Oral Metronomic Chemotherapy in Advanced and Metastatic Oral Squamous Cell Carcinoma: A Need of the Hour.

Aim: The present review article aims to compile the best available evidence-based data on oral metronomic chemotherapy (OMCT) including its mechanism of action, its utility, and future directions. Methods: A systematic search was carried out in PubMed database for available English literature from last 10 years between 2011 and 2021. Keyword combinations used were 'Oral Metronomic chemotherapy for oral cancer, mechanism of action of OMCT, Oral metronomic chemotherapy in India, OMCT in recurrent and palliative treatment of oral cancers.' Results: Multitudes of studies have been published recently stating the role of OMCT in head and neck squamous cell carcinoma (HNSCC), but the studies with the category of level of evidence required to advocate OMCT as a recognized therapy are still scarce. On careful stratification of these studies, we found that OMCT has a lot to offer in palliative settings, recurrent, and metastatic HNSCC. There is some limited evidence of its role in adjuvant therapy as maintenance and in neoadjuvant setting. Conclusion: With current evidence, there is a definite role of OMCT in treatment of oral SCC. OMCT can be an alternative in patients who are not tolerable or affordable for standard palliative chemotherapy and also an option for patient who are waiting for surgery. However, results of ongoing and future studies on exact mechanism, indications, and implications of this drug regimen would help in integration OMCT in current standard of therapy.

Intraperitoneal Dedifferentiated Liposarcoma: Unveiling a Rare Diagnosis in Peritoneal Fluid Cytology - A Case Report with Literature Review.

INTRODUCTION: Sarcomas presenting as malignant effusions are rare, and diagnosing them on fluid cytology requires expertise and clinicoradiological correlation as cells undergo morphological changes, mimicking carcinoma or mesothelioma. CASE PRESENTATION: We present a case of a 70-year-old man with abdominal distention and pain, initially suggestive of carcinoma on peritoneal fluid cytology. However, subsequent analysis with immunohistochemistry on the cell block revealed diffuse nuclear positivity for MDM2, leading to the diagnosis of dedifferentiated liposarcoma. CONCLUSION: The cytological diagnosis of dedifferentiated liposarcoma is challenging and requires a high index of suspicion, with clinicoradiological correlation. Utilizing immunohistochemistry on cell block samples enhances diagnostic accuracy and guides appropriate patient management.

How to do it: excision of carotid space tumours in proximity to skull base.

This article along with the descriptive video demonstrates the step-by-step surgical approach for excision of tumours located in carotid space in proximity to skull base. We have described the surgical steps without mandibular osteotomy and also demonstrated the technique to safeguard all neuro-vascular anatomy in the vicinity of the carotid space and skull base.

Periarterial and Sub-adventitial Divestment Along with Triangle Operation and RAMPS for Pancreatic Body Cancer.

