Mid-term oncologic outcomes of radical prostatectomy in lymph node metastatic prostate cancer patients.

OBJECTIVES: Lymph node invasion (LNI) has been reported in 10-15% of pelvic lymph node dissection during radical prostatectomy (RP). The objective of this study was to describe the mid-term oncological outcomes in prostate cancer (PCa) patients with metastatic lymph node. METHODS: We conducted a retrospective study at two French referral centers including consecutive cN0 PCa patients who underwent RP and extended pelvic lymph node dissection and had lymph node metastases on final pathological analysis (pN1) between January 2000 and May 2020. Follow-up was per institution, which generally included a PSA level measurement every 3 to 12 months for 5 years and annually thereafter. RESULTS: A total of 123 patients were included: two (1.6%) low-risk, 64 (52%) intermediate-risk and 57 (46.4%) high-risk PCa according to the D'Amico risk classification. The median number of nodes removed and metastatic nodes per patient was 15 (IQR 11-22) and 1 (IQR 1-2), respectively. Adverse pathological features, i.e., ≥pT3a stage, ISUP grade ≥3, and positive surgical margins were reported in 113 (91.9%), 103 (83.7%), and 73 (59%) of cases, respectively. Postoperative treatment was administered in 104 patients, including radiotherapy alone (n=6), androgen deprivation therapy alone (n=27) or combination with androgen deprivation therapy and radiotherapy (n=71). The mean follow-up was 42.7 months. The estimated 3-year biochemical-free survival, clinical recurrence-free survival, and cancer-specific survival was 66% and 85% and 98.8%, respectively. In Cox regression analysis, the number of metastatic nodes was associated with clinical recurrence (P=0.04) and a persistently elevated PSA with biochemical recurrence (P<0.001). CONCLUSION: The management of lymph node metastatic PCa patients is challenging. Risk stratification of node-positive patients, based on postoperative PSA levels and pathologic features being identified, should help physicians determine which patient would best benefit from multimodal treatment.

Comparison of Lobectomy vs Total Thyroidectomy for Intermediate-Risk Papillary Thyroid Carcinoma With Lymph Node Metastasis.

Importance: Surgical treatment of patients with papillary thyroid cancer (PTC) by either lobectomy or total thyroidectomy (TT) has long been a topic of debate, especially for patients with intermediate-risk PTC. Objective: To compare recurrence-free survival (RFS) for patients with PTC and lymph node metastasis after lobectomy vs TT. Design, Setting, and Participants: This retrospective cohort study included a review of patients with PTC treated from January 1, 2000, to December 31, 2017. Propensity score matching (PSM) was performed between patients treated with lobectomy and TT. This study involved a single institute in a cancer referral center. Enrolled were adult patients (aged 18-75 years) with unilateral PTC and ipsilateral clinical lateral neck metastasis (cN1b). Patients with the following characteristics were excluded: a lymph node yield less than 20, primary tumor size greater than 4 cm, gross extrathyroidal extension, metastatic lymph node size greater than 3 cm, and distant metastasis. Data analysis was performed from April 1 to April 30, 2022. Exposures: Lobectomy and TT. Main Outcomes and Measures: The primary outcome was the association between extent of surgery and RFS, assessed using Cox proportional hazards regression models. Results: A total of 946 patients with PTC (mean [SD] age, 37.0 [12.1] years, 630 female individuals [66.6%]) were analyzed. Lobectomy (624 [66.0%]) was negatively correlated with the frequencies of older age (≥65 years, 17 [2.7%]), female sex (393 [63.0%]), multifocality (132 [21.2%]), minor extrathyroidal extension (259 [41.5%]), number of metastatic lymph nodes (median [range], 9 [6-14] nodes), and radioactive iodine ablation (0). After PSM with treatment period and potential prognostic factors (age, sex, primary tumor size, multifocality, minor extrathyroidal extension, number of lymph node metastases and lymph node ratio), 265 pairs of patients were available for analysis. After a median (range) follow-up of 60 (9-150) months in the lobectomy group and 58 (8-161) months in the TT group, 21 (7.9%) and 17 (6.4%) structural recurrences were identified in the lobectomy and TT groups, respectively. Lobectomy was not associated with significantly compromised 5-year RFS rate (lobectomy, 92.3% vs TT, 93.7%; adjusted hazard ratio, 1.10; 95% CI, 0.58-2.11; P = .77). Power analysis indicated that the test had 90% power to detect a more than 4.9% RFS difference. No significant difference in RFS was observed between patients treated with TT and radioactive iodine ablation (n = 75) and their counterparts (adjusted hazard ratio, 0.59; 95% CI, 0.14-2.41; P = .46). Conclusions and Relevance: Results of this cohort study suggest that patients with PTC and lymph node metastasis had a similar RFS after lobectomy vs those who had TT. If radioactive iodine ablation is not going to be performed, lobectomy may be an effective alternative option.

