William Sperduto

Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA).

Importance Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. As systemic therapies improve, patients with lung cancer live longer and thus are at increased risk for brain metastases. Understanding how prognosis varies across this heterogeneous patient population is essential to individualize care and design future clinical trials. Objective To update the current Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with non–small-cell lung cancer (NSCLC) and brain metastases. The DS-GPA is based on data from patients diagnosed between 1985 and 2005, and we set out to update it by incorporating more recently reported gene and molecular alteration data for patients with NSCLC and brain metastases. This new index is called the Lung-molGPA. Design, Setting, and Participants This is a multi-institutional retrospective database analysis of 2186 patients diagnosed between 2006 and 2014 with NSCLC and newly diagnosed brain metastases. The multivariable analyses took place between December 2015 and May 2016, and all prognostic factors were weighted for significance by hazard ratios. Significant factors were included in the updated Lung-molGPA prognostic index. Main Outcomes and Measures The main outcome was survival. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. Log rank tests were used to compare adjacent classes and to compare overall survival for adenocarcinoma vs nonadenocarcinoma groups. Results The original DS-GPA was based on 4 factors found in 1833 patients with NSCLC and brain metastases diagnosed between 1985 and 2005: patient age, Karnofsky Performance Status, extracranial metastases, and number of brain metastases. The patients studied for the creation of the DS-GPA had a median survival of 7 months from the time of initial treatment of brain metastases. To design the updated Lung-molGPA, we analyzed data from 2186 patients from 2006 through 2014 with NSCLC and newly diagnosed brain metastases (1521 adenocarcinoma and 665 nonadenocarcinoma). Significant prognostic factors included the original 4 factors used in the DS-GPA index plus 2 new factors: EGFR and ALK alterations in patients with adenocarcinoma (mutation status was not routinely tested for nonadenocarcinoma). The overall median survival for the cohort in the present study was 12 months, and those with NSCLC-adenocarcinoma and Lung-molGPA scores of 3.5 to 4.0 had a median survival of nearly 4 years. Conclusions and Relevance In recent years, patient survival and physicians’ ability to predict survival in NSCLC with brain metastases has improved significantly. The updated Lung-molGPA incorporating gene alteration data into the DS-GPA is a user-friendly tool that may facilitate clinical decision making and appropriate stratification of future clinical trials.

Early Initiation of Breastfeeding Among Maya Mothers in the Western Highlands of Guatemala: Practices and Beliefs:

Background: Guatemala exhibits the sixth highest rate of child stunting worldwide, and stunting disproportionately affects Guatemala indigenous communities. In a country struggling to combat this result of malnutrition, early child nutrition is especially critical. Specifically, early initiation of breastfeeding is important for the development of newborn infants. Understanding beliefs and practices related to early initiation of breastfeeding in Maya Guatemala may provide an avenue to guide nutrition interventions in indigenous communities. Research aim: This study aimed to determine major beliefs and practices associated with early initiation of breastfeeding among Maya mothers in Lake Atitlán, Guatemala. Methods: As part of a larger study to assess child nutrition in the Lake Atitlán region, we created a series of semistructured interview questions to document breastfeeding practices and beliefs among mothers. We conducted and audio-recorded in-person interviews that were translated from Kaqchikel, the local language, to Spanish by a community assistant. Results: We conducted 178 interviews with mothers; 76% practiced early initiation. Early initiation was associated with the village and complementary feeding practices. Mothers held a variety of beliefs about the value of colostrum, and these beliefs were associated with the village. Mothers who held negative beliefs toward colostrum were more likely to delay breastfeeding initiation. Conclusion: Although most Maya mothers practice early initiation, the intervillage disparity in breastfeeding practices demonstrates a need to geographically focus breastfeeding interventions. Our novel insights into the breastfeeding beliefs among Maya mothers will serve as a guide to structure culturally competent breastfeeding education interventions in indigenous communities.

Chemotherapy-Induced Tunneling Nanotubes Mediate Intercellular Drug Efflux in Pancreatic Cancer

Intercellular communication plays a critical role in the ever-evolving landscape of invasive cancers. Recent studies have elucidated the potential role of tunneling nanotubes (TNTs) in this function. TNTs are long, filamentous, actin-based cell protrusions that mediate direct cell-to-cell communication between malignant cells. In this study, we investigated the formation of TNTs in response to variable concentrations of the chemotherapeutic drug doxorubicin, which is used extensively in the treatment of cancer patients. Doxorubicin stimulated an increased formation of TNTs in pancreatic cancer cells, and this occurred in a dose-dependent fashion. Furthermore, TNTs facilitated the intercellular redistribution of this drug between connected cells in both pancreatic and ovarian cancer systems in vitro. To provide supportive evidence for the relevance of TNTs in pancreatic cancer in vivo, we performed multiphoton fluorescence microscopy and imaged TNTs in tumor specimens resected from three human patients with pancreatic adenocarcinoma, and one with neuroendocrine carcinoma. In sum, TNT formation was upregulated in aggressive forms of pancreatic carcinoma, was further stimulated after chemotherapy exposure, and acted as a novel method for drug efflux. These findings implicate TNTs as a potential novel mechanism of drug resistance in chemorefractory forms of cancer.

Case Report of Extended Survival and Quality of Life in a Melanoma Patient with Multiple Brain Metastases and Review of Literature

Long-term survival for melanoma patients with multiple brain metastases is rare. A review of the literature reveals only three reported melanoma patients with multiple brain metastases who survived more than 10 years. We present a patient who is recurrence-free 11 years after the diagnosis of three brain metastases. Her treatment consisted of cytokine (interferon and interleukin-2) and chemotherapy nine months prior to developing brain and soft tissue metastases, which were treated with stereotactic radiosurgery and stereotactic ablative radiotherapy, respectively, followed by six months of chemotherapy. Notably, she has not received any treatment for over 10 years, never underwent craniotomy or whole brain radiation therapy, currently has a perfect score on the functional assessment of cancer therapy for brain (FACT-Br) quality of life (QoL) scale, and runs marathons. This treatment course is consistent with emerging literature on the abscopal effect (radiation-induced immune response). Clinical trials are needed to better understand and harness the abscopal effect in order to optimally integrate targeted drug and radiation therapies.

Exosomes and Tunneling Nanotube Conduits: Synergistic Interaction That Facilitates Intercellular Communication Between Malignant and Stromal Cells in the Tumor Microenvironment

Abstract Extracellular vesicles—including exosomes—facilitate long-range intercellular communication in cancer. These membrane-lined vesicles are diffusible carriers of vital cellular signals that can alter the phenotype of recipient cells. However, they are not the only mediator of long-range intercellular cross talk in the complex and heterogeneous tumor microenvironment. Tunneling nanotubes (TNTs) and tumor microtubes are long, thin, filamentous actin-based cell extensions formed by cancer cells to create direct pipeline-like connections that also mediate direct intercellular signaling. Exosomes and TNTs can, in fact, act synergistically: tumor-derived exosomes stimulate the formation of TNTs in cancer, and in turn TNTs can serve as direct physical conduits for cell-to-cell transport of exosomes and their contents. Here, we will examine the interface of exosomes and TNTs; discuss how they work together rather than in isolation; review physiologic conditions that enhance their formation; and explore common mechanisms and markers of formation that serve as potential therapeutic targets.

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool

Background Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors. Methods A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively. Results The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively. Conclusion The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.