Synergistic effects of radiotherapy and targeted immunotherapy in improving tumor treatment efficacy: a review

Radiotherapy (RT), unlike chemotherapy, is one of the most routinely used and effective genotoxic and immune response inducing cancer therapies with an advantage of reduced side effects. However, cancer can relapse after RT owing to multiple factors, including acquired tumor resistance, immune suppressive microenvironment buildup, increased DNA repair, thus favoring tumor metastasis. Efforts to mitigate these undesirable effects have drawn interest in combining RT with immunotherapy, particularly the use of immune checkpoint inhibitors, to tilt the pre-existing tumor stromal microenvironment into long-lasting therapy-induced antitumor immunity at multiple metastatic sites (abscopal effects). This multimodal therapeutic strategy can alleviate the increased T cell priming and decrease tumor growth and metastasis, thus emerging as a significant approach to sustain as long-term antitumor immunity. To understand more about this synergism, a detailed cellular mechanism underlying the dynamic interaction between tumor and immune cells within the irradiated tumor microenvironment needs to be explored. Hence, in the present review, we have attempted to evaluate various RT-inducible immune factors, which can be targeted by immunotherapy and provide detailed explanation to optimally maximize their synergy with immunotherapy for long-lasting antitumor immunity. Moreover, we have critically assessed various combinatorial approaches along with their challenges and described strategies to modify them in addition to providing approaches for optimal synergistic effects of the combination (AU)

miR766-3p and miR124-3p Dictate Drug Resistance and Clinical Outcome in HNSCC.

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive disease with poor prognosis, which is mainly due to drug resistance. The biology determining the response to chemo-radiotherapy in HNSCC is poorly understood. Using clinical samples, we found that miR124-3p and miR766-3p are overexpressed in chemo-radiotherapy-resistant (non-responder) HNSCC, as compared to responder tumors. Our study shows that inhibition of miR124-3p and miR766-3p enhances the sensitivity of HNSCC cell lines, CAL27 and FaDu, to 5-fluorouracil and cisplatin (FP) chemotherapy and radiotherapy. In contrast, overexpression of miR766-3p and miR124-3p confers a resistance phenotype in HNSCC cells. The upregulation of miR124-3p and miR766-3p is associated with increased HNSCC cell invasion and migration. In a xenograft mouse model, inhibition of miR124-3p and miR766-3p enhanced the efficacy of chemo-radiotherapy with reduced growth of resistant HNSCC. For the first time, we identified that miR124-3p and miR766-3p attenuate expression of CREBRF and NR3C2, respectively, in HNSCC, which promotes aggressive tumor behavior by inducing the signaling axes CREB3/ATG5 and ß-catenin/c-Myc. Since miR124-3p and miR766-3p affect complementary pathways, combined inhibition of these two miRNAs shows an additive effect on sensitizing cancer cells to chemo-radiotherapy. In conclusion, our study demonstrated a novel miR124-3p- and miR766-3p-based biological mechanism governing treatment-resistant HNSCC, which can be targeted to improve clinical outcomes in HNSCC.

Synergistic effects of radiotherapy and targeted immunotherapy in improving tumor treatment efficacy: a review.

Radiotherapy (RT), unlike chemotherapy, is one of the most routinely used and effective genotoxic and immune response inducing cancer therapies with an advantage of reduced side effects. However, cancer can relapse after RT owing to multiple factors, including acquired tumor resistance, immune suppressive microenvironment buildup, increased DNA repair, thus favoring tumor metastasis. Efforts to mitigate these undesirable effects have drawn interest in combining RT with immunotherapy, particularly the use of immune checkpoint inhibitors, to tilt the pre-existing tumor stromal microenvironment into long-lasting therapy-induced antitumor immunity at multiple metastatic sites (abscopal effects). This multimodal therapeutic strategy can alleviate the increased T cell priming and decrease tumor growth and metastasis, thus emerging as a significant approach to sustain as long-term antitumor immunity. To understand more about this synergism, a detailed cellular mechanism underlying the dynamic interaction between tumor and immune cells within the irradiated tumor microenvironment needs to be explored. Hence, in the present review, we have attempted to evaluate various RT-inducible immune factors, which can be targeted by immunotherapy and provide detailed explanation to optimally maximize their synergy with immunotherapy for long-lasting antitumor immunity. Moreover, we have critically assessed various combinatorial approaches along with their challenges and described strategies to modify them in addition to providing approaches for optimal synergistic effects of the combination.

A case report of the Hoffa fracture and a review of literature.

