Synergic Induction of Autophagic Cell Death in Anaplastic Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) has poor prognosis, high mortality rate and lack of effective therapy. A synergic combination of PD-L1 antibody together with cell death promoting substances like deacetylase inhibitors (DACi) and multi-kinase inhibitors (MKI) could sensitize ATC cells and promote decay by autophagic cell death. The PD-L1-inhibitor atezolizumab synergized with panobinostat (DACi) and sorafenib (MKI) leading to significant reduction of the viability, measured by real time luminescence, of three different patient-derived primary ATC cells, of C643 cells and follicular epithelial thyroid cells too. Solo administration of these compounds caused a significant over-expression of autophagy transcripts; meanwhile autophagy proteins were almost not detectable after the single administration of panobinostat, thus supporting a massive autophagy degradation process. Instead, the administration of atezolizumab caused an accumulation of autophagy proteins and the cleavage of the active caspases 8 and 3. Interestingly, only panobinostat and atezolizumab were able to exacerbate the autophagy process by increasing the synthesis, the maturation and final fusion with the lysosomes of the autophagosome vesicles. Despite ATC cells could be sensitized by atezolizumab via the cleavage of the caspases, no reduction of cell proliferation or promotion of cell death was observed. The apoptosis assay evidenced the ability of panobinostat alone and in combination with atezolizumab to induce the phosphatidil serine exposure (early apoptosis) and further the secondary necrosis. Instead, sorafenib was only able to cause necrosis. The increase of caspases activity induced by atezolizumab, the apoptosis and autophagy processes promoted by panobinostat synergize thus promoting cell death in well-established and primary anaplastic thyroid cancer cells. The combined therapy could represent a future clinical application for the treatment of such lethal and untreatable solid cancer.

Serum amylase on postoperative day 1 is superior to serum lipase in predicting clinically relevant pancreatic fistula after partial pancreaticoduodenectomy.

PURPOSE: To compare the predictive value of serum amylase and lipase regarding the occurrence of clinically relevant postoperative pancreatic fistula (cr-POPF) after partial pancreaticoduodenectomy (PD). METHODS: Data from 228 consecutive patients undergoing PD were obtained from a prospective database. Serum amylase and lipase were measured on postoperative days (PODs) 0-2. Receiver-operating characteristics analysis was performed and cutoff values were tested using logistic regression. RESULTS: Serum amylase had a larger area under the curve (AUC) on POD1 (AUC 0.89, p <0.001) than serum lipase. For serum amylase POD 1, a cutoff value of 70 U/l showed sensitivity and specificity of 100% and 70% for the diagnosis of cr-POPF. Serum amylase POD 1 > 70 U/l (OR 9.815, 95% CI 3.683-26.152, p < 0.001), drain amylase POD 1 > 300 U/l (OR 2.777, 95% CI 1.071-7.197, p= 0.036), and a small (≤ 3mm) pancreatic duct diameter (OR 3.705, 95% CI 1.426-9.627, p= 0.007) were significant predictors of cr-POPF in the multivariable analysis. Patients were divided into three risk groups based on serum amylase POD 1 and pancreatic duct diameter. This model had a good performance in discriminating cr-POPF (AUC 0.846, 95% CI 0.793-0.898). The sensitivity, specificity, and negative predictive value for the combination of serum amylase POD 1 <70 U/l and pancreatic duct diameter >3 mm were 100%, 70%, and 100%. CONCLUSION: Serum amylase POD 1 was superior to serum lipase in predicting cr-POPF after PD. The proposed risk prediction model had a sensitivity and negative predictive value of 100%, allowing for early identification of cr-POPF.

Long Non-Coding RNA H19 Expression Correlates with Autophagy Process in Adrenocortical Carcinoma.