BACKGROUND: Locally advanced cancers of the pancreatic body can abut or involve the celiac axis, hepatic artery, or superior mesenteric artery. Recent evidence suggests that these tumors are amenable to surgery after neoadjuvant chemotherapy (Hackert et al., Locally advanced pancreatic cancer: neoadjuvant therapy with FOLFIRINOX results in resectability in 60 % of the patients. Ann Surg 264:457-463, 2016; Rangelova et al., Surgery improves survival after neoadjuvant therapy for borderline and locally advanced pancreatic cancer: a single-institution experience. Ann Surg 273:579-86, 2021). An arterial divestment technique can be used for these cancers to get an R0 clearance, thereby avoiding morbid arterial resections (Miao et al., Arterial divestment instead of resection for locally advanced pancreatic cancer (LAPC). Pancreatology 16:S59, 2016; Habib et al., Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: surgical planning with the "halo sign" and "string sign." Surgery 169(5):1026-1031, 2021; Diener et al., Periarterial divestment in pancreatic cancer surgery. Surgery 169(5):1026-31, 2020). Two techniques are described for arterial divestment. In the periarterial divestment technique, the plane of the dissection is between the tumor and the adventitia (Habib et al., Periadventitial dissection of the superior mesenteric artery for locally advanced pancreatic cancer: surgical planning with the "halo sign" and "string sign." Surgery 169(5):1026-1031, 2021; Diener et al., Periarterial divestment in pancreatic cancer surgery. Surgery 169(5):1026-31, 2020). In sub-adventitial dissection, the plane of dissection is between the tunica adventitia and the external elastic lamina (Gao et al., Sub-adventitial divestment technique for resecting artery-involved pancreatic cancer: a retrospective cohort study. Langenbecks Arch Surg 406:691-701, 2021). The TRIANGLE operation also is one of the surgical techniques to achieve R0 resection in locally advanced pancreatic cancer (Hackert et al., The TRIANGLE operation: radical surgery after neoadjuvant treatment for advanced pancreatic cancer: a single-arm observational study. HPB Oxford 19:1001-1007, 2017). This multimedia article aims to demonstrate peri-arterial and sub-adventitial divestment techniques as well as the TRIANGLE operation for a locally advanced cancer of the body of the pancreas. The video also highlights the technique of posterior radical antegrade modular pancreato-splenectomy (RAMPS) together with lymph node clearance. PATIENT AND METHODS: A 57-year-old women was detected to have pancreatic body adenocarcinoma with tumor contact of the artery and superior mesenteric artery. After neoadjuvant chemotherapy, she was planned to undergo surgical resection. RESULTS: The surgical technique consisted of peri-arterial and sub-adventitial divestment, the TRIANGLE operation and RAMPS (Fig. 1). The procedure was performed within 240 min and involved blood loss of 250 mL. After the procedure, pancreatic leak (POPF-B), chyle leak and diarrhea developed, which were managed conservatively. The final histopathology showed residual, viable, moderately differentiated adenocarcinoma (ypT2N1M0) with all resection margins free. CONCLUSION: The surgical technique consisting of peri-arterial and sub-adventitial divestment, the TRIANGLE operation and RAMPS helps in R0 resection of locally advanced pancreatic body cancer without any compromise in oncologic outcomes and offers an alternative surgical approach to morbid arterial resection.

Dynein functions in galectin-3 mediated processes of clathrin-independent endocytosis.

Multiple endocytic processes operate in cells in tandem to uptake multiple cargoes involved in diverse cellular functions, including cell adhesion and migration. The best-studied clathrin-mediated endocytosis (CME) involves the formation of a well-defined cytoplasmic clathrin coat to facilitate cargo uptake. According to the glycolipid-lectin (GL-Lect) hypothesis, galectin-3 (Gal3) binds to glycosylated membrane receptors and glycosphingolipids (GSLs) to drive membrane bending and tubular membrane invaginations that undergo scission to form a morphologically distinct class of uptake structures, termed clathrin-independent carriers (CLICs). Which components from cytoskeletal machinery are involved in the scission of CLICs remains to be explored. In this study, we propose that dynein is recruited onto Gal3-induced tubular endocytic pits and provides the pulling force for friction-driven scission. The uptake of Gal3 and its cargoes (CD98/CD147) is significantly dependent on dynein activity, whereas only transferrin (CME marker) is slightly affected upon dynein inhibition. Our study reveals that Gal3 and Gal3-dependent (CD98 and CD147) clathrin-independent cargoes require dynein for the clathrin-independent endocytosis.

Effect of Single Acupuncture Point (Liver 7) on Pain and Range of Motion on Osteoarthritis of Knee.

Background: : Osteoarthritis of the knee (OAK) is a chronic degenerative musculoskeletal disorder that strongly affects the elderly population and decreases their quality of life. Pain, stiffness, and restricted knee movements are the major characteristic features of OAK. There are no studies available on the effect of the liver 7 (LR 7) acupuncture point on pain and range of motion. Objectives: : To study the effectiveness of the LR 7 acupuncture point on pain and range of motion in chronic OAK patients. Methods: : Thirty-five subjects aged between 40 and 65 years were recruited from Government Yoga and Naturopathy Medical College, Chennai. Participants were included in the study after they fulfilled the eligibility criteria. The duration of acupuncture was 20 minutes (5 days/week) for 2 weeks. Baseline and post-intervention assessments were performed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the degree of knee flexion and extension was measured using a goniometer. Results: : Pre- and post-trial outcomes were compared using paired t-tests. LR 7 acupuncture reduced the WOMAC score from 49 to 30 (p < 0.001), indicating that pain was alleviated. Treatment increased the range of knee flexion from 110 to 115 degrees and reduced knee extension (p < 0.01) from 16 to 9 degrees (p < 0.001). These findings indicate that acupuncture treatment improved the range of knee movement. Conclusion: : The present study showed that 10 sessions of LR 7 acupuncture for people with OAK significantly reduced pain and increased range of motion. We conclude that LR 7 acupuncture is an adjuvant therapy for alleviating pain and managing OAK.

