Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Chemoradiotherapy is the standard of care for unresected locally advanced squamous cell carcinoma of the head and neck. We aimed to assess if addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for this patient population. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 study, patients were recruited from 196 hospitals and cancer treatment centres in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an Eastern Cooperative Oncology Group performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomisation with block size four (stratified by human papillomavirus status, tumour stage, and nodal stage, and done by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was progression-free survival by investigator assessment per modified Response Evaluation Criteria in Solid Tumors, version 1.1, in all randomly assigned patients. Adverse events were assessed in patients who received at least one dose of avelumab or placebo. This trial is registered with ClinicalTrials.gov, NCT02952586. Enrolment is no longer ongoing, and the trial has been discontinued. FINDINGS: Between Dec 12, 2016, and Jan 29, 2019, from 907 patients screened, 697 patients were randomly assigned to the avelumab group (n=350) or the placebo group (n=347). Median follow-up for progression-free survival was 14·6 months (IQR 8·5-19·6) in the avelumab group and 14·8 months (11·6-18·8) in the placebo group. Median progression-free survival was not reached (95% CI 16·9 months-not estimable) in the avelumab group and not reached (23·0 months-not estimable) in the placebo group (stratified hazard ratio 1·21 [95% CI 0·93-1·57] favouring the placebo group; one-sided p=0·92). The most common grade 3 or worse treatment-related adverse events were neutropenia (57 [16%] of 348 patients in the avelumab group vs 52 [15%] of 344 patients in the placebo group), mucosal inflammation (50 [14%] vs 45 [13%]), dysphagia (49 [14%] vs 47 [14%]), and anaemia (41 [12%] vs 44 [13%]). Serious treatment-related adverse events occurred in 124 (36%) patients in the avelumab group and in 109 (32%) patients in the placebo group. Treatment-related deaths occurred in two (1%) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and one (<1%) in the placebo group (due to acute respiratory failure). INTERPRETATION: The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met. These findings may help inform the design of future trials investigating the combination of immune checkpoint inhibitors plus CRT. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.

Tipifarnib in recurrent, metastatic HRAS-mutant salivary gland cancer.

BACKGROUND: To the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC. METHODS: The current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response. RESULTS: A total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity. CONCLUSIONS: Tipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.

Outcomes Of Distal Femur Fracture Treated With Dynamic Condylar Screw.

BACKROUND: Implants for open reduction and internal fixation of distal femoral fracture includes angle blade plate, rush nails, enders nail and interlocking nails. But all these devices are technically demanding and less effective in providing inter-fragmentary compression in osteoporotic bones. These problems can be solved with dynamic condylar screw (DCS).The objective of the study was to determine the frequency of different outcomes of distal femoral fracture treated with dynamic condylar screw. METHODS: This case series study was carried out in the Department of Trauma & Orthopaedics, Ayub Teaching Hospital Abbottabad from 1st October 2014 to August 2015, after approval of the ethical committee of the institution. Data of all patients with distal femoral fractures aged 20-70 years, recruited through emergency, OPD or consultant clinic collected on a pro forma. Standard treatment of trauma was given to the patients. Detailed history was taken including the past medical and surgical history. Detailed examination including air-way, breathing and circulation, general physical examination and abdomino-pelvic examination was done in each patient. Investigations including urinalysis, haemoglobin %, full blood count, X-ray (both AP and lateral view) of the involved femur (including hip and knee) was done. RESULTS: Mean age of the patients was 43.18±14.647 ranging from 20 to 70 years. Mean duration of hospital stay in days was 2.21±1.111 ranging from 1 to 6 days. Patients' follow-up assessment after 4 months of surgery for union of femoral fracture treated with dynamic condylar screw was found in 96 (94.1%), wound infection was found in 7 (6.9%), knee stiffness was found in 21 (20.6%) and limb shortening was found in 7 (6.9%). CONCLUSIONS: Dynamic condylar screw is an easy, scientifically less difficult and satisfying method of treatment for fra.ctures of femur.