Adrenocortical carcinoma (ACC) is characterized by poor prognosis and high mortality. The suppression of the long-non-coding RNA H19, counterbalanced by IGF2 over-expression, leads to down-regulation of the autophagy markers, high proliferation rate and metastatic potential in patients affected by ACC. The administration of the deacetylase inhibitors (DACi) panobinostat, trichostatin A (TSA) and SAHA affected the cell viability of H295R monolayer and spheroids and induced the over-expression of H19 and autophagy transcripts. H19 knock down in H295R cells was not able to modulate the expression level of autophagy transcripts. Instead, H19 knock down was able to impede the ability of DACi to modulate the protein level of the autophagy markers. Furthermore, the administration of higher concentration of DACi was able to down-regulate the protein level of Beclin1 and p62 and to induce the conversion of LC3B-I into the active LC3B-II form, thus confirming an active autophagic process. Neither the active protein level nor the activity of caspases 8 and 3 was prompted by the DACi, thus excluding the involvement of the executioners of apoptosis in H295R decay. The DACi restore H19, the autophagy markers and trigger cell death in ACC cells. The re-activation of autophagy would represent a novel strategy for the treatment of patients affected by this severe malignancy.

Gastric enterochromaffin-like cell changes in multiple endocrine neoplasia type 1.

BACKGROUND: Gastric enterochromaffin-like cell (ECL) tumours can occur in patients with multiple endocrine neoplasia type 1 (MEN1), especially in those affected by Zollinger Ellison syndrome (ZES). Since the prevalence of ECL lesions is not well defined yet, the present study evaluated the presence and extent of ECL lesions in MEN1 patients with and without ZES. METHODS: Multiple endocrine neoplasia type 1 patients being part of a regular screening program (2014-2018) underwent gastroduodenoscopies with biopsies of the stomach and determination of serum gastrin and chromogranin A levels. Haematoxylin- and immunostaining with chromogranin A, gastrin and VMAT I and II (vesicular monoamine transporter I and II) of the biopsies were performed. RESULTS: Thirty-eight MEN1 patients, of whom 16 (42%) were diagnosed and treated earlier for ZES, were analysed. In ten of 16 (62.5%) ZES patients, a locally scattered, mixed image of diffuse, linear and micronodular mild hyperplasia was present. In addition, two of these patients (13%) showed small (max 1.5 mm in size) intramucosal ECL tumours. Neither ECL changes, nor tumours were found in MEN1 patients without ZES (n = 22). In MEN1/ZES patients, the median serum gastrin level was significantly elevated compared to MEN1 patients without ZES (206 pg/ml vs. 30.5 pg/ml, p < .001). A subgroup analysis of the serum gastrin and chromogranin A levels of MEN1/ZES patients with or without ECL hyperplasia did not show significant differences (gastrin level: p = .302, chromogranin A: p = .464). CONCLUSION: Enterochromaffin-like cell hyperplasia and gastric carcinoids occur only in MEN1 patients with ZES, but less frequently than reported.

Single gland excision for MEN1-associated primary hyperparathyroidism.

IMPORTANCE: Guidelines advocate subtotal parathyroidectomy (SPTX) or total parathyroidectomy with autotransplantation (TPTX) with bilateral cervical thymectomy for primary hyperparathyroidism (pHPT) associated with multiple endocrine neoplasia type 1 (MEN1). However, both procedures are associated with a significant risk of permanent hypoparathyroidism. OBJECTIVE: The aim of the current study was to compare long-term results of either single gland excision (SGE, 1-2 glands), SPTX and TPTX for the treatment of MEN1-associated pHPT. DESIGN AND SETTING: Data of genetically confirmed MEN1 patients who underwent surgery for pHPT between 1987 and 2017 were retrieved from a prospective database and were retrospectively analysed. RESULTS: Eighty-nine MEN1 patients underwent either TPTX (n = 38, 42.7%), SPTX (n = 23, 25.8%) or SGE (n = 28, 31.5%). The rate of disease persistence after initial surgery was 2.6%, 0% and 14.2% in the TPTX, SPTX and SGE groups, respectively. After median follow-up of 112 (range 7-411) months, the rate of recurrent pHPT was significantly higher in the SGE group (n = 19, 21.3%) compared with the TPTX (n = 4, 4.4%, P = .001) and the SPTX (n = 9, 10.1%, P = .03) groups. Analysis of the recurrence-free time among the surgical groups revealed a significant difference (P = .036). The median time to recurrence was significantly shorter after SGE (101, range 3-301 months) than after SPTX (139, range 28-278 months, P = .018) and TPTX (204, range 75-396 months, P = .049). Twelve (32%) patients who underwent TPTX developed permanent hypoparathyroidism compared with only 4 (17%, P = .06) in the SPTX and 0 in the SGE group (P = .001). CONCLUSION: Given the high rate of postoperative permanent hypoparathyroidism after TPTX and SPTX, SGE is a valid option for the treatment of MEN1-associated pHPT.

