Phase I Trial of Ipatasertib Plus Carboplatin, Carboplatin/Paclitaxel, or Capecitabine and Atezolizumab in Metastatic Triple-Negative Breast Cancer.

BACKGROUND: This trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C). Primary endpoints were safety and RP2D. Secondary endpoints were progression-free survival (PFS), response rate, and overall survival. RESULTS: RP2D for Arm A (n = 10) was ipatasertib 300 mg daily, carboplatin AUC2, and paclitaxel 80 mg m-2 days 1, 8, and 15 every 28 days. RP2D for Arm B (n = 12) was ipatasertib 400 mg daily and carboplatin AUC2 days 1, 8, and 15 every 28 days. RP2D for Arm C (n = 6) was likely ipatasertib 300 mg 21 days on 7 days off, capecitabine 750 mg m-2, twice a day, 7 days on 7 days off, and atezolizumab 840 mg days 1 and 15 every 28 days. The most common (≥10%) grade 3-4 AEs at RP2D for Arm A (N = 7 at RP2D) were neutropenia (29%), diarrhea (14%), oral mucositis (14%), and neuropathy (14%); Arm B had diarrhea (17%) and lymphopenia (25%); and Arm C had anemia, fatigue, cognitive disturbance, and maculopapular rash (17% each). Overall responses at RP2D were 29% Arm A, 25% Arm B, and 33% Arm C. PFS was 4.8, 3.9, and 8.2 months for patients on Arms A, B, and C, respectively. CONCLUSIONS: Continuous dosing of ipatasertib with chemotherapy was safe and well-tolerated. Further study is warranted in understanding the role of AKT inhibition in treatment of TNBCs. TRIAL REGISTRATION: NCT03853707.

Effective osimertinib treatment in a patient with discordant T790 M mutation detection between liquid biopsy and tissue biopsy.

BACKGROUND: We report the successful treatment of the patient with osimertinib 80 mg/day following disease progression and a discordance in the detection of a mechanism of resistance epithelial growth factor receptor (EGFR) T790 M between liquid biopsy and tissue biopsy methods. CASE PRESENTATION: A 57-year-old Hispanic male patient initially diagnosed with an EGFR 19 deletion positive lung adenocarcinoma and clinically responded to initial erlotinib treatment. The patient subsequently progressed on erlotinib 150 mg/day and repeat biopsies both tissue and liquid were sent for next-generation sequencing (NGS). A T790 M EGFR mutation was detected in the blood sample using a liquid biopsy technique, but the tissue biopsy failed to show a T790 M mutation in a newly biopsied tissue sample. He was then successfully treated with osimertinib 80 mg/day, has clinically and radiologically responded, and remains on osimertinib treatment after 10 months. CONCLUSIONS: Second-line osimertinib treatment, when administered at 80 mg/day, is both well tolerated and efficacious in a patient with previously erlotinib treated lung adenocarcinoma and a T790 M mutation detected by liquid biopsy.

Comparison of the efficacy and safety of ultrasound-guided core needle biopsy versus fine-needle aspiration for evaluating thyroid nodules.