Comparative Study of Initial Post-Therapeutic 131I Single-Photon Emission Computed Tomography/Computed Tomography and Reoperation for the Detection of Residual Lymph Node Metastasis in Patients With Papillary Thyroid Cancer.

OBJECTIVE: To assess the diagnostic performance of initial post-therapeutic 131I single-photon emission computed tomography/computed tomography (SPECT/CT) compared with that of reoperation in detecting residual lymph node metastasis (LNM). METHODS: Patients with iodine-avid LNM detected on the initial post-therapeutic 131I SPECT/CT and who underwent reoperative dissection within 6 months were included. LNMs (numbers and locations) detected via both methods were compared. The American Thyroid Association dynamic risk stratification was performed for patients receiving second radioactive iodine therapy after reoperation. RESULTS: Fifty-three patients with 95 iodine-avid LNMs detected by 131I SPECT/CT were enrolled. Fifty-one (96.2%) patients had 212 LNMs confirmed by reoperation (P = .004). The sensitivity and specificity of 131I SPECT/CT in detecting LNM were 44.8% (95/212) and 91.6% (87/95), respectively. The location frequency of residual LNMs found by 131I SPECT/CT was similar to that of reoperation (P = .057). Thirty-two patients received a second radioactive iodine treatment, and 6 (18.8%) patients still had residual iodine-avid LNM on SPECT/CT. Therapeutic response was evaluated by American Thyroid Association dynamic risk stratification in 16 patients. The number of patients with structural incomplete response, biochemical incomplete response, indeterminate response, and excellent response was 4 (23.5%), 4 (23.5%), 5 (29.4%), and 3 (17.6%), respectively. CONCLUSION: 131I SPECT/CT has high specificity but relatively low sensitivity in detecting all residual LNMs. Approximately 80% of patients were rendered structurally disease free after reoperation.

[A Case of Metastatic Urothelial Carcinoma with Pseudoprogression of Liver Metastasis during the Treatment with Pembrolizumab].

A 75-year-old woman with a complaint of gross hematuria was referred to our hospital. The patient was diagnosed as having bladder cancer (cT3bN1M0) and received two cycles of chemotherapy with gemcitabine and cisplatin. Radical cystectomy with pelvic lymph node dissection and bilateral ureterostomy was performed after achieving partial response in a lymph node metastasis following chemotherapy. Based on the pathological diagnosis of high-grade (G3) urothelial carcinoma (ypT3aN2), two more cycles of adjuvant chemotherapy with gemcitabine and cisplatin were administered. Four months after completing adjuvant chemotherapy, pulmonary and hepatic metastases appeared, and treatment with pembrolizumab was initiated. The size of the lung metastasis decreased, while that of the liver metastasis increased 2 months after administering pembrolizumab. However, considering treatment beyond progression using checkpoint inhibitors, pembrolizumab was continued, resulting in marked tumor shrinkage of the liver metastasis. After that, pembrolizumab treatment was temporarily discontinued, and radiation therapy was administered for a new lymph node metastasis at the tracheal bifurcation. Eventually, the lymph node metastasis shrank, and the treatment with pembrolizumab was recommenced for 1 year and the metastases remained shrumken.