Anaplastic thyroid carcinoma: changing trends of treatment strategies and associated overall survival.

PURPOSE: The prognosis of anaplastic thyroid cancer (ATC) is poor. Despite various attempts to modify common treatment modalities, including surgery, external beam radiation (EBRT) and chemotherapy (CTX), no standardized treatment is yet established. This study aimed to analyze the changing trends of treatment concepts and associated overall survival (OS) over the last two decades. METHODS: A retrospective analysis was conducted on 42 patients with histologically confirmed ATC. The outcome measures included the evaluation of clinical characteristics and treatments performed with regard to OS. RESULTS: Median OS for all tumor stages was 6 (range 1 week-79) months, 6.5 months for stage IVA/B and 4 months for stage IVC carcinoma patients. Twenty-one patients with stage IVA/B carcinomas underwent curative treatment, including thyroidectomy with lymphadenectomy (TTX plus LAD, n = 11) or multimodal treatment with TTX plus LAD and EBRT plus/minus CTX (n = 10). The median OS of patients with stage IVA/B carcinomas was significantly prolonged after multimodal treatment than after surgery alone (25 vs. 3 months, p = 0.04). Fifteen of 18 patients with stage IVC carcinomas received palliative, 3 patients multimodal treatment. The median OS of stage IVC patients after trimodal therapy was not significantly longer than after debulking procedures (6 vs. 7 months, p = 0.25). In the time period 1999-2009, only 4 (21%) patients received multimodal treatment compared to 9 (39%) in the period from 2009 to 2019, but this did not result in a significantly prolonged survival in the latter period (8.5 vs. 15 months, p = 0.61). CONCLUSION: Concurrent radio- and/or chemotherapy in combination with surgery seems to result in improved survival in stage IVA/B ATC, whereas this is not the case in patients with stage IVC tumors. Novel treatment regimens are urgently needed to improve the dismal prognosis of ATC.

Palliative surgical bypass is superior to palliative endoscopic stenting in patients with malignant gastric outlet obstruction: systematic review and meta-analysis.

BACKGROUND: Gastrojejunostomy (GJ) and self-expanding metal stents (SEMS) are the two most common palliative treatment options for patients with malignant gastric outlet obstruction (GOO). Randomised trials and retrospective studies have shown discrepant results, so that there is still a controversy regarding the optimal treatment of GOO. METHODS: Medline, Web of Science and Cochrane Library were systematically searched for studies comparing GJ to SEMS in patients with malignant GOO. Primary outcomes were survival and postoperative mortality. Secondary outcomes were frequency of re-interventions, major complications, time to oral intake and length of hospital stay. RESULTS: Twenty-seven studies, with a total of 2.354 patients, 1.306 (55.5%) patients in the SEMS and 1.048 (44.5%) patients in the GJ group, were considered suitable for inclusion. GJ was associated with significantly longer survival than SEMS (mean difference 43 days, CI 12.00, 73.70, p = 0.006). Postoperative mortality (OR 0.55, CI 0.27, 1.16, p = 0.12) and major complications (OR 0.73, CI 0.5, 1.06, p = 0.10) were similar in both groups. The frequency of re-interventions, however, was almost three times higher in the SEMS group (OR 2.95, CI: 1.70, 5.14, p < 0.001), whereas the mean time to oral intake and length of hospital stay were shorter in the SEMS group (mean differences - 5 days, CI - 6.75, - 3.05 days, p < 0.001 and - 10 days, CI - 11.6, - 7.9 days, p < 0.001, respectively). CONCLUSIONS: Patients with malignant GOO and acceptable performance status should be primarily considered for a palliative GJ rather than SEMS.

Minimally Invasive Versus Open Treatment for Benign Sporadic Insulinoma Comparison of Short-Term and Long-Term Outcomes.

