CCND1 as a predictive biomarker of neoadjuvant chemotherapy in patients with locally advanced head and neck squamous cell carcinoma

Background

Cyclin D1 (CCND1) has been associated with chemotherapy resistance and poor prognosis. In this study, we tested the hypothesis that CCND1 expression determines response and clinical outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) patients treated with neoadjuvant chemotherapy followed by surgery and radiotherapy.

Methodology and Findings

224 patients with HNSCC were treated with either cisplatin-based chemotherapy followed by surgery and radiotherapy (neoadjuvant group, n = 100) or surgery and radiotherapy (non-neoadjuvant group, n = 124). CCND1 expression was assessed by immunohistochemistry. CCND1 levels were analyzed with chemotherapy response, disease-free survival (DFS) and overall survival (OS). There was no significant difference between the neoadjuvant group and non-neoadjuvant group in DFS and OS (p = 0.929 and p = 0.760) when patients treated with the indiscriminate administration of cisplatin-based chemotherapy. However, in the neoadjuvant group, patients whose tumors showed a low CCND1 expression more likely respond to chemotherapy (p<0.001) and had a significantly better OS and DFS than those whose tumors showed a high CCND1 expression (73% vs 8%, p<0.001; 63% vs 6%, p<0.001). Importantly, patients with a low CCND1 expression in neoadjuvant group received more survival benefits than those in non-neoadjuvant group (p = 0.016), however patients with a high CCND1 expression and treated with neoadjuvant chemotherapy had a significantly poor OS compared to those treated with surgery and radiotherapy (p = 0.032). A multivariate survival analysis also showed CCND1 expression was an independent predictive factor (p<0.001).

Conclusions

This study suggests that some but not all patients with HNSCC may benefit from neoadjuvant chemotherapy with cisplatin-based regimen and CCND1 expression may serve as a predictive biomarker in selecting patients undergo less than two cycles of neoadjuvant chemotherapy.     

Total neoadjuvant treatment in locally advanced rectal cancer

Locally advanced rectal cancer requires a multidisciplinary management, traditionally based on neo-adjuvant (chemo) radiotherapy, conservative surgery with total mesorectal excision and adjuvant chemotherapy. Despite effective in term of local control, this strategy is linked to a high risk of distant metastasis (up to 30%). In this context, recent published randomized phase III clinical trials have tested the potential benefits with a different sequencing and/or intensification of the standard components of the trimodal therapy.Here, we briefly assess the efficacy and discuss the clinical relevance of total neoadjuvant treatment with a focus on indications and results in the short-course radiotherapy followed by chemotherapy use for this setting of patients. Long term results and additional prospective studies are necessary to more accurately estimate the clinical benefit and further establish the role of total neoadjuvant therapy in locally advanced rectal cancer disease.     

Damage Control Surgery in a <1kg Neonate: A Brief Report

Damage control surgery is a feasible and successful approach for the management of unstable neonates with intra-abdominal catastrophes, including liver injuries. We report the case of a premature infant with a liver injury secondary to the placement of an umbilical vein catheter who was successfully managed using damage control surgery techniques.     

Complete clinical remission and disappearance of liver metastases after treatment with somatostatin analogue in a 40-year-old woman with a malignant insulinoma positive for somatostatin receptors type 2

Insulinoma is the most common pancreatic endocrine tumor, accounting for 40% of all pancreatic functional neoplasm, and is characterized by hypersecretion of insulin and hypoglycemia. Elective treatment for insulinomas is surgical enucleation. Medical therapy with diazoxide, followed by somatostatin analogues in some cases, may be necessary to treat the hypoglycemic symptoms. We report a case of a patient affected by metastatic insulinoma with severe hypoglycemia. After surgery, histopathology confirmed the presence of a malignant insulinoma with multiple metastases in the liver. Due to the persistence of hypoglycemia, the patient was started on octreotide LAR treatment, which determined a complete clinical remission with regression of the metastatic lesions in the liver after one year. Repeated CT scans 2 and 3 years after surgery confirmed the remission. To our knowledge, the complete regression of the disease in insulinomas treated with long-standing somatostatin analogue therapy has never been reported. Immunohistochemical analysis in tissue specimens showed a strong membrane immunoreactivity for somatostatin receptors type 2 (SSTR2) in both the primary nodule and the metastases. The capacity of somatostatin analogues to negatively regulate cell proliferation through indirect and direct mechanisms has been experimentally demonstrated. Furthermore, SSTR2 activation may exert pro-apoptotic effects in neoplastic cells. Thus, both mechanisms may have been responsible of the remission of the disease in this patient. This case underlies the potential impact of the treatment of pancreatic insulinomas with somatostatin analogues, and, if confirmed, the usefulness of SSTR determination in these neoplastic specimens.     