Merkel cell carcinoma: treatment and outcomes over a 10-year period at a high-volume academic center.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, highly aggressive malignancy which lacks high-level evidence-based treatment guidelines. METHODS: To determine outcomes of MCC patients and assess the role of radiation in treatment, we performed a retrospective chart review of patients treated for MCC between 2006 and 2016 at a single high-volume academic medical center. The primary outcome was overall survival (OS) for the entire population and for those populations receiving specific therapies. RESULTS: Forty-two patients were evaluable. OS for all patients was not reached since most remain alive at time of analysis. OS for the American Joint Committee on Cancer (AJCC) stage I was not reached. OS for stages II, III, and IV was 37.3 months (6.8, -), 49.5 months (14.2, 49.5), and 14.5 months (10.8, -), respectively. OS could not be reached in the high radiotherapy (RT) dose group (biologically equivalent dose [BED] ≥ 60) and was 49.5 months (10.8, -) in the low-dose group (BED < 60). For surgical margin status, OS was 14.9158 months (6.8008, -) for positive margins and 37.3 months (10.8, -) for negative margins. CONCLUSIONS: No conclusive findings for OS were identified; however, trends for improved OS were associated with lower AJCC staging, negative surgical margins, and high RT doses.

Phase 1/2a, open-label, multicenter study of RM-1929 photoimmunotherapy in patients with locoregional, recurrent head and neck squamous cell carcinoma.

BACKGROUND: Recurrent head and neck squamous cell carcinoma (rHNSCC) represents a significant global health burden with an unmet medical need. In this study we determined the safety and efficacy of RM-1929 photoimmunotherapy in patients with heavily pretreated rHNSCC. METHODS: RM-1929 (anti-EGFR-IR700 dye conjugate) was infused, followed by tumor illumination. We evaluated safety, tumor response, and pharmacokinetics. RESULTS: Nine patients were enrolled in Part 1 (dose-finding) and 30 patients in Part 2 (safety and efficacy). No dose-limiting toxicities were experienced in Part 1; 640 mg/m2 with fixed light dose (50 J/cm2 or 100 J/cm) was recommended for Part 2. Adverse events (AEs) in Part 2 were mostly mild to moderate but 19 (63.3%) patients had AE ≥Grade 3, including 3 (10.0%) with serious AEs leading to death (not treatment related). Efficacy in Part 2: unconfirmed objective response rate (ORR) 43.3% (95% CI 25.46%-62.57%); confirmed ORR 26.7% (95% CI 12.28%-45.89%); median overall survival 9.30 months (95% CI 5.16-16.92 months). CONCLUSIONS: Treatment was well tolerated. Responses and survival following RM-1929 photoimmunotherapy in heavily pretreated patients with rHNSCC were clinically meaningful and warrant further investigation. CLINICAL TRIAL INFORMATION: NCT02422979.

Exchange nailing for non-union of femoral shaft fractures.

BACKGROUND: There are many ways to treat aseptic non-union of femoral shaft fractures with reported varied success rate. Amongst all these, Exchange nailing is the simplest and most successful technique for treating aseptic non union of femoral shaft fractures. We have carried out a prospective study in the Department of Trauma & Orthopaedics, Ayub Medical College Abbottabad to analyse the role of exchange nailing for aseptic non union of femoral shaft fractures. METHODS: Forty-three femoral shaft aseptic non-unions in 41 consecutive patients were treated using exchange IM nailing, from January 2006 to December 2007. The inclusion criteria for patients in the study was a femoral shaft fractures aseptic non-union, has less than 1 Cm shortening with no segmental bone defect, and a radiolucent line of the non-union, and which had previously been treated by intra-medullary nail. The surgical technique included removal of previously inserted intra-medullary nail, reaming of medullary cavity up to 2 mm above the previous size, and re-insertion of statically locked exchange intra-medullary nail. RESULTS: Forty-three femoral shaft aseptic non-union in 41 patients were treated; the mean age of the patients was 38.81 +/- 13.75 years. Thirty-nine non-union out of total 43 cases (39/43) had healed giving a union rate of 90%. Non-union persisted in the remaining four cases (4/43) in-spite of extended post operative follow up of these patients for 18 months. Mean union was 4.97 +/- 1.53 months. No major surgical complications were noted. CONCLUSION: Exchange nailing is a simple technique for treating aseptic non union of femoral shaft fractures. Based on the results of our study, we recommend it as the procedure of choice for non comminuted, aseptic non union of femoral shaft fracture.