BACKGROUND: Benign insulinoma is the most common functioning neuroendocrine tumor of the pancreas, and its incidence is estimated at 0.4%. The treatment of choice is organ-preserving resection. The aim of this study was to compare short-term and long-term outcomes of minimally invasive laparoscopic or robotic enucleation (MIC-EN) and open enucleation (O-EN) for sporadic benign insulinoma. METHODS: A retrospective bi-institutional analysis of 71 patients who underwent an enucleation for sporadic benign insulinoma between 2003 and 2016 was performed. Patients were analyzed according to intention-to-treat principle. RESULTS: Fifteen (21%) patients underwent MIC-EN (three robotic and 12 laparoscopic) and 56 (79%) patients O-EN. In all MIC-EN patients, the insulinoma was localized by preoperative imaging compared to only 62.5% (35 of 56) patients in the O-EN group (p = 0.005). Three of the MIC-EN patients (20%) with insulinomas in the pancreatic head had to undergo a conversion. Excluding conversions, MIC-EN procedures were shorter (145 vs 180, p = 0.036) compared to O-EN surgery. Late complications and pathological data did not differ between groups, excluding margin status R1 MIC-EN (26.7%) compared to O-EN (10.7%, p = 0.115). After a median follow-up of 75 (range 1-151) months, all patients were alive, but four (5.6%) patients (one after MIC-EN and three after O-EN) developed a functional recurrence. No patient with a R1 resection had a disease recurrence. CONCLUSIONS: MIC-EN for benign sporadic insulinoma is a safe procedure with at least similar short-term and long-term postoperative outcomes as the open technique. Thus, preoperatively localized benign insulinoma should be approached laparoscopically, if technically feasible.

Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs.

BACKGROUND: The MEK (mitogen-activated protein kinase)⁻inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. METHODS: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. RESULTS: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down-regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down-regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. CONCLUSIONS: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC.

[Transaxillary Robot-assisted Thyroidectomy - Results and Acceptance of a New Surgical Technique]. / Die transaxilläre roboterassistierte Thyreoidektomie ­ Ergebnisse und Akzeptanz einer neuen Operationsmethode.

BACKGROUND: In recent years, different remote-access approaches in thyroid surgery have been developed and partially established. The aim is mainly to improve cosmetics by avoiding a visible scar on the neck. We report here our experiences with transaxillary robot-assisted thyroidectomy (TRAT). METHODS: As part of an observational trial, TRAT was offered to patients with indication for a hemithyroidectomy because of benign goitre with a lobe volume up to 40 ml. The acceptance of the new method and the surgical results, especially operation time and intra- and postoperative complications, were monitored and evaluated. In addition, patient satisfaction with the cosmetic results was recorded 8 to 12 weeks after surgery. RESULTS: From January 2013 to January 2018, TRAT was offered to 151 patients, of whom 65 (43.0%) chose this new surgical technique. 51 hemithyroidectomies, 6 isthmus resections and 8 Dunhill procedures were performed in these 65 patients. The mean operation time was 121.5 minutes (range 83 - 221) for isthmus resections, 165.0 minutes (range 100 - 300) for hemithyroidectomies and 259 minutes (range 197 - 320) for Dunhill resections. The rate of recurrent laryngeal nerve palsy was 8.2% (6 of 73 nerves at risk), of which 2 (2.7%) were permanent. Postoperative hypoparathyroidism or revisions due to bleeding did not appear and no tracheal, esophageal or vessel injuries. 9 patients (13.8%) suffered from transient paraesthesia of the skin flap. In 2 of the first 5 patients, transient brachial plexopathy occurred. 93% of all patients rated the cosmetic result as good or very good. The rate of recommendation was also 93%. CONCLUSION: TRAT for unilateral benign goitre is feasible and safe. The operation time is acceptable. TRAT is only used in Germany for selected patients because of low acceptance by the patients and high costs due to technical effort and its limitations to a large goitre.

[Do We Have to Wait for the Result of the Intraoperative Quick Parathormone Test in Preoperative Localised Sporadic Parathyroid Adenoma?] / Muss der intraoperative Quick-Parathormonwert beim lokalisierten, sporadischen Hyperparathyreoidismus abgewartet werden?