Danazol and multiple hepatic adenomas: peculiar clinical findings in an acromegalic patient.

Hepatic adenomas are rare tumors; they have been associated with the use of anabolic steroids. Acromegaly increases the overall risk of neoplasms. We report the case of a female acromegalic patient in whom multiple hepatic adenomas appeared soon after danazol treatment for uterine fibromatosis. Treatment of acromegaly with octreotide, followed by successful selective pituitary adenomectomy, stabilized the number and the size of the liver tumors. We suggest that oversecretions of GH and IGF-I were strong promoting factors for liver tumorigenesis in this patient.     

探究新辅助化疗对胃癌细胞Bcl-2和p53基因表达的影响

胃癌在中国的发病率和死亡率居恶性肿瘤前列,现在胃癌的治疗主要以手术和化疗为主的综合治疗,新辅助化疗是胃癌综合治疗的重要组成部分,通过新辅助化疗能够有效抑制癌细胞增殖、缩小肿瘤体积等优点,从而为手术切除创造条件。本研究用新辅助化疗处理患胃癌的小鼠,并检测了新辅助化疗处理前后胃癌细胞内p53和Bcl-2 (细胞凋亡相关因子)基因在组织内的表达变化情况,以及与对照相比新辅助化疗对肿瘤大小的影响。结果表明,新辅助化疗可以减缓肿瘤的增长,显著上调小鼠胃癌组织内细胞凋亡因子p53的表达,并且显著下调Bcl-2抗凋亡因子的表达,从而有效地抑制胃癌细胞的增殖。这一结果可能为新辅助化疗对胃癌的治疗分子机制提供一些理论支持。     

Neoadjuvant chemotherapy in woman with early or locally advanced cervical cancer

Cervical cancer is a major global health problem for women. Despite the screening and vaccines available today, it continues to be the fourth most common cancer in women worldwide with 85% of cases occurring in developing countries. Standard treatments for early or locally advanced cervical cancer are surgery (S) or concomitant chemo-radiotherapy (CT-RT). Neoadjuvant chemotherapy (NACT) prior to surgery or radiotherapy has been proposed and tested in clinical trials and has been included in clinical practice in some countries.In order to determine the true role of NACT either prior to S or RT in terms of achieving benefits in OS or DFS, randomized clinical trials and meta-analyses published from its beginnings to the present have been searched and analyzed in this study.The analysis of published clinical trials shows that NACT followed by S and NACT followed by RT have failed to demonstrate benefits in OS or DFS. Clinical trials comparing NACT followed by S versus exclusive RT have also been analyzed, where NACT followed by S could not show benefits for RT either.ConclusionAdding neoadjuvant chemotherapy to S or RT cannot be recommended outside the context of clinical trials.     

