PD1 ligand functionality a biomarker of response to anti PD1 treatment in patients with HNSCC.

Therapies targeting the PD-1/PD-L1 pathway have transformed head and neck squamous cell carcinoma (HNSCC) treatment. However, predicting the response to anti-PD-1 therapy remains a clinical challenge. This study evaluated the functional binding of PD-1 ligands in 29 HNSCC patients and compared it to the standard PD-L1 Combined Positive Score (CPS). The assessment of PD-1 ligands' functionality advances the current ability to predict the response of HNSCC patients to anti-PD-1 therapy.

Rectal adenocarcinoma in the eye: An unexpected destination.

Colorectal cancer ranks third in cancer incidence in the United States, commonly metastasizing to the liver and lungs. Despite its high prevalence, colorectal cancer with intraocular metastasis is exceedingly rare, with only a few cases reported in the literature. This study presents a 58-year-old male, previously treated for rectal adenocarcinoma with liver and lung metastases, who developed choroidal metastasis causing visual impairment. Despite radiotherapy, moderate improvement was observed, and subsequent disease progression led to systemic chemotherapy. Intraocular metastasis, primarily affecting the choroid, is infrequent, often originating from breast and lung cancers. The presented case, originating from primary KRAS wild-type rectal cancer, adds to the limited gastrointestinal-tract-related occurrences. This report underscores the importance of recognizing intraocular metastasis in colorectal cancer, contributing valuable insights for improved understanding and potential guidance for future clinical decisions. Choroidal metastasis carries a poor prognosis, emphasizing the need for tailored management strategies.

Oncological outcomes and failure patterns of laser cordectomy in recurrent glottic cancer.

PURPOSE: Laser cordectomy is a widely accepted treatment modality for selected cases of early glottic cancers, but its role as a salvage treatment remains unclear. We aimed to investigate the oncological outcomes and failure patterns of salvage cordectomy. MATERIALS AND METHODS: This was a retrospective cohort study of patients who underwent cordectomy for early glottic cancer between 2013 and 2022 at a tertiary referral center. The main outcome measures were overall survival, larynx-preservation rate, tracheostomy dependency rate, and disease-free survival. RESULTS: A total of 142 patients (mean age: 63 years, interquartile range [IQR]: 45-72, 123[86.9 %] males) were analyzed. There were 38 (26.8 %) recurrences after a mean of 22 months (IQR: 17-26). Among them, 25 (17.6 %) underwent salvage cordectomy, while 13 (9.1 %) received other salvage treatments (11[7.7 %] (chemo)radiotherapy and 2[1.4 %] total laryngectomy). In comparison to the other salvage treatments, salvage cordectomy demonstrated lower tracheostomy rates (0 vs. 31 %, p = 0.05), comparable 5-year disease-free survival (62 % vs. 54 %, p = 0.4), higher 5-year larynx preservation rate (92 % vs. 54 %, p = 0.02), and improved 5-year overall survival rate (84 % vs. 62 %, p = 0.01). Factors associated with salvage cordectomy failure were age >60 years (odds ratio [OR]: 1.3, 95 % confidence interval [CI]: 1.15-1.53), smoking continuation (OR: 3.73, 95 % CI: 3.5-4.4), heavy smoking (OR: 1.24, 95 % CI:1.07-2.15), and pT1b + (OR: 2.26, 95 % CI: 2.1-2.9). CONCLUSIONS: Salvage cordectomy offers favorable larynx preservation rates and oncological outcomes for recurrent disease amenable to conservative surgery. Smoking, advanced age, and advanced tumor stages are associated with salvage cordectomy failure.

Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629.

INTRODUCTION: At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48 weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented. METHODS: Patients received pembrolizumab 200 mg every 3 weeks for ≤ 2 years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively. RESULTS: At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (-0.27 points [95% confidence interval (CI) -10.93 to 10.39]), physical functioning (-1.29 points [95% CI -8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI -7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. CONCLUSIONS: Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03284424-September 15, 2017.