OBJECTIVE: Ultrasound-guided core needle biopsy (UG-CNB) is a procedure that is often performed either after repeated inadequate or nondiagnostic ultrasound-guided fine-needle aspiration (UG-FNA) or in combination with UG-FNA in the evaluation of thyroid nodules. The purpose of this study was to compare the efficacy and safety of UG-CNB and UG-FNA for evaluating thyroid nodules. METHODS: This was a retrospective study of 350 consecutive patients who had thyroid nodules biopsied by UG-CNB or UG-FNA from January 2007 until November 2011 at our institution. Biopsy results were compared to the surgical specimen pathology reports for the 105 patients who subsequently underwent hemi- or total thyroidectomy in order to determine whether UG-CNB has advantages over UG-FNA for diagnosing thyroid malignancy and neoplasia. RESULTS: Out of 461 thyroid nodules biopsied from 350 patients, 365 (79%) involved UG-CNB and 96 (21%) involved UG-FNA. The UG-FNA biopsy group had a significantly higher rate of inadequate sampling than the UG-CNB group (P<.0001; Fisher's exact test). Out of 365 UG-CNB samples, 6 (2%) were deemed inadequate for histologic diagnosis, whereas 26 (27%) of the 96 UG-FNA samples were considered inadequate for cellularity. Comparison of biopsy results with the surgical specimen pathology reports revealed that the diagnostic accuracy of UG-CNB and UG-FNA for detecting malignancy was similar, at 89 and 94%, respectively (not significant by Fisher's exact test). However, the UG-CNB group had a higher detection rate for benign follicular lesions compared to the UG-FNA group (65% versus 48% for UG-FNA; P = .002). Although UG-FNA detected neoplasia with high sensitivity (100%), the specificity was poor (30%). Neither biopsy group had any significant immediate or delayed procedure-related complications. CONCLUSION: Our study demonstrated that UG-CNB is safe and is less likely to result in a nondiagnostic biopsy. The accuracy of the UG-CNB technique is similar to that of UG-FNA for detecting thyroid malignancy.

Molnupiravir: A Versatile Prodrug against SARS-CoV-2 Variants.

The nucleoside analog ß-D-N4-hydroxycytidine is the active metabolite of the prodrug molnupiravir and is accepted as an efficient drug against COVID-19. Molnupiravir targets the RNA-dependent RNA polymerase (RdRp) enzyme, which is responsible for replicating the viral genome during the replication process of certain types of viruses. It works by disrupting the normal function of the RdRp enzyme, causing it to make mistakes during the replication of the viral genome. These mistakes can prevent the viral RNA from being transcribed, converted into a complementary DNA template, translated, or converted into a functional protein. By disrupting these crucial steps in the viral replication process, molnupiravir can effectively inhibit the replication of the virus and reduce its ability to cause disease. This review article sheds light on the impact of molnupiravir and its metabolite on SARS-CoV-2 variants of concern, such as delta, omicron, and hybrid/recombinant variants. The detailed mechanism and molecular interactions using molecular docking and dynamics have also been covered. The safety and tolerability of molnupiravir in patients with comorbidities have also been emphasized.

Current status of Cancer Nanotheranostics: Emerging strategies for cancer management.

Cancer diagnosis and management have been a slow-evolving area in medical science. Conventional therapies have by far proved to have various limitations. Also, the concept of immunotherapy which was thought to revolutionize the management of cancer has presented its range of drawbacks. To overcome these limitations nanoparticulate-derived diagnostic and therapeutic strategies are emerging. These nanomaterials are to be explored as they serve as a prospect for cancer theranostics. Nanoparticles have a significant yet unclear role in screening as well as therapy of cancer. However, nanogels and Photodynamic therapy is one such approach to be developed in cancer theranostics. Photoactive cancer theranostics is a vivid area that might prove to help manage cancer. Also, the utilization of the quantum dots as a diagnostic tool and to selectively kill cancer cells, especially in CNS tumors. Additionally, the redox-sensitive micelles targeting the tumor microenvironment of the cancer are also an important theranostic tool. This review focuses on exploring various agents that are currently being studied or can further be studied as cancer theranostics.

Polymeric Microarray Patches for Enhanced Transdermal Delivery of the Poorly Soluble Drug Olanzapine.