Progress in extracellular vesicle biology and their application in cancer medicine.

Under the broader category of extracellular vesicles (EVs), exosomes are now well recognized for their contribution and potential for biomedical research. During the last ten years, numerous technologies for purification and characterization of EVs have been developed. This enhanced knowledge has resulted in the development of novel applications of EVs. This review is an attempt to capture the exponential growth observed in EV science in the last decade and discuss the future potential to improve our understanding of EVs, develop technologies to overcome current limitations, and advance their utility for human benefit, especially in cancer medicine. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Exosomes as drug delivery vehicle and contributor of resistance to anticancer drugs.

Exosomes are small membranous vesicles implicated in intercellular signalling. Through their uncanny ability to carry and deliver donor cellular cargo (biomolecules) to target cells, they exert a profound effect on the regular functioning of healthy cells and play a significant role in pathogenesis and progression of several diseases, including cancer. The composition and number of endogenously circulating exosomes frequently vary, which is often reflective of the pathophysiological status of the cell. Applicability of exosomes derived from normal cells as a drug carrier with or without modifying their intraluminal and surface components are generally tested. Conversely, exosomes also are reported to contribute to resistance towards several anti-cancer therapies. Therefore, it is necessary to carefully evaluate the role of exosomes in cancer progression, resistance and the potential use of exosomes as a delivery vehicle of cancer therapeutics. In this review, we summarize the recent advancements in the exploitation of exosomes as a drug delivery vehicle. We also discuss the role of exosomes in conferring resistance to anti-cancer therapeutics. While this review is focused on cancer, the exosome-based drug delivery and resistance is also applicable to other human diseases.

Multisite, Randomized Trial of Early Integrated Palliative and Oncology Care in Patients with Advanced Lung and Gastrointestinal Cancer: Alliance A221303.

Background: We conducted a multicenter, randomized trial of early integrated palliative and oncology care in patients with advanced cancer to confirm the benefits of early palliative care (PC) seen in prior single-center studies. Methods: We randomly assigned patients with newly diagnosed incurable cancer to early integrated palliative and oncology care (n = 195) or usual oncology care (n = 196) at sites through the Alliance for Clinical Trials in Oncology. Patients assigned to the intervention were expected to meet with a PC clinician at least monthly until death, whereas usual care patients consulted PC on request. The primary endpoint was the change in quality of life from baseline to week 12 per the Functional Assessment of Cancer Therapy-General (FACT-G). Secondary outcomes included anxiety, depression, and communication about prognosis and end-of-life care. Results: Due to significant morbidity and a high proportion of measures that were not completed within the protocol window or for unknown reasons, the rate of missing data was high. We anticipated that 70% of patients (n = 280) would complete the FACT-G at baseline and week 12, but only 49.3% (n = 193/391) completed the measure. Delivery of the intervention was also suboptimal, as 14.9% (n = 29/195) of intervention patients had no PC visits by week 12. Intervention patients reported a mean 3.35 (standard deviation [SD] = 14.7) increase in FACT-G scores from baseline to week 12 compared with usual care patients who reported a 0.12 (SD = 12.7) increase from baseline (p = 0.10). Conclusion: This study highlights the difficulties of conducting multicenter trials of supportive care interventions in patients with advanced cancer. Clinical Trials Registration: NCT02349412.

Management outcome of closed femoral shaft fractures by open Surgical Implant Generation Network (SIGN) interlocking nails.