Anaplastic thyroid cancer: outcomes of trimodal therapy

BackroundThe purpose of this study is to assess the impact of trimodal therapy [surgery, chemotherapy and external beam radiotherapy (EBRT)] in patients with anaplastic thyroid cancer (ATC) treated with curative intent.Materials and methodsRetrospective review of patients with ATC treated at a tertiary referral centre between January 2009 and June 2020. Data were collected regarding demographics, histology, staging, treatment and outcomes.ResultsSeven patients (4 female) were identified. Median age was 58 years (range 52–83 years). All patients received EBRT with concurrent doxorubicin. Six patients received surgery followed by chemoradiotherapy (CRT), and one underwent neoadjuvant CRT followed by surgery. Median radiological tumour size was 50mm (range 40–90 mm). Six patients had gross extrathyroidal extension and three had N1b disease. Prescribed radiotherapy schedules were 46.4 Gy in 29 bidaily fractions (n = 2, treated 2010), 60 Gy in 30 daily fractions (n = 2), 66 Gy in 30 fractions (n = 2) and 70 Gy in 35 fractions (n = 1; patient received neoadjuvant CRT). CRT was discontinued early for two patients due to toxicities. At median follow up of 5.8 months, 42.9% (3/7) patients were alive and disease-free. Only one patient developed a local failure. Three patients died from distant metastases without locoregional recurrence.ConclusionsDespite poor prognosis of ATC, selected patients with operable tumours may achieve high locoregional control rates with trimodal therapy, with possibility of long-term survival in select cases.     

新辅助化疗配合手术治疗中晚期乳腺癌的临床效果分析

目的:观察新辅助化疗配合手术治疗中晚期乳腺癌的临床效果,为临床研究提供参考。方法:选取我院2009年5月-2011年4月收治的中晚期乳腺癌患者107例,根据治疗方法的不同,将患者分为新辅助化疗组和对照组。新辅助化疗组采取术前辅助化疗,而对照组术前不接受化疗。观察新辅助化疗组患者的近期临床疗效、毒副反应发生率;比较两组患者的手术时间、术中出血量等;术后随访三年,记录两组患者的肿瘤局部复发率及远处转移率。结果:新辅助化疗组患者治疗的总有效率为79.66%,毒副反应的发生率为33.89%;新辅助化疗组的平均手术时间、术中出血量均低于对照组,差异具有统计学意义(P0.05)。新辅助化疗组患者的局部复发率为5.08%,远处转移率为6.78%;对照组患者局部复发率为12.50%,远处转移率为18.75%。新辅助化疗组患者的肿瘤复发转移率低于对照组,差异具有统计学意义(P0.05)。结论:在中晚期乳腺癌的临床治疗中,术前对患者实施新辅助化疗具有明显的效果,患者近期疗效良好,毒副反应可耐受,且手术后的复发转移率相对较低,值得推广应用。     

Correlation between baseline 18F-FDG PET/CT features and pathological complete response after neoadjuvant chemotherapy in early triple negative breast cancer

Aim of the studyTo evaluate correlation between metabolic and textural parameters on baseline ¹⁸F-FDG PET/CT and pathological response after neoadjuvant chemotherapy in non-metastatic triple negative breast cancer (TNBC).MethodsAll consecutive non-metastatic TNBC women treated by neoadjuvant chemotherapy followed by breast surgery who underwent ¹⁸F-FDG PET/CT examination at diagnosis between 2012 and 2018 were retrospectively included. Metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG) of the primary tumour and lymph nodes, and textural features (entropy, homogeneity, SRE, LRE, LGZE, HGZE) of the primary tumour were collected. Pathological response was defined according to Sataloff classification.ResultsSeventy-four patients were enrolled. In univariate analysis, metabolic and textural features of the primary breast lesion or metabolic parameters of regional lymph nodes were not predictive of pathological complete response after neoadjuvant chemotherapy.ConclusionMetabolic and textural features of baseline PET/CT do not seem to predict pathological response after neoadjuvant chemotherapy in non-metastatic triple negative breast cancer.     

RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes

The current standard of care for locally advanced rectal cancer (RC) is neoadjuvant radio-chemotherapy (NRC) with 5-fluorouracil (5Fu) as the main drug, followed by surgery and adjuvant chemotherapy. While a group of patients will achieve a pathological complete response, a significant percentage will not respond to the treatment. The Unfolding Protein Response (UPR) pathway is generally activated in tumors and results in resistance to radio-chemotherapy. We previously showed that RHBDD2 gene is overexpressed in the advanced stages of colorectal cancer (CRC) and that it could modulate the UPR pathway. Moreover, RHBDD2 expression is induced by 5Fu. In this study, we demonstrate that the overexpression of RHBDD2 in CACO2 cell line confers resistance to 5Fu, favors cell migration, adhesion and proliferation and has a profound impact on the expression of both, the UPR genes BiP, PERK and CHOP, and on the cell adhesion genes FAK and PXN. We also determined that RHBDD2 binds to BiP protein, the master UPR regulator. Finally, we confirmed that a high expression of RHBDD2 in RC tumors after NRC treatment is associated with the development of local or distant metastases. The collected evidence positions RHBDD2 as a promising prognostic biomarker to predict the response to neoadjuvant therapy in patients with RC.     

Neoadjuvant checkpoint inhibition in non-small cell lung cancer: Is earlier unquestionably better than later?

On March 4th 2022, nivolumab received regular US Food and Drug Administration approval, based on the CheckMate 816 trial results, for use “with platinum-doublet chemotherapy for adult patients with resectable NSCLC in the neoadjuvant setting”. This is the first neoadjuvant approval of a checkpoint inhibitor, a unique event in the history of lung cancer treatment. However, open questions remains. First, the co-primary endpoints of the CheckMate 816 trial (event-free survival and pathological complete response) are not yet validated surrogate endpoints in this setting. Second, the control arm was not reflecting the most common approach, being upfront surgery followed by adjuvant chemotherapy. Third, protocol changes were not plainly justified, questioning the analytic plan of the trial. Fourth and last, a subpar access to checkpoint inhibitor for patients upon progression may weaken overall survival results. Neoadjuvant strategies allow to study initial response under treatment, and constitute an encouraging therapeutic avenue. However, the best sequence of treatment is the key question in the neoadjuvant or adjuvant settings: is treating everyone upfront better than treating only patients that will eventually recur?Investigating optimal sequence strategy is even more critical within the checkpoint-inhibitor era, where patients with advanced or metastatic disease may present long-term advantage. Trials with optimal post-progression treatment are needed to help optimize our treatment algorithm, and spare toxicity for patients who don't derive benefit.     

Polycystic liver disease presenting with an exudative pleural effusion: a case report

Introduction

Polycystic liver disease is asymptomatic in 95% of patients. In the remaining 5% it causes symptoms due to the local mass effect of the polycystic liver. We describe the case of a patient who presented with symptoms of a pleural effusion and was also found to have polycystic liver disease. The effusion recurred despite repeated efforts at drainage and only resolved following surgical debridement of the cystic liver.

Case presentation

A 50-year-old Caucasian woman presented with a two-week history of increasing dyspnoea. An examination revealed a large right pleural effusion and gross hepatomegaly. An ultrasound confirmed a large polycystic liver and diagnostic thoracocentesis revealed an exudate, which was sterile to culture. The pleural effusion proved refractory to drainage and our patient underwent surgery to deroof the main hepatic cysts in an attempt to reduce the pressure on her right diaphragm. The histology was compatible with that of polycystic liver disease. No evidence of malignancy was found. After surgery, our patient had no recurrence of her effusion and, to date, has remained asymptomatic from her polycystic liver disease.

Conclusion

The case in this report illustrates that an exudative pleural effusion is a rare complication of polycystic liver disease. We feel that the mechanical effects of a large polycystic liver, and subsequent disruption of sub-diaphragmatic capillaries, resulted in a persistent exudative pleural effusion. Thus, surgical debulking of the hepatic cysts is required to manage these effusions.     