Ipsilateral Cervicodeltopectoral Flap: A Forgotten Technique, Revival in the Era of Microvascular Reconstruction.

Oral cavity cancer is one of the most common cancers in India responsible for significant morbidity and mortality in Indian subcontinent. Majority of cases present in advanced stages which requires extensive reconstruction following tumor resection. Microvascular free flap reconstruction is now considered standard of care for reconstruction for major head and neck skin-mucosal defects but, many factors still act as hindrance like patient's comorbidities, long operating hours for microvascular reconstruction, logistic and financial issues from patient's side. In such situation it is better to have a backup plan for reconstruction of major head and neck defects using pedicled flaps. Pectoralis major myocutaneous (PMMC) flap has been the workhorse flap for head and neck reconstruction since its introduction four decades ago. But relying too much on PMMC flap for major skin-mucosal defects especially in female patients is associated with complications and risk for flap failure leading to catastrophic and significant patient morbidities. Our study involves the use of two flaps for head and neck reconstuction involving skin-mucosal defects i.e PMMC flap for mucosal defect and cervicodeltopectoral (CDP) flap for skin defect. As of now there has been no retrospective or prospective study done which has given a conclusive statement regarding use of these two flaps simultaneously for head and neck reconstruction to the best of our knowledge. In our experience from the present study, CDP flap offers an excellent alternative for extensive head and neck reconstruction and can be readily included in the surgeon's armamentarium with proper planning and meticulous handling.

Increased Gene Expression of C1orf74 Is Associated with Poor Prognosis in Cervical Cancer.

C1orf74, also known as URCL4, has been reported to have higher expression and be associated with poor prognosis in lung adenocarcinoma patients, and its role in regulation of the EGFR/AKT/mTORC1 pathway has been recently elucidated. In the current study, we used publicly available data and experimental validation of C1orf74 gene expression and its association with prognosis in cervical cancer patients. qRT-PCR was performed using RNA from cervical cancer cell lines and twenty-five cervical cancer patients. Data from TNMplot revealed that mRNA expression of the C1orf74 gene in primary tumor tissues, as well as metastatic tissues from cervical cancer patients, was significantly higher compared to normal cervical tissues. HPV-positive tumors had higher expression of this gene compared to HPV-negative tumors. qPCR analysis also demonstrated higher expression of C1orf74 in HPV-positive cervical cancer cell lines and most cervical cancer patients. The promoter methylation levels of the C1orf74 gene in cervical cancer tissues were lower compared to normal cervical tissues (p < 0.05). Collectively, our study indicates that higher expression of the C1orf74 gene caused by hypomethylation of its promoter is associated with poor overall survival in cervical cancer patients. Thus, C1orf74 is a novel prognostic marker in cervical cancer.

Parietal Peritoneum Interposition Tube Graft as an Autologous Substitute for the Reconstruction of Inferior Vena cava Following Resection of Retroperitoneal Sarcoma.

Complete resection of large retroperitoneal tumors often requires vascular resection and reconstruction, which is frequently performed using prosthetic grafts. We report our experience with inferior vena cava reconstruction utilizing a large peritoneal interposition tube graft performed during en bloc resection of retroperitoneal sarcoma and multiorgan resection. This study aimed to increase the awareness of surgical oncologists about the venous reconstruction technique using a large autologous peritoneal graft. An elderly male presented to our cancer center with a history of persistent abdominal pain. The computed tomography (CT) scan reported a large retroperitoneal mass involving the right kidney and the inferior vena cava (IVC). En bloc tumor resection with right nephrectomy and resection of the IVC extending from just above the bifurcation up to the origin of the renal veins was done. IVC reconstruction was performed using autologous parietal peritoneum tube graft. Harvesting the peritoneum and fashioning a large peritoneal tube graft was challenging. Post-operatively, the patient recovered without any complications and was discharged on oral anticoagulants. The CT scan during the follow-up visit at 6 months revealed that the IVC graft was patent with a good flow. Autologous peritoneal grafts are a safe, valid, and readily available option for venous reconstruction.