BACKGROUND: Many hospitals in our country lack surgical expertise and operating room facilities like image intensifier and fractures table to carry out closed interlocking nails (ILN) in femoral shaft fractures. But availability of Surgical Implant Generation Network (SIGN) interlocking nails & nailing instrumentation have made open ILN of these fractures possible at very basic level of our health care system. We have carried out open SIGN nailing in patients with closed fractures of shaft femur without the use of image intensifier. Result for fracture union was evaluated both clinically and radio-logically, and graded at 8 months (32 weeks) after treatment by Thoressen's criteria. METHODS: An experimental study of open SIGN nailing was carried out on 47 patients with fractures shaft of femur who had been admitted to our tertiary care hospital from January 2006 to December 2007. Inclusion criteria were adult patients older than 16 years with closed fractures of the shaft femur, and have presented within a week of the injury, and have not had any previous surgical treatment for the fracture. Malnourished patients and patients with open, pathological fractures and non union cases were excluded from the study. A standard protocol was followed on all patients, which is describing below. The data obtained was analysed using SPSS. RESULTS: The union rate was 97.83% in open nailing at 32 weeks after surgery and the Mean +/- SD time to union was 19.65 +/- 5.19 weeks (ranges from 16-32 weeks).We obtained excellent results in 39 patients (83.33%), good in 4 patients (8.50%), fair in 3 patients (6.38%) and poor in one (2.12%). CONCLUSIONS: The open SIGN nailing, without the use of image intensifier, for treatment of closed fractures of shaft femur achieves excellent result in term of fracture union. Results obtained are comparable to the results of closed interlocking nailing, requires less expertise and resources, and its use is recommended for long bones fracture care at the very level of our health care system.

Circulating Tumor Cells Accurately Predicting Progressive Disease After Treatment in a Patient with Non-small Cell Lung Cancer Showing Response on Scans.

Lung cancer is the leading cause of cancer-related deaths worldwide. Most patients present with advanced inoperable disease. Traditionally, responses to treatments are evaluated using different imaging modalities, which can sometimes be confusing. This is particularly more relevant in stage 3 disease where, after radiation therapy, persistent tumors on scans can represent active disease or scar tissue. We have been evaluating role of circulating tumor cells (CTCs) in that setting. Here we present the case of a 68-year-old male with stage 3 disease whose primary tumor responded to chemoradiotherapy on imaging, but whose CTC count was higher than the pre-treatment value. The patient later developed liver metastases. In this case, the CTC count more accurately predicted the patient's prognosis and highlights the need for exploration of the CTC count as a tool supplemental to imaging modalities.

Neurological Recovery In Traumatic Spinal Cord Injuries After Surgical Intervention.

BACKGROUND: Spinal injuries are the most devastating injuries and affect every aspect of patients' lives. This may cause lifelong disability due to spinal cord injury. Recovery of neurological functions is highly desirable. Early or late surgical intervention is still debatable, but majority recommend early intervention. The result of late surgical intervention in term of neurological recovery is not clear. This study focuses on neurological recovery after late surgical intervention. The objective of this study was to assess neurological recovery in term of ASIA grading in patients with traumatic spinal cord injury. METHODS: This descriptive cross-sectional study was performed from June 2013 to June 2016. All patients treated for spinal trauma with spinal cord injury, operated after 24 hrs of injury were included in the study. Neurology was assessed according to ASIA scale preoperative and at 6 months. Data was analysed with the help of SPSS. RESULTS: Total of 149 patients, 32 (21.5%) were female and 117 (78.5%) male were included. mean age was 32±13.11 years. Ninety-six (64.4%) patients presented with fall while 53 (35.6%) presented with motor vehicular accidents (MVA). according to AO comprehensive classification 76 (51.1%) patients were type C, 47 (31.5) were type B and 26 (17.4%) were type A. preoperative neurology was ASIA A 65 (43.6%), B12 (8.1%), C 59 (39.6%) and D 13 (8.7%). Mean delay in surgery was 3.6±1.8 days with minimum of 1 and maximum 14 days. ASIA grading on 6 months was ASIA "A" 61 (40.9%), B4 (2.7%), C 26 (17.4%), D 33 (22.1%) and E 25 (16.8%). the overall improvement in neurology was in 67 (45%) of patients. improvement by one grade was documented in 49 (32.9%) patients, by two grades in 17 (11.4%) and by three grades in one patient (.7%). CONCLUSIONS: fall from height is a major cause of spine injuries in our set up followed by RTA. Preventive measures need to be instituted to lessen the devastating outcome.

Exosomes as Theranostics for Lung Cancer.