A late presentation of inguinoscrotal cutaneous squamous cell carcinoma (cSCC) masquerading as hidradenitis suppurativa-a case report.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that affects apocrine gland-bearing skin in intertriginous areas; it is characterized by persistent or recurrent abscesses that culminate in a purulent discharge, sinuses and scarring. Although it is a common condition, it is rarely associated with cutaneous squamous cell carcinoma (cSCC). Whereas the female-to-male ratio of HS is 3:1, SCC in HS has a female-to-male ratio of 1:5. In this study, we present a 50-year-old male patient with a late presentation of inguinoscrotal cSCC with extensive ulceration and erythema that was hidden by neglected HS and the presence of underlying human papillomavirus in the affected area. The histomorphologic and immunohistochemical findings support the diagnosis of cSCC. Timely detection is the key to improve prognosis, regular clinical examination and biopsy of any suspicious lesions in high-risk patients is highly recommended.

The Clinical Characteristics and Outcomes of Human Papillomavirus-Positive Nasopharyngeal Carcinoma in a Single-Institution Cohort.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a head and neck cancer more frequent among East Asian populations compared with Western populations. While much is known about human papillomavirus's (HPV's) role in oropharyngeal cancer (OPC), little is known about its prevalence and prognostic value in NPC. The aim of this study is to investigate the role of HPV in NPC treated with definitive radiotherapy at a single institution. METHODS: A retrospective cohort analysis of patient's medical records and HPV status treated for NPC in Rambam Health Care Campus (Rambam HCC). Immunohistochemical staining for p16 was used as a surrogate marker of HPV infection in the tumor cells. All specimens were stained and evaluated by pathologists at the referring center independently. RESULTS: In total, 87 patients diagnosed with NPC were treated at Rambam HCC between 2005 and 2018. Seventy-four patients had accessible data on the disease's clinical parameters and p16 status. In total, 10/74 (13.5%) had p16-positive staining in tumor cells; 75% were men and over 50% were smokers. The average age of diagnosis for the whole cohort was 48 years, being lower for p16-positive patients compared with p16-negative patients at 43 and 49 years old, respectively. A total of 84% of the patients had advanced disease of stage III and IV at presentation. Only 16% were diagnosed with stage I and II. Unlike the p16-negative group, the p16-positive group did not include any stage I or II disease. In univariate and multivariate analysis of overall survival rates, the age at diagnosis and the nodal spread status were the only statistically significant measures. P16 status was not found to be associated with survival. CONCLUSIONS: The HPV prevalence in NPC is nontrivial. p16-positive patients had significantly less nodal spread and tended to be younger. Both age and nodal status were significantly correlated with the survival, but P16 status was not prognostic. Further large-scale trials are needed to elucidate the role of HPV in NPC.

Primary Tumor Staging for Oral Cancer and a Proposed Modification Incorporating Perineural Invasion: An International Multicenter Study.

The objective of this study is to determine if the incorporation of perineural invasion (PNI) into the T-classification would improve the prognostic performance of TNM-8. An international, multicenter study of 1049 patients with oral cavity squamous cell carcinoma that were treated from 1994 to 2018 is performed. Various classification models are developed within each T-category and evaluated using the Harrel-concordance index (C-index), Akaike-information criterion (AIC), and visual inspection. Stratification into distinct prognostic categories, with internal validation, is performed using bootstrapping analysis (SPSS and R-software). Through multivariate analysis, PNI is significantly associated with disease-specific survival (p < 0.001). PNI integration into the staging system results in a significantly improved model compared with the current T category alone (lower AIC, p < 0.001). The PNI-integrated model is superior in predicting differential outcomes between T3 and T4 patients. A new model for T-classification of oral cavity squamous cell carcinoma is proposed, which is based on incorporating PNI into the staging system. These data can be used for future evaluations of the TNM staging system.