Transdermal drug delivery is an alternative route of administration that offers avoidance of the associated drawbacks of orally and parenterally administered hydrophobics. However, owing to the extremely specific set of physicochemical characteristics required for passive transdermal drug permeation, the development of marketed transdermal products containing poorly soluble drugs has been severely limited. Microarray patches (MAPs) are a type of transdermal patch that differ from the traditional patch design due to the presence of tiny, micron-sized needles that permit enhanced drug permeation on their application surface. To date, MAPs have predominantly been used to deliver hydrophilic compounds. However, this work challenges this trend and focuses on the use of MAPs, in combination with commonly utilized solubility-enhancing techniques, to deliver the hydrophobic drug olanzapine (OLP) across the skin. Specifically, cyclodextrin (CD) complexation and particle size reduction were employed in tandem with hydrogel-forming and dissolving MAPs, respectively. In vivo experimentation using a female Sprague-Dawley rat model confirmed the successful delivery of OLP from hydrogel-forming MAPs (Cmax = 611.13 ± 153.34 ng/mL, Tmax = 2 h) and dissolving MAPs (Cmax = 690.56 ± 161.33 ng/mL, Tmax = 2 h) in a manner similar to that of oral therapy in terms of the rate and extent of drug absorption, as well as overall drug exposure and bioavailability. This work is the first reported use of polymeric MAPs in combination with the solubility-enhancing techniques of CD complexation and particle size reduction to successfully deliver the poorly soluble drug OLP via the transdermal route. Accordingly, this paper provides significant evidence to support an expansion of the library of molecules amenable to MAP-mediated drug delivery to include those that exhibit poor aqueous solubility.

Vidutolimod in Combination With Atezolizumab With and Without Radiation Therapy in Patients With Programmed Cell Death Protein 1 or Programmed Death-Ligand 1 Blockade-Resistant Advanced NSCLC.

Introduction: Vidutolimod, a CpG-A TLR9 agonist, was investigated in a phase 1b study (CMP-001-003; ClinicalTrials.gov, NCT03438318) in combination with atezolizumab with and without radiation therapy (RT) in patients with advanced NSCLC. Methods: Patients with progressive disease after anti-programmed cell death protein 1 or programmed death-ligand 1 therapy received either vidutolimod and atezolizumab (part A) or vidutolimod, atezolizumab, and RT (part B). The primary objective was to evaluate the safety of vidutolimod and atezolizumab with and without RT. Key secondary end point was best objective response rate per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Between March 28, 2018, and July 25, 2019, a total of 29 patients were enrolled and received at least one dose of vidutolimod (part A, n = 13; part B, n = 16). Intratumoral injections of vidutolimod were administered successfully, including injection of visceral lesions. The most common treatment-related adverse events (≥30%) were flu-like symptoms and hypotension. No objective responses were observed; 23.1% and 50.0% of the patients in parts A and B, respectively, had stable disease as best response. In parts A and B, 15.4% and 25.0% of the patients, respectively, had tumor shrinkage (<30% decrease in tumor size, nonirradiated). Enrollment was stopped owing to lack of objective responses. In the two patients with initial tumor shrinkage in part A, a strong serum induction of C-X-C motif chemokine ligand 10 was observed. Conclusions: Vidutolimod and atezolizumab with and without RT had a manageable safety profile, with minimal clinical activity in heavily pretreated patients with programmed cell death protein 1 or programmed death-ligand 1 blockade-resistant NSCLC.

Microneedle array systems for long-acting drug delivery.

The development of microneedles (MNs) assisted drug delivery technologies have been highly active for more than two decades. The minimally invasive and self-administered MN technology bypasses many challenges associated with injectable drug delivery systems, by delivering the therapeutic materials directly into the dermal and ocular space and allowing the release of the active ingredient in a sustained or controlled manner. Different types of MNs (biodegradable solid/dissolving MNs and nanoparticle loaded/coated polymeric MNs or delivery by hollow MNs) have been envisioned for long-acting sustained delivery of therapeutic payloads, with the aim of reducing the side effects and administration frequency to improve the patient compliance. In this review, we covered the different types of MNs loaded with different nano/biotherapeutics for long-acting delivery for a wide range of potential clinical applications. We also outlined the future development scenario of such long-acting MN delivery systems for different disease conditions to achieve improved clinical benefit. Finally, we discussed the challenges lie ahead to realize the full potential of sustained-release long-acting MNs in the clinic.

Enhancing intradermal delivery of tofacitinib citrate: Comparison between powder-loaded hollow microneedle arrays and dissolving microneedle arrays.