BACKGROUND: In the recent years, targeted surgery, especially minimally invasive parathyroidectomy, has become the procedure of choice to treat sporadic primary hyperparathyroidism (pHPT) and is performed after preoperative standardised, accurate and reliable localisation. The intraoperative quick parathyroid hormone (qPTH) test is considered as a condition for successful resection of the parathyroid adenoma. The intraoperative qPTH test prolongs surgery and anaesthesia. The aim of this study was to evaluate whether there are disadvantages if patients do not wait for the qPTH result before terminating the procedure. METHODS: Between March 2009 and September 2017, 202 patients with solitary parathyroid adenoma - diagnosed on the basis of concordant positive results in 99mTc-sestamibi scintigraphy and neck ultrasound - were scheduled for a focused procedure. In all patients, frozen section and qPTH test (baseline and 15 minutes after adenoma resection) were performed, but in patients with parathyroid adenoma that was evident to the responsible surgeon after macroscopic resection, surgery was not finished before the results of the qPTH test were available. The result of frozen section was awaited in all cases. Patients were informed that re-exploration has to be performed on the following day if there were persistently high levels of PTH after adenoma excision. RESULTS: Overall, 176 (87.1%) of the 202 targeted procedures were finished without waiting for the qPTH test result. The mean operation time was 60.4 min (SD 32.9). In all patients, the result of the qPTH test was received after extubation. Successful excision of the adenoma was confirmed by a PTH drop of at least 50% into the standard range. In 26 (12.9%) patients the qPTH result was waited for. The mean operation time in these cases was significantly longer with 112.0 min (SD 43.1). In 8 of these 26 patients, the operation was extended with unilateral or bilateral exploration, due to the inadequate decrease in qPTH. Overall, 2 of 202 (0.99%) patients suffered persistent disease after the focussed approach. CONCLUSION: In patients with sporadic pHPT and preoperative and consistently solitary parathyroid adenoma - localised by neck ultrasound and 99mTc-sestamibi scintigraphy -, the result of the qPTH test must not generally be awaited. The prerequisite is an adenoma that is convincing for the surgeon and which can be confirmed in frozen section analyses. This approach is safe and spares operative time and money.

[Personalized approach to anaplastic thyroid carcinoma]. / Personalisiertes Vorgehen beim anaplastischen Schilddrüsenkarzinom.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) represents the rarest but most aggressive tumor entity of the thyroid gland. In this respect, the treatment of advanced ATC has rapidly evolved in recent years. Recently, new personalized forms of treatment that address the somatic mutational status of the tumor have been increasingly used. The aim of this article is to provide an overview of current molecular-based and personalized treatment options for ATC. METHODS: A current literature search was performed with a focus on personalized molecular-based treatment options for ATC. RESULTS: The majority of patients suffering from ATC have an advanced tumor disease at the time of initial diagnosis. Despite multimodal treatment approaches consisting of surgery, external beam radiation therapy (EBRT) and chemotherapy (CTX), the prognosis of ATC is still poor. Accordingly, the focus of innovative treatment approaches is on molecular-based, individualized tumor therapy, including in particular BRAFV600E and multikinase inhibitors. The potential of the latter seems to lie particularly in combination therapy with immune checkpoint inhibitors. These treatment options can be used in both adjuvant and neoadjuvant settings. Neoadjuvant treatment of advanced ATC can achieve a potentially resectable treatment setting and improve the poor prognosis of affected patients; however, larger prospective and randomized studies on these combination therapies are currently pending. CONCLUSION: The focus of future treatment approaches for ATC will be on individualized, molecular-based tumor therapy. In particular, the neoadjuvant use of these therapies may change the paradigm of ATC surgery as locally advanced as well as metastatic carcinomas can be converted to a potentially resectable status and made amenable to surgery.

Acinar content at pancreatic resection margin is significantly associated with clinically relevant pancreatic fistula after partial pancreatoduodenectomy.

