cohort. Trial registry number ClinicalTrials.gov identifier NCT02171078.

Breast cancer survivor's perspectives on the role different providers play in follow-up care.

IMPORTANCE: Significant variation in the number and types of oncologists that provide breast cancer follow-up exists. However, there is limited understanding regarding breast cancer survivors' preferences for who provides their follow-up. Our objective was to explore breast cancer survivors' perspectives on the goals of breast cancer follow-up, the preferred role for primary care providers, and the perceived roles of different types of oncologists during follow-up. METHODS: A convenience sample of stage 0-III breast cancer survivors was identified and in-depth one-on-one interviews conducted. Data were analyzed using inductive content analysis. RESULTS: Survivors cited a strong preference for oncology-based follow-up within the first 5 years after diagnosis, driven by their need for reassurance that cancer had not recurred. Survivors also thought that their primary care provider needed to be involved. Survivors assumed that oncology follow-up was directed by a standard protocol that included streamlining the follow-up team. Survivors recognized that patients with more complex cancers or challenging treatment courses may require more intensive follow-up and deviate from the standard protocol. Most survivors were comfortable deferring decisions regarding who participated in follow-up to the oncology team. CONCLUSIONS: Most patients think a streamlined approach to oncology-based breast cancer follow-up already occurs, driven by a standard protocol. The use of a standard protocol to provide guidance for which types of oncology providers should participate in breast cancer follow-up will streamline care and represents a significant opportunity to reduce unnecessary variation. This approach is especially critical given patients' strong preferences for oncology-based follow-up.

Historical changes in the postoperative treatment of appendicitis in children: impact on medical outcome.

BACKGROUND/PURPOSE: The introduction of managed care in the 1980s caused increased pressure to reduce costs for hospitalized patients. The authors hypothesized that these market forces have resulted in a decreased hospital stay and utilization of sophisticated diagnostic testing in children treated for appendicitis. If true, the impact of this paradigm shift on patient outcome is unknown. METHODS: Hospital records for 913 pediatric patients treated for appendicitis from 1974 to 1998 were reviewed retrospectively. Patients were stratified into those with perforated appendicitis (PA) and nonperforated appendicitis (NPA). Demographics, perioperative hospital course, diagnostic testing, complications, and long-term outcomes were analyzed after stratification into time intervals. RESULTS: Over time, children with NPA were treated with shorter antibiotic courses (P<.05) and were placed on a regular diet earlier (P<.05). These changes in treatment resulted in an earlier discharge (P<.05). The amount of time to become afebrile with a normal white blood cell count (WBC) did not change over time. Children with PA exhibited similar results with shorter antibiotic courses (P<.05), earlier dietary intake (P<.05) and earlier hospital discharge (P<.05) over time. In all children with appendicitis there was no significant difference in the rate of wound infections, abscesses requiring drains, readmission, or reoperations overtime. The utilization of abdominal radiographs (83%) and ultrasonography (USN; 40%) was high and remained unchanged over time. Utilization of computed tomography (CT scan) was low (4.3%) in the early decades and was not used as a preoperative test from 1991 to 1994. Given the high diagnostic accuracy of a pediatric surgeon for this disease, Bayesian analysis indicates that USN utilization rates should be 15%. CONCLUSIONS: The market pressures of managed care have resulted in a new treatment paradigm with an earlier discharge of all children with appendicitis. There has been no concomitant increase in the complication rate in either group as a result of this paradigm shift. Bayesian analysis indicates that USN and abdominal radiographs are overutilized in our institution.

Hypertension in unilaterally nephrectomized rats induced by single-kidney transfection with angiotensinogen cDNA.

Plasmid expression vectors containing angiotensinogen (ATG) cDNA were complexed to cationic liposomes and injected into the renal artery of unilaterally nephrectomized rats to evaluate the effect of intrarenal ATG cDNA on arterial blood pressure and the renin-angiotensin system. Systolic blood pressures measured by tail cuff on days 12, 16, and 18 after transfection were significantly higher in rats that received ATG cDNA than in control rats that received the lac Z reporter gene. Plasma renin activity and plasma ATG concentration were unchanged. These results provide direct evidence that the availability of intrarenal ATG may be instrumental in the development of systemic hypertension.

In vivo transfection and expression of exogenous genes within proximal tubules of rats.

An in vivo technique for expressing exogenous DNA within the renal cortical proximal tubules of rats was was developed and validated. Cationic liposomes were complexed with either water or 25 microg of plasmid DNA containing the lac Z gene, and injected into the left renal artery of anesthetized rats. Under transcriptional control of the chicken beta-actin, SV40, and CMV promoters, beta-galactosidase expression was consistently observed in rats that received plasmid DNA, while no blue staining was observed in kidneys of control rats. Using an injection volume of 400 microl, lac Z expression was confined to the proximal tubules, with no lac Z expression noted within serial sections of the liver, adrenal, lung, spleen, or heart. Because lac Z expression was observed for up to 20 days without apparent systemic or renal insult, this technique may be a valuable tool for evaluating physiological and pathophysiological changes associated with gene expression within this isolated site.

[Follow-up study of auditory evoked brain stem potentials--a contribution to the differential diagnosis of facial paralysis]. / Verlaufsbeobachtung akustisch evozierter Hirnstammpotentiale--ein Beitrag zur Differentialdiagnostik der Fazialisparese.

The case report of a 5-year-old girl suffering from an acute peripheral facial paralysis is used to discuss the clinical picture of Bell's paralysis. In the present case the sign was due to a brain-stem encephalitis, the diagnosis being based on brain-stem acoustically evoked potentials. Although not significantly influencing further practical procedure the authors consider it worth mentioning that apparently banal "peripheral" facial paralyses can actually be part of complex CNS lesions.

Monitoring the progression of renal failure in a horse with polycystic kidney disease: use of the reciprocal of serum creatinine concentration and sodium sulfanilate clearance half-time.

Sequential reciprocals of serum creatinine concentration and sodium sulfanilate clearance half-times were used to monitor a horse with chronic renal failure. The horse was diagnosed as having polycystic kidney disease; at least one cyst was of distal tubular origin. Using the plots of the sequential data, a reasonably accurate prediction was made for complete renal decompensation to develop.

Plasma renin activity during controlled hemorrhage in the dog.

Purebred 1-year-old Beagles were made hypotensive by controlled hemorrhage (3 ml/kg-1/min-1). Femoral artery blood samples were collected every 5 minutes during controlled hemorrhage, until the blood pressure decreased to 30+/-5 mm Hg. Samples were then collected every 10 minutes for 40 minutes. Blood was not reinfused during the procedure. Carotid blood pressure, electrocardiogram lead II, and respiration rate were recorded. The results of the radioimmunoassay for renin activity indicated that arterial plasma renin activity formed a bimodal activity curve. Plasma renin activity did not reach any plateau, and it continued to increase throughout the experiment. Decreasing blood pressure and heart rate statistically showed a relationship with plasma renin activity (P less than 0.001). There was no interaction between pressure and heart rate; both were strong and independent. Female dogs had a higher plasma renin activity than did male dogs (P less than 0.001) throughout the experimental period. Plasma renin activity remained above resting activity throughout the development of hemorrhagic shock.