The Hoffa fracture is an uncommon fracture. There is a lot of confusion about its diagnosis and management with several conflicting reports in literature. We reported a 25-year-old patient with non-union of Hoffa fracture, and meanwhile tried to develop an algorithm-based treatment for Hoffa fractures. A systematic review of the available literature was performed. Medline, Embase, the Cochrane Library and PubMed were searched for relevant articles. Fifty-five articles were reviewed, and the clinical knowledge base was summarized. The understanding of the mechanism of trauma has become more nuanced. The literature has also evolved to classify the fracture with the purpose of surgical management in mind. This can be used to plan approach and fixation with preservation of blood supply. Classification can also prognosticate the outcomes in Hoffa fracture.

Commensal bacteria and fungi differentially regulate tumor responses to radiation therapy.

Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.

Management of Infected Nonunion of the Forearm by the Masquelet Technique.

PURPOSE: Infected nonunion of the forearm bones is a challenge for the orthopedic surgeon on several fronts. The forearm itself is unique as the difficulties include the relation between restoration of shaft length with the anatomy and long-term functional outcome of adjacent joints, and the risk of elbow and wrist stiffness related to prolonged immobilization. The problem of infection is complex due to the presence of bone necrosis, segmental bone loss, sinus tract formation, fracture instability, and scar adhesion of the soft tissues. The ideal management method for these situations is still debated. MATERIALS AND METHODS: We used the two-stage-induced membrane technique devised by Alain Masquelet for the management of these infected nonunion of 12 forearm bones. RESULTS: All 12 bones united uneventfully. The bones united in a period ranging from 6 to 12 months with a mean of 7.8 months. CONCLUSION: Our results show that this technique addresses several of the challenges pertinent to the forearm nonunion simultaneously and results are uniformly predictable. HOW TO CITE THIS ARTICLE: Dhar SA, Dar TA, Mir NA. Management of Infected Nonunion of the Forearm by the Masquelet Technique. Strategies Trauma Limb Reconstr 2019;14(1):1-5.

Outcome of Extra-Articular Distal Humerus Fractures Fixed by Single Column Extra-Articular Distal Humerus Locking Compression Plate Using Triceps Sparing Postero-Lateral Approach.

OBJECTIVE: To determine the time to radiological union and final functional outcome of fixation of extra-articular distal humeral fractures with extra-artricular distal humerus locking plate. METHODS: This prospective study was conducted from March 2014 to February 2018 and included extra-articular distal humeral fractures managed by operative fixation using extra-articular distal humerus locking plate. All the fractures were approached using lateral para-tricepetal approach of Gervin, and stabilized with extra-articular distal humerus locking plate with or without lag screws. Time to radiological union was assessed in the follow up and at the final follow up functional outcome was evaluated using Mayo Performance Elbow Score (MEPS). Complications and need for any additional procedures was also recorded. RESULTS: A total of 20 patients with mean age of 36.5 years and an average follow up of 17 months were included. The mean time to radiological union was 17.4 weeks (12 to 36 weeks) which included one delayed union that required bone grafting. The mean flexion at elbow was 127o with only one patient having flexion extension arc movement of less than 100o at the final follow up. The average MEPS at final follow up was 94.7±8 with 19 patients having excellent and good results. CONCLUSION: Use of extra-articular distal humeral locking plate using lateral para-tricepetal approach in extra-articular distal humeral fractures allows stable fixation of the fracture to allow early return to function with minimal soft tissue dissection and excellent final functional results and minimum complications.

Targeting Innate Immunity to Enhance the Efficacy of Radiation Therapy.

Radiation continues to play a major role in the treatment of almost every cancer type. Traditional radiation studies focused on its ability to damage DNA, but recent evidence has demonstrated that a key mechanism driving the efficacy of radiation in vivo is the immune response triggered in irradiated tissue. Innate immune cells including macrophages, dendritic cells, and natural killer cells are key mediators of the radiation-induced immune response. They regulate the sensing of radiation-mediated damage and subsequent radiation-induced inflammation. Given the importance of innate immune cells as determinants of the post-radiation anti-tumor immune response, much research has been devoted to identify ways to both enhance the innate immune response and prevent their ability to suppress ongoing immune responses. In this review, we will discuss how the innate immune system shapes anti-tumor immunity following radiation and highlight key strategies directed at the innate immune response to enhance the efficacy of radiation.

Antibiotic Impregnated Cement Coated Ilizarov Rod For The Management Of Infected Non Union Of Long Bone.