Can lymphocytes serve as a predictor of response to preoperative chemoradiation therapy for locally advanced rectal cancer?

Introduction: The aim of this study is to identify factors that may predict the response of locally advanced rectal cancer tumors (LARC) to neoadjuvant chemoradiotherapy (CRT) and to evaluate the effect of circulating lymphocytes on pathological tumor response. Methods: This retrospective study included neoadjuvant CRT-treated, LARC-diagnosed patients at the Rambam Health Care Campus in Haifa, Israel. CHAID analysis, t-test, χ2 test, and ROC curve analyses were performed to explore the association between pathological complete response (pCR) and several factors including patient demographics, tumor characteristics, type of treatment, and levels of circulating lymphocytes measured on a weekly basis. Results: Out of 198 patients enrolled in the study, pCR was achieved in 50 patients (25%). ROC curve and CHAID analyses showed that absolute lymphopenia was significantly associated with lower pCR rates (p=0.046 and p=0.001, respectively). Other factors that were found to have a significant impact were radiation therapy type (p=0.033) and tumor distance from the anal verge (p= 0.041). Conclusion: An absolute decrease in the level of circulating lymphocytes during preoperative CRT to LARC is associated with poorer tumor response to treatment and thus may serve as a predictive biomarker for treatment resistance.

First-line programmed death-1 inhibitor treatment for locoregionally advanced or metastatic cutaneous squamous cell carcinoma - A real-world experience from Israel.

Objective: Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer worldwide. It is usually treated surgically, with very high cure rates. However, in 3%-7% of cases, cSCC metastasizes to lymph nodes or distant organs. Many of the affected patients are elderly with comorbidities who are not candidates for standard-of-care curative-intent treatment with surgery and/or radio-/chemotherapy. Immune checkpoint inhibitors, which target programmed cell death protein 1 (PD-1) pathways, have recently emerged as a potent therapeutic option. The present report presents the Israeli experience with PD-1 inhibitors for the treatment of loco-regionally advanced or metastatic cSCC in a diverse and elderly population, with or without the addition of radiotherapy. Material and methods: The databases of two university medical centers were retrospectively searched for patients with cSCC treated with the PD-1 inhibitors cemiplimab or pembrolizumab between January 2019 and May 2022. Data on baseline, disease-related, treatment-related, and outcome parameters were collected and analyzed. Results: The cohort included 102 patients of a median age 78.5 years. Evaluable response data were available for 93. The overall response rate was 80.6%: complete response in 42 patients (45.2%) and partial response in 33 (35.5%). Stable disease was recorded in 7 (7.5%) and progressive disease in 11 (11.8%). Median progression-free survival was 29.5 months. Radiotherapy was administered to the target lesion during PD-1 treatment in 22.5% of patients. mPFS was not significantly different in patients who treated with RT than patients how did not (NR vs 18.4 months, HR=0.93, 95%CI: 0.39 - 2.17, p<0.859). Any-grade toxicity was recorded in 57 patients (55%), including grade _3 in 25, of whom 5 (5% of cohort) died. Compared to toxicity-free patients, patients with drug toxicity had better progression-free survival (18.4 months vs not reached, HR=0.33, 95% CI: 0.13-0.82, p=0.012) and higher overall response rate (87% vs 71.8%, p=0.06). Conclusion: This retrospective real-world study showed that PD-1 inhibitors were effective in the treatment of locally advanced or metastatic cSCC and appeared to be amenable for use in elderly or fragile patients with comorbidities. However, the high toxicity warrants consideration against other modalities. Induction or consolidation radiotherapy may improve the results. These findings need to be corroborated in a prospective trial.

Case series report: radiation-induced oropharyngeal carcinoma.