Autoimmune-mediated inflammatory skin diseases, such as psoriasis, alopecia areata, and vitiligo, have been reported as the 4th leading cause of nonfatal disease burden worldwide. This is mainly related to the poor quality of life experienced by these patients. Although topical and systemic steroids represent the most common treatment, the variability in success rates and side effects often lead to treatment discontinuation. Recent off-label clinical studies using oral Janus Kinase (JAK) inhibitors (e.g., ruxolitinib, tofacitinib, baraticinib) have shown promising results. However, frequent side effects, such as infections and blood clots have been reported. Therefore, the aim of this research was to enhance the intradermal delivery of tofacitinib citrate with MN arrays. Using crosslinked hydrogels containing modifying agents (urea, sorbitol and sodium chloride), hollow MN arrays were fabricated and then loaded with tofacitinib citrate. Their efficiency in intradermal delivery of tofacitinib was compared with dissolving MN arrays and a control (Aqueous cream BP), using neonatal porcine skin. Despite the fact that the hydrogel was only present on the outer surface, hollow MN arrays showed comparable resistance to compression values and insertion capabilities to dissolving MN arrays. Although hollow MN arrays containing NaCl in the formulation led to slightly higher depositions of tofacitinib in epidermis and dermis of neonatal porcine skin when compared to a control cream, dissolving MN arrays showed superiority in terms of tofacitinib deposition in the dermis. Indeed, at 24 h of the study, control cream and dissolving MN arrays delivered 143.98 ug/cm2 and 835 ug/cm2 of drug in the dermis, respectively, confirming the enhanced intradermal drug delivery capacity of MN arrays and their potential for treatment of autoimmune skin diseases.

Versatility of hydrogel-forming microneedles in in vitro transdermal delivery of tuberculosis drugs.

Current therapy of tuberculosis (TB) has several limitations, such as risk of liver injury and intestinal dysbiosis due to frequent oral administration of antibiotics. Transdermal administration could be used to improve antibiotic delivery for treatment of Mycobacterium tuberculosis infection. Therefore, we developed a novel approach, using hydrogel-forming microneedle (MN) arrays to transdermally deliver TB drugs, namely rifampicin, isoniazid, pyrazinamide and ethambutol, which have different physicochemical properties. These drugs were individually prepared into three types of drug reservoirs, including lyophilised tablets, directly compressed tablets and poly(ethylene glycol) tablets. Formulations of each drug reservoir type were optimised to achieve a rapidly dissolving tablet, and further integrated with hydrogel-forming MN arrays for in vitro permeation studies. Three types of hydrogel formulation were manufactured using different type of polymers and crosslinking processes. These MN arrays were then evaluated in terms of swelling ability, morphology and physical properties. Results of solute diffusion studies showed that drug permeation across the swollen hydrogel membrane was affected mostly by physiochemical properties and functional groups of each drug. In the in vitro studies, the amount of permeated drug through the hydrogel-forming MN arrays across the dermatomed neonatal porcine skin was affected by the drug solubility and reservoir design. The highest permeation of rifampicin (3.64 mg) and ethambutol (46.99 mg) were achieved using MN arrays combined with the poly(ethylene glycol) tablets and directly compressed tablet, respectively. For isoniazid and pyrazinamide, the highest drug permeation was attained using lyophilised reservoir with the amount of drug delivered approximately 58.45 mg and 20.08 mg, respectively. These equate to transdermal delivery of approximately 75% (rifampicin), 79% (isoniazid), 20% (pyrazinamide) and 47% (ethambutol) of the drugs loaded into the reservoirs on average. Importantly, the results of this work have demonstrated the versatility of hydrogel formulations to deliver a TB drug regime using MN arrays. Accordingly, this is a promising approach to deliver high dose of TB drugs.

Nanocarrier vaccines for SARS-CoV-2.

The SARS-CoV-2 global pandemic has seen rapid spread, disease morbidities and death associated with substantive social, economic and societal impacts. Treatments rely on re-purposed antivirals and immune modulatory agents focusing on attenuating the acute respiratory distress syndrome. No curative therapies exist. Vaccines remain the best hope for disease control and the principal global effort to end the pandemic. Herein, we summarize those developments with a focus on the role played by nanocarrier delivery.