Extensive research in genetics and genomics has revealed that lung cancer is a physiologically complex and genetically heterogeneous disease. Although molecular targets that can yield favorable response have been identified, those targets cannot be exploited due to the lack of suitable drug carriers. Furthermore, lung cancer often is diagnosed at an advanced stage when the disease has metastasized. Conventional treatments are not effective for treating metastatic lung cancer. Targeted therapeutics while beneficial has challenges that include poor tumor-targeting, off-target effects, and development of resistance to therapy. Therefore, improved drug delivery systems that can deliver drugs specifically to tumor will produce improved treatment outcomes. Exosomes have a natural ability to carry functional biomolecules, such as small RNAs, DNAs, and proteins, in their lumen. This property makes exosomes attractive for use in drug delivery and molecular diagnosis. Moreover, exosomes can be attached to nanoparticles and used for high precision imaging. Exosomes are now considered an important component in liquid biopsy assessments, which are useful for detecting cancers, including lung cancer. Several studies are currently underway to develop methods of exploiting exosomes for use as efficient drug delivery vehicles and to develop novel diagnostic modalities. This chapter summarizes the current status of exosome studies with regard to their use as theranostics in lung cancer. Examples from other cancers have also been cited to illustrate the extensive applicability of exosomes to therapy and diagnosis.

Outcomes and Prognostic Factors of Resected Salivary Gland Malignancies: Examining a Single Institution's 12-year Experience.

BACKGROUND: Despite adjuvant radiotherapy, survival outcomes remain poor in patients with salivary gland malignancies who have multiple poor prognostic factors. This study aimed to determine which patients may benefit from treatment intensification. PATIENTS AND METHODS: Patients who underwent curative resection with or without adjuvant radiotherapy between 2002 and 2014 were identified and a retrospective chart review was performed. Overall survival (OS) and disease-free survival (DFS) were the main outcomes measured. RESULTS: A total of 95 patients met the inclusion criteria. The median follow-up was 46.8 months. The median age was 60 years. Radiotherapy was given to 78 patients. Multivariate analysis revealed that male sex and perineural invasion significantly reduced overall and disease-free survival. Distant metastases comprised of 67% of recurrences and 33% were locoregional. CONCLUSION: Adjuvant chemoradiotherapy should be considered for patients with tumors with perineural invasion, especially in males with high-risk histopathology or high-grade, late-stage disease. To our knowledge, this is the first study to assess the impact of pack-year smoking history on survival outcomes.

Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells.

Successful chemotherapeutic intervention for management of lung cancer requires an efficient drug delivery system. Gold nanoparticles (GNPs) can incorporate various therapeutics; however, GNPs have limitations as drug carriers. Nano-sized cellular vesicles like exosomes (Exo) can ferry GNP-therapeutic complexes without causing any particle aggregation or immune response. In the present study, we describe the development and testing of a novel Exo-GNP-based therapeutic delivery system -'nanosomes'- for lung cancer therapy. This system consists of GNPs conjugated to anticancer drug doxorubicin (Dox) by a pH-cleavable bond that is physically loaded onto the exosomes (Exo-GNP-Dox). The therapeutic efficacy of Dox in nanosomes was assessed in H1299 and A549 non-small cell lung cancer cells, normal MRC9 lung fibroblasts, and Dox-sensitive human coronary artery smooth muscle cells (HCASM). The enhanced rate of drug release under acidic conditions, successful uptake of the nanosomes by the recipient cells and the cell viability assays demonstrated that nanosomes exhibit preferential cytotoxicity towards cancer cells and have minimal activity on non-cancerous cells. Finally, the underlying mechanism of cytotoxicity involved ROS-mediated DNA damage. Results from this study mark the establishment of an amenable drug delivery vehicle and highlight the advantages of a natural drug carrier that demonstrates reduced cellular toxicity and efficient delivery of therapeutics to cancer cells.

Cat scratch disease mimicking Richter's Syndrome in a patient with chronic lymphocytic leukemia.

Richter's Syndrome is a highly refractory and usually fatal condition. It occurs as a result of transformation of chronic lymphocytic leukemia (CLL) or low grade lymphoma into highly aggressive lymphoma. Patients usually present with rapidly enlarging lymph nodes and systemic symptoms like night sweats, fever and weight loss. We are reporting a case of CLL presenting with similar symptoms. Initial suspicion of Richter's Syndrome proved wrong when lymph node biopsy did not reveal evidence of high grade lymphoma. Instead it showed findings consistent with cat scratch disease (CSD), later confirmed by serology. To our knowledge this is the first reported case of CSD in a patient with CLL.