The infected non union of the long bones in the presence of the intramedullary nail is a dreaded complication of fracture management. Around 7% patients may develop an infected non union of the long bones in intramedullary nailing. Amongst the various grades of infection, grade three infection is the most difficult to cure and manage as it involves an osteomyelitic bone. Amongst an array of therapeutic modalities, the two stage methods are commonly used with the first stage aimed at controlling the infection and the second stage at inducing union. This increases the number of surgical procedures. We used an Ilizarov threaded rod coated with antibiotic impregnated cement to replace the intramedullary nail with the idea of delivering higher concentration of antibiotic locally as well as provide stability. We achieved a union rate of 91% in a relatively small number of patients with this single procedure. The antibiotic impregnated cement coated Ilizarov rod that we used in our study achieves both infection control and union simultaneously and does not allow cement debonding at removal.

Management of humeral fracture nonunion in severe osteoporosis by a combination of locking plating and intramedullary fibular grafting.

Nonunion of the humerus in a severely osteoporotic bone is a likely event especially if the fracture is transverse. The management of such a combination is a challenge. Most of the conventional fixation methods are unlikely to succeed as the bone failure precedes implant failure in osteoporosis. The challenge is further compounded in severe osteoporosis when the cortical thickness is affected more severely. We used a combination of an intramedullary fibula with a locking plate in 5 cases. The results show that it may be a good combination in such situations as the bone strength is augmented and the plate pullout is less likely.

Pattern of rubber bullet injuries in the lower limbs: A report from Kashmir.

PURPOSE: Rubber bullets are considered a non-lethal method of crowd control and are being used over the world. However the literature regarding the pattern and management of these injuries is scarce for the forensic pathologist as well as for the traumatologist. The objective of this report was to add our experience to the existing literature. METHODS: From June 2008 to August 2010 the Government Hospital for Bone and Joint Surgery Barzulla and the Department of Orthopaedics, SKIMS Medical College/Hospital Bemina Srinagar received 28 patients for management of their orthopaedic injuries caused by rubber bullets. We documented all injuries and also recorded the management issues and complications that we encountered. RESULTS: All patients weremales with an age range of 11e32 years and were civilians who had been hit by rubber bullets fired by the police and the paramilitary forces. Among them, 19 patients had injuries of the lower limbs and 9 patients had injuries of the upper limbs. All patients were received within 6 h of being shot. CONCLUSION: Our findings suggest that these weapons are capable of causing significant injuries including fractures and it is important for the surgeon to be well versed with the management of such injuries especially in areas of unrest. The report is also supportive of the opinion that these weapons are lethal and should hence be reclassified.

The Musculoskeletal Manifestations of Type 2 Diabetes Mellitus in a Kashmiri Population.

OBJECTIVES: Diabetes mellitus (DM), is affecting an ever increasing number of people worldwide. Diabetes is associated with several musculoskeletal manifestations. These may involve, the upper as well as the lower limb. We conducted this study to find out the prevalence of musculoskeletal problems in type 2 diabetics in the Kashmiri population. METHODOLOGY: The study was conducted on 403 patients with diabetes and 300 controls. All patients underwent screening for any musculoskeletal abnormalities. The patients with musculoskeletal abnormalities were further assessed to find the exact diagnosis according to predefined criteria. RESULTS: The hand was involved in 80 patients [19.8%] in the diabetic group and 15 (5%) patients of the control group. The elbow was affected in 56 patients [14%] in the diabetic group and 24 patients [5.9%] in the non-diabetic group. The shoulder involvement was diagnosed in 61 patients [15%] on the diabetic cohort and 15 patients in the non-diabetic cohort. All the upper limb figures showed a statistically significant difference i.e. P value <0.05. CONCLUSION: The prevalence of musculoskeletal complications in type 2 diabetics in Kashmir is quite high.

Pattern and epidemiology of pediatric musculoskeletal injuries in Kashmir valley, a retrospective single-center study of 1467 patients.