Surgery and Radioactive Iodine Therapeutic Strategy for Patients Greater Than 60 Years of Age with Differentiated Thyroid Cancer.

PURPOSE: The purpose of the current study was to determine whether older patients with differentiated thyroid cancer (DTC) who received surgical treatment had a better cause-specific survival (CSS) than patients who were recommended surgery, but declined, and whether patients who underwent postoperative RAI-131 therapy had an impact on CSS based on TNM staging and number of lymph node metastases for all total or near-total thyroidectomy patients. Patients and Methods: This retrospective, population-based study analyzed the clinical data of 162 DTC patients from signal institution in China and 26,487 cases from the Surveillance, Epidemiology, and End Results (SEER) program registry. The patients were divided into two groups (underwent surgery and surgery recommended, but not performed) in the SEER cohort. Furthermore, patients were grouped as follows: T4; N1b; M1; T1-3N0-1a; specific number of lymph node metastases; and total or near-total thyroidectomy. Results: The 120-month cause-specific survival (CSS) rate of women and men showed a gradual declining trend from 60-64 to ≥80 years of age in the group that underwent surgery. The CSS rate of women and men showed a marked downward and irregular trend with an increase in age in the recommended, but no surgery group in the SEER cohort. Univariate analysis indicated that the surgery group had a higher 120-month CSS in women in most stages and men, compared with the no surgery group in the SEER cohort. The analysis of the SEER cohort showed that RAI-131 therapy was associated with an improved 80-month CSS in T4/N1b/M1 women (P < 0.0183) and men (P < 0.0011). However, there were no CSS differences between the RAI-131 therapy and the no-RAI-131 group for the patients with T4/N1b/M1 (AJCC 7th) thyroid cancer in the Chinese cohort. There was no CSS difference in women or men between the T1-3N0 and T1-3N1a patients in the SEER cohort. And similar findings were observed in T1-3N1a patients in the Chinese cohort. There was no statistical difference between the two subgroups. Conclusions: Surgical treatment should be recommended for elderly DTC patients because surgery can lead to a better CSS. High-risk patients achieve a higher benefit-to-risk ratio with RAI-131 therapy. To avoid the adverse effects associated with RAI-131 therapy, a multidisciplinary discussion should be arranged for intermediate- and low-risk patients.

Radiation recall pneumonitis triggered by an immune checkpoint inhibitor following re-irradiation in a lung cancer patient: a case report.

BACKGROUND: Radiation recall pneumonitis (RRP) is unpredictable but associated with severe radiation damage in previously irradiated fields. Chemotherapy and targeted drugs have been reported to contribute to RRP. Here we report a case of a patient with non-small cell lung cancer (NSCLC) who developed RRP following administration of immune checkpoint inhibitor (ICI) 18 months after the end of re-irradiation. CASE PRESENTATION: A 69-year-old man received adjuvant chemoradiotherapy post-operatively. He underwent thoracic re-irradiation for oligometastatic NSCLC. On second recurrence, pembrolizumab combined with nab-paclitaxel were administered. After six months, he developed symptoms of persistent cough and dyspnea, with consistent pneumonitis on CT images. The clinical time frame and significant radiographic evidence raised suspicion for RRP. Symptoms resolved after steroids. CONCLUSIONS: RRP is a rare occurrence. Patients undergoing immunotherapy after prior irradiation may be at increased risk of this rare radiation pneumonitis.