A Role for Extracellular Vesicles in SARS-CoV-2 Therapeutics and Prevention.

Extracellular vesicles (EVs) are the common designation for ectosomes, microparticles and microvesicles serving dominant roles in intercellular communication. Both viable and dying cells release EVs to the extracellular environment for transfer of cell, immune and infectious materials. Defined morphologically as lipid bi-layered structures EVs show molecular, biochemical, distribution, and entry mechanisms similar to viruses within cells and tissues. In recent years their functional capacities have been harnessed to deliver biomolecules and drugs and immunological agents to specific cells and organs of interest or disease. Interest in EVs as putative vaccines or drug delivery vehicles are substantial. The vesicles have properties of receptors nanoassembly on their surface. EVs can interact with specific immunocytes that include antigen presenting cells (dendritic cells and other mononuclear phagocytes) to elicit immune responses or affect tissue and cellular homeostasis or disease. Due to potential advantages like biocompatibility, biodegradation and efficient immune activation, EVs have gained attraction for the development of treatment or a vaccine system against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection. In this review efforts to use EVs to contain SARS CoV-2 and affect the current viral pandemic are discussed. An emphasis is made on mesenchymal stem cell derived EVs' as a vaccine candidate delivery system.

Papillary carcinoma of the breast: an overview.

Papillary carcinoma of the breast represents approximately 0.5% of all newly diagnosed cases of breast cancer. The prevalence of both invasive and in situ papillary carcinoma seems to be greater in older postmenopausal women and, in relative terms, in males. Histologic features of the tumor include cellular proliferations surrounding fibrovascular cores, with or without invasion. In this review, characteristics of both in situ and invasive disease are outlined. Immunohistochemical analyses of papillary carcinoma suggest the utility of markers such as smooth muscle myosin heavy chain, calponin, p63, and high molecular weight keratins, which can characterize the myoepithelial cell layer. With respect to radiographic evaluation of papillary carcinoma, ultrasonography is the most extensively studied imaging modality, though magnetic resonance mammography has potential utility. Available data suggest improved outcome for papillary carcinoma as compared to invasive ductal carcinoma. Treatment-related information for patients with papillary carcinoma is limited, and patterns noted in available series suggest a variable approach to this disease. The scarcity of information underscores the need for further treatment- and outcome-related studies in papillary carcinoma of the breast.

An Analysis and Comparison of Survival and Functional Outcomes in Oropharyngeal Squamous Cell Carcinoma Patients Treated with Concurrent Chemoradiation Therapy within City of Hope Cancer Center Sites.

Oropharyngeal squamous cell carcinoma (OPSCC) is a subset of head and neck cancers that can arise due to human papillomavirus (HPV) infection. We designed a retrospective analysis to determine differences in outcomes of OPSCC patients treated at City of Hope (COH) Cancer Center's main campus versus selected satellite sites with COH-associated faculty and facilities. Patients diagnosed with OPSCC and treated with concurrent chemoradiation therapy (n = 94) were identified and included in the study. Patients underwent treatment at the COH main campus site (n = 50) or satellite sites (n = 44). The majority of patients were Caucasian, male, and diagnosed with p16 positive stage IV locally advanced OPSCC by AJCC 7th edition. Most patients completed their prescribed cumulative radiation therapy dose and had a complete response to treatment. No significant difference in overall survival and progression-free survival was observed between the main campus and the satellite sites. Our study demonstrates successful treatment completion rates as well as comparable recurrence rates between the main campus and COH-associated satellite sites. A trend toward significant difference in feeding tube dependency at 6-months was observed. Differences in feeding tube placement and dependency rates could be addressed by the establishment of on-site supportive services in satellite sites.

Hydrogel-forming microneedle arrays as a therapeutic option for transdermal esketamine delivery.