Sialoadenectomy alters liver cell turn-over and function in mice

In rodents, submandibular salivary glands accumulate a number of biologically active peptides, and release some of them to both saliva and the bloodstream. Surgical removal of these glands (sialoadenectomy) alters the ability of the liver to regenerate after partial hepatectomy. We show here that 5 weeks after surgery, the liver of sialoadenectomized mice contained 40% fewer hepatocytes than the liver of sham-operated mice. We did not obtain evidence of necrotic cell death after surgery. In contrast, sialoadenectomy transiently increased apoptotic hepatocyte death, as revealed by terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick-end labeling (TUNEL) assay. DNA synthesis was determined in vivo by the incorporation of bromo-deoxyuridine (BrdU) into hepatocyte nuclei. BrdU-labeling progressively increased after sialoadenectomy. We conclude that sialoadenectomy induced a transient wave of apoptotic cell death followed by a rise in DNA synthesis but not by cell division. This reduced cell number but increased mean cell volume. In spite of these alterations in cellularity, the liver responded adequately to several stressful conditions, as judged by the lack of any differential effect of sialoadenectomy on liver glycogen and plasma glucose concentration after immobilization, aggressive encounter, or fasting. However, the liver of sialoadenectomized mice was more sensitive to the effect of a non-lethal dose of bacterial lipopolysaccharide (LPS) combined with d-galactosamine, as shown by the enhanced rise in plasma alanine aminotransferase and aspartate aminotransferase, and liver myeloperoxidase (MPO) activities. All these results indicate that a submandibular salivary glands-liver axis is involved in the maintenance of liver structure in mice. A disturbance of this axis induces an adaptive response that preserves the metabolic function of the liver but renders it more sensitive to bacterial endotoxins.     

Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice

It is well established that liver ischemia-reperfusion induces the expression of heat shock protein (HSP) 70. However, the biological function of HSP70 in this injury is unclear. In this study, we sought to determine the role of HSP70 in hepatic ischemia-reperfusion injury in mice. Male mice were subjected to 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion. HSP70 was rapidly upregulated after reperfusion. To explore the function of HSP70, sodium arsenite (8 mg/kg iv) was injected before surgery. We found that this dose induced HSP70 expression within 6 h of treatment. Induction of HSP70 with arsenite resulted in a >50% reduction in liver injury as determined by serum transaminases and histology. In addition, arsenite similarly reduced liver neutrophil recruitment and liver nuclear factor-kappaB activation, and attenuated serum levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2, but increased levels of interleukin (IL)-6. In HSP70 knockout mice, arsenite did not protect against liver injury but did reduce liver neutrophil accumulation. Arsenite-induced reductions in neutrophil accumulation in HSP70 knockout mice were found to be mediated by IL-6. To determine whether extracellular HSP70 contributed to the injury, recombinant HSP70 was injected before surgery. Intravenous injection of 10 microg of recombinant HSP70 had no effect on liver injury after ischemia-reperfusion. The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia-reperfusion injury and that extracellular HSP70 is not a significant contributor to the injury response in this model. Targeted induction of HSP70 may represent a potential therapeutic option for postischemic liver injury.     

Apport de la TEP-FDG dans le staging initial des cancers du sein localement avancés traités par chimiothérapie néo-adjuvante

Axillary lymph node and distant metastases are unfavourable prognostic factors in breast cancer. The aim of our study was to evaluate the performance of PET-FDG in the staging of locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy (NAC) and surgery, and to compare the findings of pretherapeutic PET to those of axillary nodal status obtained by surgery after NAC (Sataloff classification). This retrospective study involved 89 patients with LABC explored at presentation by PET in addition to conventional clinical and imaging staging (CS). Breast cancer excision and axillary dissection were performed after NAC. PET and CS found an axillary involvement in 58 patients (65%) and 39 patients (44%), respectively. Compared to the histology of post-NAC axillary dissection, PET had sensitivity and specificity of 80% and 63%, respectively. PET revealed an extra-axillary lymph node involvement, not suspected by the CS, in 25 patients (28%). Bone and lung metastases, not suspected by the CS were found in two and one patients, respectively. A case of false-positive PET in the liver was observed (adenomatosis). This study confirms the value of PET in the initial staging of LABC, especially in assessing extra-axillary nodal status. In the determination of axillary status, PET has a high positive predictive value, cases of doubtful interpretation suggesting to perform ultrasound-guided fine needle aspiration in addition.     