BACKGROUND: This study aimed to evaluate the clinical significance of acinar content at the pancreatic resection margin after partial pancreatoduodenectomy (PD). METHODS: A total of 228 consecutive patients undergoing PD were included for analysis. Resection margins were assessed for acinar, fibrosis, and fat contents by 2 pathologists blinded to the patients' clinical data. Univariate and multivariable analyses of possible predictors for clinically relevant postoperative pancreatic fistula (cr-POPF) were performed. RESULTS: The median acinar, fibrosis, and fat contents were 70% (IQR, 25%-82%), 13% (IQR, 5%-40%), and 15% (IQR, 9.25%-25%), respectively. The rates of cr-POPF were significantly higher in patients with an acinar content of >70% than in patients with an acinar content of ≤70% (26.4% vs 5.5%, respectively; P < .001). In addition, the rates of postoperative hyperamylasemia (POH) were significantly higher in patients with an acinar content of ≥70% than in patients with an acinar content of ≤70% (55.2% vs 13.8%, respectively; P < .001). The median fat content did not differ between patients with and without cr-POPF (13.0% [IQR, 7.5%-20.0%] vs 15.0% [IQR, 10.0%-30.0%], respectively; P = .06). An acinar content of >70% at the pancreatic resection margin (odds ratio [OR], 4.85; 95% CI, 1.61-14.58; P = .005) and a soft pancreatic texture (OR, 2.82; 95% CI, 1.02-7.76; P = .046) were independent predictive factors of cr-POPF in the multivariable analysis. CONCLUSION: An acinar content of ≥70% at the pancreatic resection margin was a significant predictive factor for cr-POPF after PD and was also significantly associated with POH, a precursor of cr-POPF after PD in many cases. Fatty infiltration of the pancreatic resection margin was not associated with cr-POPF.

Anti-Proliferative Effect of Radiotherapy and Implication of Immunotherapy in Anaplastic Thyroid Cancer Cells.

Radiotherapy and immunotherapy have shown promising efficacy for the treatment of solid malignancies. Here, we aim to clarify the potential of a combined application of radiotherapy and programmed cell death-ligand 1 (PD-L1) monoclonal antibody atezolizumab in primary anaplastic thyroid cancer (ATC) cells. The radiation caused a significant reduction in cell proliferation, measured by luminescence, and of the number of colonies. The addition of atezolizumab caused a further reduction in cell proliferation of the irradiated ATC cells. However, the combined treatment did not cause either the exposure of the phosphatidylserine or the necrosis, assessed by luminescence/fluorescence. Additionally, a reduction in both uncleaved and cleaved forms of caspases 8 and 3 proteins was detectable in radiated cells. The DNA damage evidenced the over-expression of TP53, CDKN1A and CDKN1B transcripts detected by RT-qPCR and the increase in the protein level of P-γH2AX and the DNA repair deputed kinases. PD-L1 protein level increased in ATC cells after radiation. Radiotherapy caused the reduction in cell viability and an increase of PD-L1-expression, but not apoptotic cell death in ATC cells. The further combination with the immunotherapeutic atezolizumab could increase the efficacy of radiotherapy in terms of reduction in cell proliferation. Further analysis of the involvement of alternative cell death mechanisms is necessary to clarify their cell demise mechanism of action. Their efficacy represents a promising therapy for patients affected by ATC.

Clinical Implications of Postoperative Hyperamylasemia after Partial Pancreaticoduodenectomy.

Introduction: The present study aimed to examine the clinical implications of postoperative hyperamylasemia (POH) after partial pancreaticoduodenectomy (PD). Methods: Data from all consecutive patients undergoing PD were obtained from a prospectively maintained database and reviewed. POH was defined as an elevation of serum pancreatic amylase above the upper limit of normal (53 U/L) on postoperative days 0-2. Clinically relevant POH (cr-POH) was defined as POH in patients with clinically relevant (Clavien-Dindo ≥ III) postoperative complications. Results: POH occurred in 61 of 170 (35.9%) and cr-POH in 24 of 170 (14.1%) patients. Patients with POH had higher rates of clinically relevant postoperative pancreatic fistula (cr-POPF) (44.3 vs. 3.7%, p < 0.001) and clinically relevant postoperative complications than those without POH (39.3 vs. 21.1%, p = 0.001). Patients with cr-POH had higher C-reactive protein (CRP, milligrams per liter) levels on third (257.7 vs. 187.85 mg/L, p = 0.016) and fourth (222.5 vs. 151, p = 0.002) postoperative day (POD) than those with POH alone. Serum procalcitonin (PCT, micrograms per liter) levels on POD 2 (1.2 vs. 0.4 µg/L, p = 0.028) and POD 3 (0.85 vs. 0.4 µg/L, p = 0.001) were also higher in patients with cr-POH. Rates of cr-POPF in patients with cr-POH were higher than in those with POH alone (70.8 vs. 27%, p = 0.001). POH (OR 0.011, 95% CI: 0.001-0.097, p < 0.001) was an independent predictor of cr-POPF in the multivariable analysis. A high-risk pathology, defined as nonadenocarcinoma/nonchronic pancreatitis pathology (OR 0.277, 95% CI: 0.106-0.727, p = 0.009), and a small duct diameter (OR 0.333, 95% CI: 0.139-0.796, p = 0.013) were independent predictors of POH in the multivariable analysis. Conclusion: POH is a frequent, but not always clinically relevant, finding after partial PD. Serum CRP and PCT levels in the early postoperative period can be used to identify patients with cr-POH. POH is an independent risk factor for increased postoperative morbidity, including cr-POPF, after partial PD.