TAMpepK Suppresses Metastasis through the Elimination of M2-Like Tumor-Associated Macrophages in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) accounts for approximately 10-15% of all breast cancer cases and is characterized by high invasiveness, high metastatic potential, relapse proneness, and poor prognosis. M2-like tumor-associated macrophages (TAMs) contribute to tumorigenesis and are promising targets for inhibiting breast cancer metastasis. Therefore, we investigated whether melittin-conjugated pro-apoptotic peptide (TAMpepK) exerts therapeutic effects on breast cancer metastasis by targeting M2-like TAMs. TAMpepK is composed of M2-like TAM binding peptide (TAMpep) and pro-apoptotic peptide d(KLAKLAK)2 (dKLA). A metastatic mouse model was constructed by injecting 4T1-luc2 cells either orthotopically or via tail vein injection, and tumor burden was quantified using a bioluminescence in vivo imaging system. We found that TAMpepK suppressed lung and lymph node metastases of breast cancer by eliminating M2-like TAMs without affecting the viability of M1-like macrophages and resident macrophages in the orthotopic model. Furthermore, TAMpepK reduced pulmonary seeding and the colonization of tumor cells in the tail vein injection model. The number of CD8+ T cells in contact with TAMs was significantly decreased in tumor nodules treated with TAMpepK, resulting in the functional activation of cytotoxic CD8+ T cells. Taken together, our findings suggest that TAMpepK could be a novel therapeutic agent for the inhibition of breast cancer metastasis by targeting M2-like TAMs.

[Analysis of pre-ablative and preoperative thyroglobulin in differentiated thyroid cancer]. / Análisis de tiroglobulina preablativa y cáncer diferenciado de tiroides preoperatorio.

BACKGROUND: The measurement of plasma thyroglobulin (Tg) is widely used in the monitoring of differentiated thyroid cancer (CDT). In recent years, its value as a prognostic marker prior to ablation with radioiodine has increased, demonstrating its high negative predictive value. Recent studies indicate that a wide variety of factors could potentially influence pre-ablative Tg values, including residual tumor burden and stimulation modality. AIM: To relate the value of pre-ablative Tg with the amount of preoperative disease burden, lymph node metastases, treatment, and presence of residual disease. MATERIAL AND METHODS: Retrospective observational study of 70 patients with CDT treated between 2012 and 2018. The amount of disease burden was defined as the sum of largest diameter of individual tumors in each patient, and as the individually largest tumor per patient and number of metastatic lymph nodes. RESULTS: A smaller tumor size and absence of remnant tissue was associated with lower Tg values, although the association was not always significant. Furthermore, no significant difference was found between Tg levels measured within or more than 14 days after the surgical procedure. Thus, an early measurement of pTg after surgery would allow an initial therapeutic decision making. CONCLUSIONS: A statistical association between pre-ablative Tg levels and the amount of preoperative tumor tissue burden was found in some subgroups of patients.

Predicting axillary response to neoadjuvant chemotherapy: the role of diffusion weighted imaging.

OBJECTIVE: The aim of this study is to investigate whether the primary tumour response to neoadjuvant chemotherapy (NAC), based on the increase in the ADC-values (apparent diffusion coefficient) within the breast lesion, could help to predict axillary complete response. METHODS: We retrospectively included 74 patients who were treated with NAC followed by surgery at Lucus Augusti Hospital between January 2015 and September 2020. Simple logistic regression was used to evaluate the factors associated with axillary pathological complete response, including the changes in breast tumour ADC-values due to the treatment. RESULTS: Axillary complete response was correlated with negative oestrogen receptor status, Her2 positivity and response of primary tumour. It was achieved in 31% of the patients. In addition, the increase in the tumour ADC-values with NAC was higher for responders. Among the tumours that demonstrated an increase in ADC-value >0.92 ×10-3 mm2/s, 42.8% (15/35) showed axillary complete response. Eight (20.5%) breast cancers with an increase in ADC below the cut-off value were found to have no metastatic nodes after treatment (p = 0.038). CONCLUSION: Our results suggest that the performance of models predicting axillary response to NAC can be improved by adding the tumour response determined also using diffusion-weighted imaging. ADVANCES IN KNOWLEDGE: For the fist time, we investigate the relation between tumour response to NAC, assessed using diffusion-weighted imaging, and axillary pathologic complete response.

Neoadjuvant chemotherapy with dose dense MVAC is associated with improved survival after radical cystectomy compared to other cytotoxic regimens: A tertiary center experience.