The incidence of radiation-induced secondary primary tumors (SPTs) is estimated to be between 1 and 20%. The oropharynx is not a common site for postradiotherapy head and neck SPTs. We describe the cases of eight patients, each with an SPT of the oropharynx. These developed after a long median latency of 17.7 years with each receiving two-dimensional radiation therapy and delivery of at least 5000 cGy per pharynx, except for one who was treated with IMRT. Tumor histological commonalities revealed squamous cell carcinoma p16 negative staining, local invasion, and limited lymphatic spread, with posterior wall of the oropharynx and the base of the tongue being the most common locations. Limited and challenging treatment options have been reported such as surgery, reirradiation, or clinical trials. Radiation-induced SP oropharyngeal carcinoma has unique clinical and pathological features. Patients with this disease have limited treatment options, which should be discussed in a multidisciplinary tumor board meeting. For this population, lifelong follow-up may help in early diagnosis and improve outcomes.

The evolving treatment paradigm of locally advanced rectal cancer: a narrative review.

Background and Objective: Surgery is still considered the mainstay of treatment of locally advanced rectal cancer (LARC). Nevertheless, "curable" disease may still pose a great risk for both local and distant relapses. Since the early eighties of the past century, we have witnessed mounting evidence supporting the multi-modality approach to tackle this disease effectively. The multi-modality approach is variable between different positive trials. In this review, we discuss the treatment evolution of LARC, highlighting the key differences between the different contemporary strategies utilized. Based on current evidence, we sought to define distinct patient subgroups and to propose a treatment algorithm that best fits patient's risk. Methods: We conducted a literature search through PubMed and Google scholar. Eligible papers were phase 2/3 trials [in organ preservation (OP), observational and retrospective studies were also acceptable] published in English. We used keywords such as "locally advanced rectal cancer", "perioperative therapy in rectal cancer", "short course radiotherapy", "chemoradiation in rectal cancer", "interval to surgery", "Neoadjuvant therapy", "Organ preservation" and "Total neoadjuvant treatment [TNT]". Key Content and Findings: Various trials consistently demonstrated the benefit of preoperative radiotherapy in LARC, the role of adjuvant chemotherapy is controversial based on published studies, TNT was associated with a risk reduction in distant metastasis, and more reassuring evidence is accumulating regarding OP. Conclusions: The treatment landscape of LARC is rapidly changing. Clinicians should carefully tailor treatment strategy based on patient's risk.

Insight into Extracellular Vesicle-Cell Communication: From Cell Recognition to Intracellular Fate.

Extracellular vesicles (EVs) are heterogamous lipid bilayer-enclosed membranous structures secreted by cells. They are comprised of apoptotic bodies, microvesicles, and exosomes, and carry a range of nucleic acids and proteins that are necessary for cell-to-cell communication via interaction on the cells surface. They initiate intracellular signaling pathways or the transference of cargo molecules, which elicit pleiotropic responses in recipient cells in physiological processes, as well as pathological processes, such as cancer. It is therefore important to understand the molecular means by which EVs are taken up into cells. Accordingly, this review summarizes the underlying mechanisms involved in EV targeting and uptake. The primary method of entry by EVs appears to be endocytosis, where clathrin-mediated, caveolae-dependent, macropinocytotic, phagocytotic, and lipid raft-mediated uptake have been variously described as being prevalent. EV uptake mechanisms may depend on proteins and lipids found on the surfaces of both vesicles and target cells. As EVs have been shown to contribute to cancer growth and progression, further exploration and targeting of the gateways utilized by EVs to internalize into tumor cells may assist in the prevention or deceleration of cancer pathogenesis.

Tyrosine kinase inhibitor treatment and long-term follow-up for metastatic malignant struma ovarii.