Severe recurrent abdominal pain: an anatomical variant of Chilaiditi's syndrome

A patient who presented to the emergency department with severe, recurrent abdominal pain demonstrated Chilaiditi's sign, a radiographic term for interposition of the hepatic flexure of the colon between the liver and right hemidiaphragm. Workup of this clinical case revealed anomalous colonic anatomy, which led to successful laparoscopic corrective surgery. We call attention to the potential importance of this sign when associated with clinically recurrent abdominal pain (Chilaiditi's syndrome).     

Calcifying nested stromal epithelial tumor of the liver in a patient with Klinefelter syndrome: a case report and review of the literature

Background

Calcifying nested stromal epithelial tumor (CNSET) is a primary neoplasm of the liver, characterized by well-demarcated nests consisting of spindle and epithelioid cells with calcification and bone formation. An association of Cushing syndrome with CNSET has drawn attention, but the origin of CNSET has not been clarified.

Case presentation

We report here the case of a 20-year-old male with Klinefelter syndrome who underwent liver resection for an increasing liver tumor that was pathologically diagnosed with CNSET. He was postoperatively followed up and received several examinations, and recurrences and extrahepatic lymph node metastases were detected on the 64th day after surgery. Chemoembolization and chemotherapy were not effective, leading to tumor progression with development of progressive liver failure, and the patient finally died 164 days after hepatectomy.

Conclusions

This case suggests that an imbalance of hormones affects the genesis and progression of CNSET, and indicates the importance of closely following patients with CNSET by imaging with attention to hepatic recurrence and extrahepatic metastases.

     

新辅助化疗在局部晚期宫颈癌治疗中的疗效观察

目的：探讨新辅助化疗联合手术治疗较传统手术治疗Ib2、IIa2局部晚期宫颈癌的临床疗效。方法：选取2008年6月～2011年12月在黑龙江省哈尔滨医科大学附属第三医院初治宫颈癌患者120例,临床分期为Ib2期、IIa2期,术前均经病理证实为宫颈鳞癌,将其分为两组：研究组（新辅助化疗联合手术治疗组）;对照组（单纯手术治疗组）。研究组给予1～2个疗程的新辅助化疗后评估其化疗疗效,有效者化疗结束后行广泛性子宫切除＋盆腔淋巴结清扫术;对照组直接行手术治疗。结果：新辅助化疗能够使肿瘤体积较化疗前缩小或消失,临床有效率高达81.43%,从而降低了宫颈癌的临床分期,提高手术的切除率,扩大手术适应征,降低术后病理高危因素,同时手术治疗能保留卵巢功能,提高年轻宫颈癌患者生活质量。结论：术前新辅助化疗可以提高手术治疗局部晚期宫颈癌的临床疗效。     

Prognostic value of the post-operative red blood cell distribution width in patients with rectal cancer with neoadjuvant chemoradiation followed by surgery

Purposes: Several studies have reported that elevated red cell distribution width (RDW) is related to poor prognosis in several cancers; however, the prognostic significance of perioperative RDW in patients with rectal cancer that received neoadjuvant chemoradiation therapy (NACRT) is unclear.Methods: A total of 120 patients with rectal cancer who received NACRT followed surgery were retrospectively reviewed from Affiliated Cancer Hospital of Zhengzhou University between 2013 and 2015. Data for peripheral blood tests prior to the initiation of NACRT, before surgery and first chemotherapy after surgery were collected, respectively. The optimal cutoff values of RDW were determined by ROC analysis, respectively. The relationship between RDW and the prognosis of patients was evaluated by the Kaplan Meier method, respectively.Results: The post-operative RDW^High patients had significantly worse 5-year overall survival (OS, P=0.001) and disease-free survival (DFS, P<0.001) than the post-operative RDW^Low patients, respectively. Whereas high pre-operative RDW was the only marker correlated with worse DFS (P=0.005) than the pre-operative RDW^Low patients, no relationship was found between pre-RDW and prognosis (OS, P=0.069; DFS, P=0.133). Multivariate analysis showed post-operative RDW had better predictive value than pre-RDW and pre-operative RDW.Conclusion: Post-operative RDW might be a useful prognostic indicator in patients with rectal cancer received neoadjuvant chemoradiation.