INTRODUCTION: Neoadjuvant chemotherapy has become standard of care for cisplatin-eligible patients with muscle-invasive bladder cancer qualified to radical cystectomy, providing a modest increase in 5-year overall survival rate. Several regimens are being employed for neoadjuvant treatment, largely because of their efficacy in metastatic setting. There is however a scarcity of evidence on the optimal cytotoxic regimen for neoadjuvant chemotherapy. OBJECTIVES: We evaluated the efficacy of different protocols of neoadjuvant chemotherapy amongst patients who underwent radical cystectomy at our institution. METHODS: This is a single-center, retrospective, observational study including a cohort of 220 patients who underwent radical cystectomy between 2014 and 2020. The neoadjuvant chemotherapy cohort included 79 patients and was compared to the cohort of historical controls including 141 patients operated prior to routine administration of neoadjuvant chemotherapy and those who opted for upfront surgery. RESULTS: Administration of neoadjuvant chemotherapy decreased the risk of overall and cancer-specific mortality HR = 0.625 (95% CI 0.414-0.944), p = 0.025 and HR = 0.579 (95% CI 0.348-0.964), p = 0.036. Rates of downstaging, complete responses, lymph node metastasis, extravesical extension and positive surgical margins significantly favored neoadjuvant chemotherapy. Out of cytotoxic regimens, dose-dense MVAC and gemcitabine-cisplatin were similarly efficacious providing 46.9% and 50% of downstaging to

Intra-arterial chemotherapy targeting metastatic cervical lymph nodes in head and neck cancer.

BACKGROUND: Large cervical lymph nodes and the extranodal extension of metastatic lymph nodes are considered poor prognostic factors in head and neck squamous cell carcinoma (HNC). AIMS/OBJECTIVES: The efficacy of intra-arterial chemotherapy (iaCT) targeting lymph node (LN) in HNC was examined. MATERIALS AND METHODS: We performed a retrospective review of 41 patients with laryngeal and hypopharyngeal cancer showing metastatic cervical LN larger than 20 mm treated with iaCT with concurrent radiotherapy. The administration of cisplatin into LN was divided into three groups: no administration (NO), via the same artery as that supplying the primary tumor (SAME), and via a different artery from that supplying the primary tumor (DIFFERENT). RESULTS: A trend toward a more favorable three-year regional control in DIFFERENT compared to NO was observed, although the mean size of LN in DIFFERENT was larger than in the other groups. A better regional control was obtained in both DIFFERENT (p < .05) and DIFFERENT + SAME (p < .05) when overall rather than partial enhancement of lymph node by CT angiography was observed. Extranodal extension could be a factor predicting unfavorable regional control. CONCLUSIONS/SIGNIFICANCE: Targeting lymph node may be helpful to avoid neck dissection when iaCT was planned in HNC with relatively large LNs.

Comparison of model fit and discriminatory ability of M category as defined by the 7th and 8th editions of the tumor-node-metastasis classification of colorectal cancer and the 9th edition of the Japanese classification.

BACKGROUND: In transitioning from the 7th edition of the tumor-node-metastasis classification (TNM-7) to the 8th edition (TNM-8), colorectal cancer with peritoneal metastasis was newly categorized as M1c. In the 9th edition of the Japanese Classification of colorectal, appendiceal, and anal carcinoma (JPC-9), M1c is further subdivided into M1c1 (without other organ involvement) and M1c2 (with other organ involvement). This study aimed to compare the model fit and discriminatory ability of the M category of these three classification systems, as no study to date has made this comparison. METHODS: The study population consisted of stage IV colorectal cancer patients who were referred to the National Cancer Center Hospital from 2000 to 2017. The Akaike information criterion (AIC), Harrell's concordance index (C-index), and time-dependent receiver operating characteristic (ROC) curves were used to compare the three classification systems. Subgroup analyses, stratified by initial treatment year, were also performed. RESULTS: According to TNM-8, 670 (55%) patients had M1a, 273 (22%) had M1b, and 279 (23%) had M1c (87 M1c1 and 192 M1c2 using JPC-9) tumors. Among the three classification systems, JPC-9 had the lowest AIC value (JPC-9: 10546.3; TNM-7: 10555.9; TNM-8: 10585.5), highest C-index (JPC-9: 0.608; TNM-7: 0.598; TNM-8: 0.599), and superior time-dependent ROC curves throughout the observation period. Subgroup analyses were consistent with these results. CONCLUSIONS: While the revised M category definition did not improve model fit and discriminatory ability from TNM-7 to TNM-8, further subdivision of M1c in JPC-9 improved these parameters. These results support further revisions to M1 subcategories in future editions of the TNM classification system.

