Faculty Bibliography

The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer.

Background: Human immunodeficiency virus (HIV) seropositivity may be associated with higher risk of local recurrence and poor survival in multiple malignancies. However, long-term disease control in HIV-positive patients with head and neck cancer (HNC) is not well described. The purpose of this study is to review the disease-related outcomes of HIV-positive patients who underwent radiotherapy (RT) or chemoradiotherapy (CRT) at our institution. Methods: We retrospectively reviewed 24 HIV-positive patients who underwent RT for HNC between 2004 and 2013. Patient characteristics, treatment details, and outcomes were collected. Overall survival (OS) and local recurrence-free survival (LRFS) were investigated. Kaplan-Meier estimated survival was calculated. Results: Median follow-up was 21 months. All patients were treated with curative intent. Eighty-three percent had stage III-IV. Primary sites of disease included oropharynx (n = 12), larynx (n = 6), oral cavity (n = 2), unknown primary (n = 2), nasal cavity (n = 1), and paranasal sinuses (n = 1). Four patients (17%) had definitive RT alone and nine had definitive CRT (38%; eight cisplatin and one cetuximab). Eleven (46%) were treated in the adjuvant setting after surgical resection; six with RT alone and five with concurrent cisplatin. Eight patients had acute Grade 3 toxicity with no acute Grade 4 or 5 toxicities. Fifteen patients (63%) were alive and disease-free. Two- and 5-year OS was 67 and 59%, respectively. LRFS at 2-years was 82%. Median OS was 83 months. Conclusion: In this cohort, HIV-positive patients treated aggressively with curative intent had excellent OS and local control following RT or CRT for HNC compared to historical controls. Treatment was relatively well tolerated. This group of patients should be managed aggressively with intent to cure.

The diagnostic and local treatment modalities of hereditary breast cancer (HBC) are evolving based on emerging evidence from new imaging, radiotherapy and surgical studies. The optimal selection of diagnostic and therapeutic strategies for the individual HBC patient remains an area of active research in this relatively new patient population. In this context, some rational pathways of intervention are currently available to both reduce cancer risk in mutation carriers without a cancer diagnosis, as well as to reduce the risk of recurrence or new cancers among the carriers already diagnosed with a malignancy. It is encouraging to notice to what degree certain interventions have successfully reduced both the risk of malignancy and the anxiety associated with this genetic diagnosis. This updated report aims at summarizing the most recent findings, while it identifies the areas of uncertainty that remain, and continue to present difficult challenges, particularly among younger HBC patients.

The success of adult ventricular assist devices (VADs), coupled with the high transplant waiting list mortality of infants (40%) has prompted Penn State to develop a pediatric version of the clinically successful adult device. Although the primary use of this device will be bridge-to-transplant, there has been sufficient clinical data to demonstrate the efficacy of VADs in a bridge-to-recovery setting. However, removing the patient from the device, a process known as weaning, demands operation of the device at a lower beat rate and concomitant increased risk for thromboembolism. Previous studies have shown that the interrelated flow characteristics necessary for the prevention of thrombosis in a pulsatile VAD are a strong inlet jet, a late diastolic recirculating flow, and a wall shear rate greater than 500/s. In an effort to develop a strong inlet jet and rotational flow pattern at a lower beat and flow rate, we have compressed diastole by altering the end-diastolic delay time (EDD). Particle image velocimetry was used to compare the flow fields and wall shear rates in the chamber of the 12 cc Penn State pulsatile pediatric VAD operated at 50 beats per minute using EDDs of 10, 50, and 100 ms. Although we expected the 100 ms EDD to have the best wall shear profiles, we found that the 50 ms EDD condition was superior to both the 10 and 100 EDD conditions, due to a longer sustained inlet jet.

The mortality rate for infants awaiting a heart transplant is 40% because of the extremely limited number of donor organs. Ventricular assist devices (VADs), a common bridge-to-transplant solution in adults, are becoming a viable option for pediatric patients. A major obstacle faced by VAD designers is thromboembolism. Previous studies have shown that the interrelated flow characteristics necessary for the prevention of thrombosis in a pulsatile VAD are a strong inlet jet, a late diastolic recirculating flow, and a wall shear rate greater than 500 s(-1). Particle image velocimetry was used to compare the flow fields in the chamber of the 12 cc Penn State pediatric pulsatile VAD using two mechanical heart valves: Bjork-Shiley monostrut (BSM) tilting disk valves and CarboMedics (CM) bileaflet valves. In conjunction with the flow evaluation, wall shear data were calculated and analyzed to help quantify wall washing. The major orifice inlet jet of the device containing BSM valves was more intense, which led to better recirculation and wall washing than the three jets produced by the CM valves. Regurgitation through the CM valve served as a significant hindrance to the development of the rotational flow.

Ventricular assist devices (VADs) have become a viable option for adult patients with end-stage heart failure during the bridge-to-transplant period and have recently shown promise in aiding in myocardial recovery. Because the number of available organs is insufficient, mechanical circulatory support systems such as VADs are also being developed for use in pediatric patients. During myocardial recovery, the system must be weaned from the patient to prepare for explant; for pulsatile devices, this often includes a reduction in flow rate, which can change the fluid dynamics of the device. These changes in flow need to be monitored because strong diastolic rotational flow, no areas of blood stasis, low blood residence time, and wall shear rates above 500 s, can help prevent thrombus deposition. Particle image velocimetry was used to observe the planar flow patterns and wall shear rates of the 12 cc Penn State Pneumatic Pediatric VAD (PVAD) at a normal operating condition and a reduced beat rate. At the reduced beat rate, the PVAD showed an earlier loss of rotational pattern, increased blood residence time, and an overall reduction in wall shear rate at the outer walls. Because this reduction in flow rate could lead to a possible increase in thrombus deposition, it may be necessary to look into other options for weaning a patient from the PVAD.