Treatment resistant depression is, by definition, difficult to treat using standard therapeutic interventions. Recently, esketamine has been shown as a viable rescue treatment option in patients in depressive crisis states. However, IV administration is associated with a number of drawbacks and advanced delivery platforms could provide an alternative parenteral route of esketamine dosing in patients. Hydrogel-forming microneedle arrays facilitate transdermal delivery of drugs by penetrating the outer layer of the skins surface, absorbing interstitial skin fluid and swelling. This subsequently facilitates permeation of medicines into the dermal microcirculation. This paper outlines the in vitro formulation development for hydrogel-forming microneedle arrays containing esketamine. Analytical methods for the detection and quantitation of esketamine were developed and validated according to International Conference on Harmonisation standards. Hydrogel-forming microneedle arrays were fully characterised for their mechanical strength and skin insertion properties. Furthermore, a series of esketamine containing polymeric films and lyophilised reservoirs were assessed as drug reservoir candidates. Dissolution testing and content drug recovery was carried out, followed by permeation studies using 350 µm thick neonatal porcine skin in modified Franz cell apparatus. Lead reservoir candidates were selected based on measured physicochemical properties and brought forward for testing in female Sprague-Dawley rats. Plasma samples were analysed using reverse phase high performance liquid chromatography for esketamine. Both polymeric film and lyophilised reservoirs candidate patches achieved esketamine plasma concentrations higher than the target concentration of 0.15-0.3 µg/ml over 24 h. Mean plasma concentrations in rats, 24 h post-application of microneedle patches with drug reservoir F3 and LW3, were 0.260 µg/ml and 0.498 µg/ml, respectively. This developmental study highlights the potential success of hydrogel-forming microneedle arrays as a transdermal drug delivery platform for ESK and supports moving to in vivo tests in a larger animal model.

Precision medicine and actionable alterations in lung cancer: A single institution experience.

OBJECTIVES: Oncology has become more reliant on new testing methods and a greater use of electronic medical records, which provide a plethora of information available to physicians and researchers. However, to take advantage of vital clinical and research data for precision medicine, we must initially make an effort to create an infrastructure for the collection, storage, and utilization of this information with uniquely designed disease-specific registries that could support the collection of a large number of patients. MATERIALS AND METHODS: In this study, we perform an in-depth analysis of a series of lung adenocarcinoma patients (n = 415) with genomic and clinical data in a recently created thoracic patient registry. RESULTS: Of the 415 patients with lung adenocarcinoma, 59% (n = 245) were female; the median age was 64 (range, 22-92) years with a median OS of 33.29 months (95% CI, 29.77-39.48). The most common actionable alterations were identified in EGFR (n = 177/415 [42.7%]), ALK (n = 28/377 [7.4%]), and BRAF V600E (n = 7/288 [2.4%]). There was also a discernible difference in survival for 222 patients, who had an actionable alteration, with a median OS of 39.8 months as compared to 193 wild-type patients with a median OS of 26.0 months (P<0.001). We identified an unprecedented number of actionable alterations [53.5% (222/415)], including distinct individual alteration rates, as compared with 15.0% and 22.3% in TCGA and GENIE respectively. CONCLUSION: The use of patient registries, focused genomic panels and the appropriate use of clinical guidelines in community and academic settings may influence cohort selection for clinical trials and improve survival outcomes.

Anaplastic Lymphoma Kinase (ALK)-positive Tumors: Clinical, Radiographic and Molecular Profiles, and Uncommon Sites of Metastases in Patients With Lung Adenocarcinoma.