The "Dextran-Magnetic Layered Double Hydroxide-Fluorouracil" Drug Delivery System Exerts Its Anti-tumor Effect by Inducing Lysosomal Membrane Permeability in the Process of Cell Death.

The "dextran-magnetic layered double hydroxide-fluorouracil" (DMF) drug delivery system is a new type of pharmaceutic preparation that can cause cancer cell oncosis. In the present study, we used different experimental methods such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cycle assay, reactive oxygen species (ROS) assay, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI), Giemsa stainings, transmission electron microscopy, immunofluorescence staining and Western blotting to study the mechanism of expansion death by using Hydroxychloroquine (HCQ) as a positive control and 5-Fluorouracil (5-Fu) as reference. The results showed that DMF exhibited a better anti-tumor effect than 5-Fu in the process of cell death, and the pharmacological mechanism of 5-Fu was changed by its preparation DMF. The mechanism of cancer cell death induced by DMF was similar to that of HCQ. But DMF intervention did not cause a large amount of accumulation of mitochondrial reactive oxygen species, and the location of lysosomotropic LysoTracker Red (LTR) staining induced by DMF was closer to the nucleus or nuclear membrane. Lysosomal membrane permeability (LMP) and its subsequent the explosive death of cancer cells may be mainly related to the direct action of DMF with different organelles.

Total Mesometrial Resection With (Neo)Adjuvant Chemotherapy in Locally Advanced Cervical Cancer: A Tumor Response Score.

BACKGROUND/AIM: There is a lack of data concerning the surgical treatment of locally advanced squamous cell carcinoma of the uterine cervix (LACC) with neoadjuvant and adjuvant chemotherapy (NACT, ACT) as well as total mesometrial resection (TMMR). The aim of the study was to present a novel approach for treating LACC using a tumor response score for NACT. PATIENTS AND METHODS: A total of 12 patients with LACC were treated with NACT [cisplatin, ifosfamide, paclitaxel (TIP)], TMMR and ACT containing TIP. To measure the response during NACT, we scored i) the maximum tumor diameter (maxTD) in gynecological examination, ii) the MRI for radiologic maxTD, iii) the tumor volume and iv) the squamous cell carcinoma antigen before and after two applications of TIP. RESULTS: TIP reduced all score-parameters in 10 of 12 patients (p<0.005). We found a possible reduction of lymph node metastasis in 72.7%. The proposed score detected sufficient and insufficient tumor response. CONCLUSION: TIP followed by TMMR with ACT could be a possibility for patients denying radiochemotherapy. The tumor response score can detect patients with inadequate benefit from NACT.

Interobserver agreement of a gastric adenocarcinoma tumor regression grading system that incorporates assessment of lymph nodes.