How to do it: popliteal lymph node dissection.

Popliteal lymph node metastasis is not very frequent. However, in case of lymph node metastasis in the popliteal fossa, template lymph node dissection needs to be performed. In view of the rarity of this procedure, we aim to describe the stepwise technique of popliteal lymph node dissection.

Recurrent Giant Myofibroblastic Sarcoma of Neck in a Teenager: Overcoming Treatment Challenges.

Sarcomas are rare tumors arising from a variety of mesenchymal tissues which are even rarer in head and neck region amounting 1% only of the 5% of sarcomas. About 80% of head and neck sarcomas originate in soft tissue while the remaining 20% arise from bone (Cormier and Pollock in J Clin 54:94-109, 2004). One among the commonly presenting variants of sarcomas in head and neck that our patient was diagnosed with is Low grade myofibroblastic sarcoma (LGMS). These even though uncommon have a predilection for head and neck region particularly the tongue (Mentzel et al. in Am J Surg Pathol 22:1228-38, 1998; Cai et al. in Virchows Arch 463:827-36, 2013; Meng et al. in Chin Med J 120:363-9, 2007; Demarosi et al. in Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 108:248-54, 2009). LGMS was reclassified as a distinct entity by the WHO classification of soft tissue tumors in 2002 (Qiu et al. in Oncol Lett 9:619-25, 2015). Oncological resection is the mainstay of treatment. In case of bulky tumor, resection and reconstruction would be challenging. We report a recurrent LGMS of 15-year-old girl who presented with a ginormous soft tissue swelling in her left neck region which made her day-to-day activities strenuous and made her non ambulatory and the line of treatment executed in order to get her back on feet, healthy & free of the debilitating tumor.

To CT or not to CT: Questioning the Cost-Effectiveness of CT Thorax in Head and Neck Cancers.

Computed tomography (CT) scan has been an integral part of the diagnostic workup for patients with head and neck squamous cell carcinoma. Our study was designed to find out the incidence of distant metastasis and second primary tumor and to correlate the cost-effectiveness of CT thorax in detecting the same. This study was conducted among 326 cancer patients who visited our center with curative intent in the year 2021, with lesions in various head and neck subsites. Data were collected based on their pathological TNM staging and the presence of distant metastasis as evident on their CT thorax imaging with various variables related to the disease. Incremental cost-effectiveness ratio (ICER) was calculated for detecting a single metastatic deposit and second primary tumor in terms of Indian currency and was correlated to each subsite and stage of disease at presentation. Out of these 326 patients, 281 patients were included in our study after considering the inclusion criteria, and among these 281 patients, 235 of them underwent CT thorax for metastatic workup. No patient was found to have a second primary. Metastases were found in 12 patients. The site of primary lesion and clinical tumor (cT) staging were found to be significantly influencing the incidence of metastasis on CT thorax. ICER was least for larynx, pharynx, and paranasal sinuses and was highest for oral cavity primaries and early-stage disease. As per our observations and results of ICER, CT thorax is indeed a valuable modality but should be used judiciously when it comes to initial diagnostic workup.

Cationic lipid modification of DNA tetrahedral nanocages enhances their cellular uptake.