This work aimed to study the pattern and epidemiology of pediatric musculoskeletal trauma and consequent morbidity in Kashmir Valley and compare the results with other studies and to formulate preventive measures and devise management strategies. This was a retrospective study of 1467 pediatric orthopedic trauma patients who presented to our hospital over a 3-year period between September 2005 and August 2008. Information was recorded in a prescribed proforma including the following: age, sex, mode of trauma, type of fracture/injury, radiological study, final diagnosis, intervention performed, and complications. The information was collected from the Medical Records Department of the hospital. The children's ages ranged from 0 to 16 years; there were 996 males and 471 females, with males outnumbering females in every age group (the overall male-to-female ratio was 2.12:1). Most fractures occurred in children aged 7-12 years [n=816 (53.96%)] and decreased in younger and older children beyond this age group. The left side was involved in 762 cases, 612 injuries involved the right side, 24 were bilateral, and 69 patients presented with multiple injuries. In children aged 0-6 years, the most common site of injury was the elbow, whereas in children aged 7-16 years, it was the forearm. In descending order, most injuries were sustained because of fall while playing (34.76%), fall from height (33.74%), road traffic accidents (14.92%), and fall from standing height (7.97%). The majority of injuries were caused by unintentional trauma (94.48 vs. 5.52%). The places where injury occurred were the home [603 (41.10%)], play field and orchards near the home [450 (30.67%)], roads [219 (14.92%)], school [183 (12.47%)], and unknown [12 (0.81%)]. The pattern and epidemiology of pediatric trauma differs from those in adults. The majority of musculoskeletal injuries are because of unintentional trauma in this young age group and hence preventable. Enhanced supervision at home and school is recommended. A safer environment and better playing conditions may decrease the high frequency of trauma in pediatric patients. Dedicated trauma centers with such facilities as orthopedics, neurosurgery, and plastic surgery need to be established for the proper management of pediatric trauma.

Open management of neglected inferior dislocation of the shoulder with proximal humeral fracture in an adolescent.

Neglected dislocation of the shoulder is a rare condition with some cases of anterior and posterior dislocation being reported. We report a case with a fracture dislocation of the proximal humerus with the dislocated head lying inferior to the glenoid. We also report on the surgical management of a case with this extremely rare condition which required shortening of the distal fragment to reduce tissue tension.

Bilateral simultaneous anterior obturator dislocation of the hip by an unusual mechanism - a case report.

A case of bilateral simultaneous anterior dislocation of the hip in a 30-year-old female is presented herein. The patient was managed conservatively. Follow-up at two years showed excellent results with no signs of avascular necrosis. The cause and mechanism of injury are discussed, which are different from those of previously reported cases.

In the line of duty: a study of ambulance drivers during the 2010 conflict in Kashmir.

PURPOSE: The purpose of this study was to identify the problems faced by ambulance drivers working in a conflict zone. METHODS: This study was conducted on ambulance drivers working for the four major hospitals in Kashmir, India. The drivers were interviewed and asked a series of 30 work-related questions. The individual interviews were conducted over a three-month period in the valley of Kashmir that was affected by continuous violence, strict curfew, and strikes. RESULTS: A total of 35 ambulance drivers were interviewed. Drivers worked an average of 60 h/wk, and they drove an average of 160 km/d. Twenty-nine (83%) of the drivers experienced >1 threat of physical harm; 18 (54%) experienced physical assaults; and 31 (89%) reported evidence of psychological morbidity associated with their jobs. CONCLUSIONS: The atmosphere of conflict on the streets of Kashmir impacted the ambulance drivers adversely, both physically as well as mentally. The stress faced by these professionals in conflict zones during their duty hours should be recognized, and corrective measures must be put in place.

The Gibson and Piggott osteotomy for adult hallux valgus.

BACKGROUND: The Gibson and Piggott procedure for hallux valgus is based on sound surgical principles addressing the basic pathologies of this disorder. However, this procedure has not been studied extensively in the literature in comparison to the Mitchell and Chevron osteotomies. MATERIAL AND METHODS: We report a prospective study conducted on 50 adult feet with hallux valgus. The Gibson and Piggot osteotomy was done on all the feet. RESULTS: We obtained 76% excellent and 18% good results with this procedure. CONCLUSION: The results bear out the fact that this procedure is a useful procedure for the management of this disorder.

Fracture of the humerus caused by a slingshot projectile.

Unconventional and 'non-lethal' weapons are being used in crowd control regularly nowadays. The use of these arms is not risk-free. The paramilitary forces in 2010 used the old fashioned slingshots for crowd control in Kashmir. A young male suffered from a fracture of the distal humerus due to a marble from a slingshot. He was managed by debridement and plaster splintage. Use of apparently innocuous weapons for crowd control is not without risk, as the projectiles fired from them can achieve high velocities and cause significant damage.

Toilet seat injury of the Achilles tendon a series of twelve cases.

Lacerations of the Achilles tendon are caused by a number of mechanisms. The toilet seat as a cause of Achilles tendon injury is rare. We report on this rare mechanism of laceration of the tendo Achilles. The injury can be avoided with the use of western toilets and the additional devascularisation caused by extending the wound should be avoided while repairing the tendon in such situations.