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.

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.

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.

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.

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.

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.

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.

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.

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.

Evaluation of expert criteria for preoperative magnetic resonance imaging of newly diagnosed breast cancer.

Despite 2 randomized trials reporting no reduction in operations or local recurrence at 1 year, preoperative magnetic resonance imaging (MRI) is increasingly used in diagnostic workup of breast cancer. We evaluated 5 utilization criteria recently proposed by experts. Of women (n = 340) newly diagnosed with unilateral breast cancer who underwent bilateral MRI, most (69.4%) met at least 1 criterion before MRI: mammographic density (44.4%), under consideration for partial breast irradiation (PBI) (19.7%), genetic-familial risk (12.9%), invasive lobular carcinoma (11.8%), and multifocal/multicentric disease (10.6%). MRI detected occult malignant lesion or extension of index lesion in 21.2% of index, 3.3% of contralateral, breasts. No expert criterion was associated with MRI-detected malignant lesion, which associated instead with pre-MRI plan of lumpectomy without PBI (48.2% of subjects): Odds Ratio 3.05, 95% CI 1.57-5.91 (p adjusted for multiple hypothesis testing = 0.007, adjusted for index-vs-contralateral breast and covariates). The expert guidelines were not confirmed by clinical evidence.

Magnetic resonance imaging-guided breast biopsy in lesions not visualized by mammogram or ultrasound.

The use of magnetic resonance imaging (MRI) for the diagnosis and evaluation of breast lesions is still in evolution. The aim of this study was to evaluate the outcome of MR-guided biopsy for suspicious lesions seen on MRI but not visualized by mammography or ultrasound. A retrospective review was conducted on all patients undergoing MRI-guided core needle biopsy at a National Cancer Institute-designated comprehensive cancer center. Biopsies were performed using a 1.5-Tesla MR with a seven-channel breast coil taking six cores in a clock face configuration with a 10-gauge vacuum-assisted VACORA biopsy device. One hundred twenty-seven patients underwent 187 biopsies without major complication. The lesion size ranged from 4 to 12 mm. Pathology on MRI-guided core biopsy material revealed 126 (68%) benign lesions. Of these, 12 were intraductal papillomas and two were fibroadenomas. Sixty-one (32%) were deemed clinically significant and included the following pathology: invasive cancer 19 patients (10%), ductal carcinoma in situ (DCIS) in 25 patients (13%), atypical ductal hyperplasia (ADH) 15 patients (8%), and lobular carcinoma in situ in one patient (1%). There were two specimens upgraded from ADH to DCIS and one specimen that was biopsied was called ADH but there was no residual atypia on final pathology. With a median follow-up of 24 months, there were no patients with benign pathology returning with a clinically significant lesion later. MRI-guided biopsy provides an accurate and safe method for sampling suspicious lesions when no other reasonable means of biopsy is available. MRI-guided biopsy yielded clinically significant findings in approximately one-third of the sampled specimens. This technique can provide a good representative sample of clinically significant pathology. MRI-guided biopsy is a relatively new modality, which can provide a nonsurgical diagnostic specimen in the absence of mammographic or ultrasound findings.

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.