Perioperative chemotherapy is increasingly used in combination with surgery for the treatment of patients with locally advanced, resectable gastric cancer. Histologic tumor regression grade (TRG) has emerged as an important prognostic factor; however, a common standard for its evaluation is lacking. Moreover, the clinical significance of regressive changes in metastatic lymph nodes (LNs) remains unclear. We conducted an international study to examine the interobserver agreement of a TRG system that is based on the Becker system for the primary tumors and additionally incorporates regression grading in LNs. Twenty observers at different levels of experience evaluated the TRG in 60 histologic slides (30 primary tumors and 30 LNs) based on the following criteria: for primary tumors, grade 1 represented complete response (no residual tumor), grade 2 represented <10%, grade 3 represented 10-50%, and grade 4 represented >50% residual tumor, as described by Becker et al. For LNs, grade "a" represented complete, grade "b" represented partial, and grade "c" represented no regression. The interobserver agreement was estimated using the Kendall's coefficient of concordance (W). Regarding primary tumors, agreement was good irrespective of the level of experience, reaching a W-value of 0.70 overall, 0.71 among subspecialized, and 0.71 among nonsubspecialized observers. Regarding LNs, interobserver agreement was moderate to good, with W-values of 0.52 overall, 0.64 among subspecialized, and 0.45 among nonsubspecialized observers. These findings indicate that the combination of the Becker TRG system with a three-tiered grading of regression in LNs generates a system that is reproducible. Future studies should investigate whether the additional information of TRG in LNs adds to the prognostic value of histologic regression grading in gastric cancer specimens.

A rare case report of transitional urothelial carcinoma metastasizing to isolated upper cervical lymph node diagnosed on cytology.

Transitional urothelial carcinoma frequently metastasizes to pelvic and retroperitoneal lymph nodes usually within 2 years of primary diagnosis but isolated metastasis to upper cervical lymph node after 5 years of primary diagnosis is extremely rare. We report here a case of a 53-year-old male who presented with Level II cervical node enlargement after 5 years of being diagnosed and treated for urothelial carcinoma. The diagnosis of cervical metastasis from urothelial carcinoma was suggested by fine-needle aspiration cytology and confirmed by immunocytochemistry.

Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma.

Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC). Although significant progress has been made in understanding the self-renewal and pro-tumorigenic potentials of CSCs, a key challenge remains on how to eliminate CSCs and halt metastasis effectively. Here we show that super-enhancers (SEs) play a critical role in the transcription of cancer stemness genes as well as pro-metastatic genes, thereby controlling their tumorigenic potential and metastasis. Mechanistically, we find that bromodomain-containing protein 4 (BRD4) recruits Mediators and NF-κB p65 to form SEs at cancer stemness genes such as TP63, MET and FOSL1, in addition to oncogenic transcripts. In vivo lineage tracing reveals that disrupting SEs by BET inhibitors potently inhibited CSC self-renewal and eliminated CSCs in addition to elimination of proliferating non-stem tumor cells in a mouse model of HNSCC. Moreover, disrupting SEs also inhibits the invasive growth and lymph node metastasis of human CSCs isolated from human HNSCC. Taken together, our results suggest that targeting SEs may serve as an effective therapy for HNSCC by eliminating CSCs.

Case Report: A New Entity: Multiple Differentiated Variant of Papillary Thyroid Carcinoma With Advanced Clinical Behavior.

There are many histological morphological types of papillary thyroid carcinoma (PTC), but the most frequently seen types are conventional. A single PTC commonly has a conventional and/or a variant morphological pattern. PTC with multiple (more than two) well-differentiated morphological patterns are extremely rare. We herein report the rare case of a 48-year-old male with initial diaphragmatic, pancreatic, and liver tumors from PTC. Then, the PTC was discovered following resection of these tumors, an ultrasound-guided fine-needle aspiration (US-FNA) cytology of a huge mass in the thyroid's left lobe revealed a PTC. After postoperative recovery, physical and ultrasound examinations identified an irregular large nodule in the thyroid's isthmus and left lobe, several swollen lymph nodes in the left neck, a mass in the left gluteus maximus, and several masses in both the bilateral parotid and salivary regions. The US-FNA's pathological examination confirmed metastatic PTCs in the left gluteus maximus and bilaterally in the parotid and salivary glands. An 18-fluorodeoxyglucose positron-emission tomography and computed tomography scan revealed abnormal uptakes in numerous locations (e.g., thyroid's isthmus and left lobe, bilateral parotid gland, and subcutaneous tissues). The patient underwent palliative therapy-including total thyroidectomy, bilateral central neck dissection, left lateral neck dissection, and excision of the bilateral parotid and salivary glands. A whole-body scan post-therapeutic radioactive iodine ablation revealed exclusive thyroid bed uptake. The patient subsequently underwent thyroid stimulating hormone (TSH) repression therapy and chemotherapy with lenvatinib, and thereafter achieved stable clinical conditions. Further histopathological analysis of the PTC revealed multiple differentiated morphological patterns in the single tumor located in the isthmus and left lobe of the thyroid, and in some metastatic lesions. Different metastatic lesions also presented different morphological patterns of PTC. In conclusions, we identified a new entity of PTC as a multiple differentiated variant of PTC (MDV-PTC) with an aggressive clinical nature.