Metastatic malignant struma ovarii (MMSO) is a very rare disease (in the United States, less than one case in 10 million females annually). However, this incidence rate is due to a paucity of data regarding diagnosis, treatment, and follow-up. Herein, we describe the case of a 14-year-old female who presented with MMSO, which later metastasized and was followed up on for over 10 years. The patient underwent right oophorectomy surgery and was then treated with a combination of radioactive iodine followed by iodine scans to detect the absorption of radioiodine in the metastatic sites, and radiation therapy to treat skeletal lesions. She subsequently received treatment with the tyrosine kinase inhibitors (TKIs), sorafenib and then lenvatinib, as treatments for advanced disease, thereby achieving long-term disease stability. This case report, which adds to the limited data available on MMSO treatment, suggests that patients treated with a combination of radioactive iodine, radiation therapy, and TKIs can result in good responses and long-term overall survival.

Merkel cell carcinoma in lymph nodes with and without primary origin.

The prognosis of MCC with lymph node involvement was better in patients with an unknown than a known primary. Treatment with a uniform aggressive combined chemoradiation regimen, with or without lymphadenectomy, led to better survival rates than previously reported.

Case report: ado-trastuzumab as second-line treatment in HER2 positive salivary duct carcinoma.

The objective of this report is to present the use and efficacy of ado-trastuzumab as an advanced line of therapy in salivary duct carcinoma (SDC) patient. An 84-year-old gentleman diagnosed with metastatic salivary duct tumor harboring overexpressed human epidermal growth factor receptor-2 has gone through resection surgery. The first line of treatment included initial doublet chemotherapy combined with trastuzumab, which was continued later as maintenance. PET-CT follow-up for 4 years has demonstrated no evidence of disease. However, upon recurrence, use of Ado-trastuzumab emtansine was prompted as second-line of treatment. This targeted patient-tailored therapy has accomplished a complete response. The effectiveness of ado-trastuzumab emtansine was notable within a short time period of two treatment cycles leading to full recovery. Specific agents aimed at altered oncogenes should be considered as a potential drug of choice in neoadjuvant HER2 positive SDC.

Next-generation sequencing in thyroid cancers: do targetable alterations lead to a therapeutic advantage?: A multicenter experience.

ABSTRACT: Radioiodine-refractory thyroid cancers (IRTCs) are uncommon and have a poor prognosis. Treatment options for radioiodine-refractory and anaplastic tumors (ATCs) are limited. Although the genomic landscape of thyroid cancer has been studied, there is little evidence on whether next-generation sequencing (NGS) findings translate to tumor control.We analyzed all patients with IRTC and ATC who underwent commercially available NGS in 3 cancer centers.Twenty-two patients were identified, 16 patients with IRTCs and 6 patients with ATCs. Eighteen (82%) had targetable findings in NGS, nine patients were treated accordingly. Median progression-free survival for targeted treatment was 50 months [95% confidence interval (CI95%) 9.8-66.6] and2 months (CI95% 0.2-16.5) for IRTC and ATC, respectively. Of 4 patients who achieved durable responses of 7 to 50 months, 2 are ongoing. The estimated median OS of IRTC receiving targeted treatment was not reached (CI95% 89.7-111.4 months) and was 77.8 months (CI95% 52.5-114.6) for patients treated conventionally (P = .3).NGS may detect clinically significant genetic alterations and benefit patients with advanced thyroid cancers.

Treatment after progression in the era of immunotherapy.

Immunotherapy represents a paradigm shift in oncology treatment. The goal of immunotherapy is to overcome immunosuppression induced by a tumour and its microenvironment, thereby allowing the immune system to target and kill cancer cells. The immunotherapy era began when the first immune checkpoint inhibitor, ipilimumab, was approved for use almost a decade ago. This therapeutic approach is associated with distinct types of response, including processes such as pseudoprogression (ie, increased tumour burden via radiology, which is not accompanied by clinical deterioration) and hyperprogression (ie, rapid progression of the disease as a result of immunotherapy). In this Review, we focus on therapeutic approaches for patients who progress on immunotherapy. We review the different types of clinical responses associated with immunotherapy and describe treatment options for this population.