Self-assembled DNA nanocages are among the most promising candidates for bioimaging and payload delivery into cells. DNA nanocages have great potential to efficiently address drug resistance and nucleic acid delivery problems due to precise control of their shape and size, and excellent biocompatibility. Although DNA nanostructures demonstrate some cellular uptake, because they bear a highly negative charge, the uptake of tetrahedral nanostructures is hindered by electrostatic repulsion. In this study, we describe a method to enhance the cellular uptake of DNA nanostructures using a binary system containing DNA and a positively charged head group with a hydrophobic lipid chain containing lipids for cellular internalization. Here we represent the functionalization of a model cage, DNA tetrahedron (TD) with a cationic lipid, N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA). Atomic force microscopy (AFM) and other standard characterization techniques were used to explore the co-assembly of the DNA tetrahedron and DOTMA. We revealed a simple confocal microscopy-based approach to show the enhancement in the cellular uptake of DNA nanocages. This new method will find multiple applications in delivery applications such as gene transfection, drug delivery and targeted bioimaging.

A Mechanistic Review of Methotrexate and Celecoxib as a Potential Metronomic Chemotherapy for Oral Squamous Cell Carcinoma.

The combination of low-dose methotrexate and celecoxib as metronomic chemotherapy (MCT) is a novel therapy, believed to act by modulating the immune response, inhibiting angiogenesis and its cytotoxic action, though the exact mechanism of action is unclear. Clinically, MCT was found to be very effective in delaying tumor progression in patients with head and neck squamous cell carcinoma in both curative and palliative settings. This review was aimed to give a brief insight into the mechanism of action and potential molecular alterations of MCT in the treatment of oral cancers taking into consideration the various in vivo and in vitro studies.

Identification of HOX signatures contributing to oral cancer phenotype.

The role of evolutionarily conserved homeobox-containing HOX genes as transcriptional regulators in the developmental specification of organisms is well known. The contribution of HOX genes involvement in oral cancer phenotype has yet to be fully ascertained. TCGA-HNSC HTSeq-counts and clinical data were retrieved from the GDC portal for oral cavity neoplasms. GEO datasets (GSE72627, GSE30784, GSE37991) were accessed and analyzed using GEO2R. Differential HOX gene expression was profiled using the DESeq2 R package with a log2 fold change cut-off (- 1 and + 1) and Benjamini-Hochberg p-adjusted value at ≤ 0.01. Gene set over-representation analysis and semantic analysis associated with the disease ontology was performed using the ClusterProfiler R package, and pathway over-representation analysis was performed using IMPaLa. HOX protein interaction network was constructed using the Pathfind R package. HOX phenotype associations were performed using Mammalian Phenotype Ontology, Human Phenotype Ontology, PhenGenI associations, Jensen tissues, and OMIM entries. Drug connectivity mapping was carried out with Dr. Insight R package. HOXA2 was upregulated in oral dysplasia but silenced during tumor progression. Loss of HOXB2 expression was consistent in the potentially malignant oral lesions as well as in the primary tumor. HOXA7, HOXA10, HOXB7, HOXC6, HOXC10, HOXD10, and HOXD11 were consistently upregulated from premalignancy to malignancy and were notably associated with risk factors. Overrepresentation analysis suggested HOXA10 was involved in the transcriptional misregulation contributing to the oral cancer phenotype. HOX genes subnetwork analysis showed crucial interactions with cell cycle regulators, growth responsive elements, and proto-oncogenes. Phenotype associations specific to the oral region involving HOX genes provide intrinsic cues to tumor development. The 5' HOX genes were aberrantly upregulated during oral carcinogenesis reflecting their posterior prevalence.

The roles of dynein and myosin VI motor proteins in endocytosis.

Endocytosis is indispensable for multiple cellular processes, including signalling, cell adhesion, migration, as well as the turnover of plasma membrane lipids and proteins. The dynamic interplay and regulation of different endocytic entry routes requires multiple cytoskeletal elements, especially motor proteins that bind to membranes and transport vesicles along the actin and microtubule cytoskeletons. Dynein and kinesin motor proteins transport vesicles along microtubules, whereas myosins drive vesicles along actin filaments. Here, we present a brief overview of multiple endocytic pathways and our current understanding of the involvement of these motor proteins in the regulation of the different cellular entry routes. We particularly focus on structural and mechanistic details of the retrograde motor proteins dynein and myosin VI (also known as MYO6), along with their adaptors, which have important roles in the early events of endocytosis. We conclude by highlighting the key challenges in elucidating the involvement of motor proteins in endocytosis and intracellular membrane trafficking.