Conditional survival for high-risk early-stage cervical cancer patients with lymph node metastasis after hysterectomy.

BACKGROUND: To estimate conditional survival (CS) for high-risk early-stage cervical cancer patients with lymph node metastasis after hysterectomy. METHODS: 1964 T1-2N1M0 cervical cancer patients who underwent primary hysterectomy from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Result (SEER) Program. Univariate and multivariate cox regression analysis were used to identify independent risk factors. 5-year conditional disease-specific survival (CDS5) and 5-year conditional relative survival (CRS5) were estimated. CDS5 and CRS5 stratified by risk factors were further calculated. RESULTS: CDS5 and CRS5 increased from 71.0% and 73.7% at 0-year to 89.2% and 91.7% at 5-year, respectively. Inversely, the actuarial disease-specific survival and RS dropped from 71.0% and 73.7% at 5-year to 63.3% and 67.6% at 10-year, respectively. Patients with unfavorable factors had a bigger gap between actuarial survival and CS. Both CDS5 and CRS5 curves across stratas of each prognostic factor had a tendency to level off with time elapsing. Notably, CRS5 couldn't exceed 95% even after 5-year follow-up except for patients with grade I disease (CRS5 at 5-year: 100%) or tumor size less than 2 cm (CRS5 at 5-year: 96%). CONCLUSION: CS increased over time while actuarial survival decreased as time passed. Patients with unfavorable factors had bigger improvement in CS than those with favorable factors. Excess mortality still existed in these patients after 5-year follow-up compared to the general population except for patients with grade I disease or tumor size <2 cm, who might gradually decrease follow-up times after 5-year.

Clinical Prognostic Factors in Patients With Metastatic Adrenocortical Carcinoma Treated With Second Line Gemcitabine Plus Capecitabine Chemotherapy.

Gemcitabine plus Capecitabine (Gem/Cape) is a frequently adopted second line chemotherapy for metastatic adrenocortical carcinoma (ACC), but only a minority of patients is destined to obtain a clinical benefit. The identification of baseline predictive factors of efficacy is relevant. We retrospectively analyzed clinical data from 50 consecutive patients with metastatic progressing ACC treated between 2011 and 2019. Patients received intravenous Gemcitabine and oral Capecitabine on a metronomic schedule. Previous mitotane therapy was maintained. Clinical benefit (partial response + stable disease) at 4 months was 30%, median progression-free survival (PFS) and disease-specific survival (DSS) from Gem/Cape start were 3 and 8 months, respectively. Among clinical variables evaluated before the start of Gem/Cape, presence of ECOG performance status ≥1 [HR 6.93 95% confidence interval (CI) 0.03-0.54, p.004] and neutrophil-to-lymphocyte ratio (NLR) ≥5 [HR 3.88, 95% (CI) 0.81-0.90, p.003] were independent indicators of poor PFS at multivariate analysis. Conversely, surgery of primary tumor, the presence of lung or lymph-node metastases, blood mitotane level, anemia, and the Advanced Lung cancer Inflammation index (ALI) failed to be independently associated. This study confirms that the Gem/Cape schedule is modestly active in heavily pretreated ACC patients (28% received at least two previous chemotherapy lines). NLR and performance status (PS) are easily available clinical parameters that are helpful to identify patients not likely to derive significant advantage from Gem/Cape chemotherapy.