INTRODUCTION: Anaplastic lymphoma kinase (ALK) gene rearrangements are observed in about 4% to 8% non-small cell lung cancer (NSCLC). ALK+ tumors have been associated with increased pleural and pericardial disease. Our primary objective was to determine the uncommon sites of metastasis of ALK+ NSCLC. Secondary objectives included study of coexisting mutations and factors impacting survival of ALK+ NSCLC. METHODS: All patients with metastatic ALK+ NSCLC at the City of Hope Cancer Center in Duarte, California from 2010 to 2017 were selected for retrospective chart review. The demographic variables were collected. The molecular statuses of patients were evaluated through commercially available platforms for next-generation sequencing. Three-dimensional volumetric images were generated for the primary lesion and different sites of metastasis. RESULTS: Sixty two patients with ALK+ NSCLC were identified from 2010 to 2017. The median age was 59 with 36 (58%) female individuals and only 20 (32%) smokers. Twenty four patients had uncommon sites of metastasis which were thyroid, soft tissue, chest and abdominal wall, spleen, peritoneum, omentum, kidney, and ovary. Common characteristics of the primary lesions were right upper lobe location (N=23 [37%]), oval shape (N=22 [35%]), irregular margins (N=26 [42%]), solid lesions (N=27 [44%]), presence of pleural contact or effusion (N=22 [35%]). Twenty four patients had next-generation sequencing testing which showed coexisting mutations such as TP53 (N=8), EGFR (N=5), KRAS (N=3). Patients with uncommon sites of metastasis had a decreased median survival compared with common sites (39 vs. 82 m, P=0.046). CONCLUSION: In NSCLC, ALK rearrangements may not be mutually exclusive mutations and can present with unique radiographic patterns. Patients with uncommon sites of metastasis may have worse outcomes.

Small Cell Lung Cancer Therapeutic Responses Through Fractal Measurements: From Radiology to Mitochondrial Biology.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine disease with an overall 5 year survival rate of ~7%. Although patients tend to respond initially to therapy, therapy-resistant disease inevitably emerges. Unfortunately, there are no validated biomarkers for early-stage SCLC to aid in early detection. Here, we used readouts of lesion image characteristics and cancer morphology that were based on fractal geometry, namely fractal dimension (FD) and lacunarity (LC), as novel biomarkers for SCLC. Scanned tumors of patients before treatment had a high FD and a low LC compared to post treatment, and this effect was reversed after treatment, suggesting that these measurements reflect the initial conditions of the tumor, its growth rate, and the condition of the lung. Fractal analysis of mitochondrial morphology showed that cisplatin-treated cells showed a discernibly decreased LC and an increased FD, as compared with control. However, treatment with mdivi-1, the small molecule that attenuates mitochondrial division, was associated with an increase in FD as compared with control. These data correlated well with the altered metabolic functions of the mitochondria in the diseased state, suggesting that morphological changes in the mitochondria predicate the tumor's future ability for mitogenesis and motogenesis, which was also observed on the CT scan images. Taken together, FD and LC present ideal tools to differentiate normal tissue from malignant SCLC tissue as a potential diagnostic biomarker for SCLC.

Combined modality radiation therapy promotes tolerogenic myeloid cell populations and STAT3-related gene expression in head and neck cancer patients.

Immunomodulation contributes to the antitumor efficacy of the fractionated radiation therapy (RT). Here, we describe immune effects of RT with concurrent systemic cisplatin or cetuximab treatment of patients with stage III-IV head and neck squamous cell carcinoma (HNSCC). Using longitudinally collected blood samples, we identified significant changes in cytokines/chemokines and immune cell populations compared to immune-related gene expression profiles in peripheral blood mononuclear cells (PBMCs). The 7-week combinatorial RT resulted in gradual elevation of proinflammatory mediators (IFNγ, IL-6, TNFɑ, CCL2), while levels of IL-12, cytokine essential for antitumor immune responses, were decreased. These effects correlated with progressive accumulation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) with detectable activity of STAT3 and PD-L1 expression, underscoring tolerogenic effects of MDSCs. Correspondingly, gene expression analysis of PBMCs harvested after two weeks of combinatorial RT, found upregulation of several immunosuppressive mediators. These included IL6, IL6R, STAT3 and PDL1, which could represent IL-6/STAT3-driven tolerogenic signaling, which inhibits T cell and NK activity. Overall, our results suggest that potential immunostimulatory effects of combinatorial RT in HNSCC patients are likely limited by tolerogenic STAT3 signaling and PD-L1 upregulation in myeloid immune cells. Further studies will clarify whether STAT3 targeting could augment RT efficacy and durability of antitumor responses.