Endoscopic vacuum therapy (EVT) for acute esophageal perforation: Could it replace surgery?

Background and study aims Acute esophageal perforation is a potentially life-threating condition that demands a multidisciplinary approach. Based on recently published data indicating that EVT may be effective in managing esophageal perforation, we report our institution's experience with EVT in this clinical setting. Patients and methods We retrospectively analyzed all 10 patients with acute esophageal perforation from May 2018 to January 2021, using descriptive statistics. The primary outcome was successful closure of the perforation. Secondary outcomes included the length of treatment, number of endoscopic procedures required, and complication rate. Results All patients (site of perforation: 4 upper, 2 middle, 4 lower esophagus; etiology: 8 iatrogenic, 2 foreign body ingestion) were treated with EVT successfully. In eight cases, EVT was started immediately after the perforation, in the other two cases 1 and 2 days later. The median (interquartile range) number of endoscopic procedures was 2.5 (range, 2-3) and the median duration of treatment was 7.5 days (range, 7-11.5). The sponge was placed in eight cases intraluminally, in the other two cases initially intracavitary. No complication occurred. Conclusions EVT is highly effective for managing acute esophageal perforation within 1 to 3 weeks. Immediate start of EVT to prevent abscess formation and induce defect closure is crucial.

Postoperative morbidity following pancreatic cancer surgery is significantly associated with worse overall patient survival; systematic review and meta-analysis.

BACKROUND: The influence of postoperative morbidity on survival after potentially curative resection for pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: Medline, Web of Science and Cochrane Library were searched for studies reporting survival in patients with and without complications, defined according to the Clavien-Dindo classification, after primary, potentially curative resection for pancreatic cancer followed by adjuvant treatment. Meta-analysis was performed using a random-effects model. RESULTS: Fourteen retrospective cohort studies comprising a total of 7.604 patients with an overall complication rate of 40.8% (n = 3.103 patients) were included. Median overall survival for the entire patient cohort ranged from 15.5 to 24 months. Overall survival in patients with severe postoperative complications ranged from 7.1 to 37.1 months and was significantly worse compared to the overall survival in patients without severe complications ranging from 16.5 to 38.2 months. Postoperative complication rates ranged from 24.3% to 64%, severe (Clavien-Dindo ≥ III) complication rates from 4.2% to 31%. Results sufficient for meta-analysis were reported by ten studies, representing 6.028 patients. Meta-analysis showed reduced overall survival following any complication (summary adjusted HR 1.47; 95% CI 1.23-1.76, p < 0.0001). Hazard of death was 1.5 times higher in patients experiencing severe postoperative complications than in patients without severe complications (summary adjusted HR 1.45; 95% CI 1.13-1.85, p = 0.003). CONCLUSIONS: Postoperative complications after potentially curative resection of PDAC are significantly associated with worse overall patient survival.

Effect of Kinase Inhibitors on the Technetium-99m Uptake into Thyroid Carcinoma Cells In Vitro.

BACKGROUND/AIM: We evaluated the potential of the kinase inhibitors sorafenib, lenvatinib and selumetinib on increasing the uptake of technetium-99m into thyroid cancer cells. MATERIALS AND METHODS: Four established cell lines and three patient's cell cultures were treated with 0.1, 1 and 5 µM of sorafenib, lenvatinib and selumetinib for 72 hours. After incubation with 1 MBq of technetium-99m, the radioactivity uptake was measured. RESULTS: The experiments showed heterogeneous results. Maximum technetium-99m uptake increases of 312% (sorafenib), 326% (lenvatinib) and 759% (selumetinib) were obtained using the highest applied concentrations. In some tests, an uptake reduction or no effect was observed. CONCLUSION: Kinase inhibitors have a positive effect on technetium-99m uptake. Due to study limitations, a redifferentiating effect of the drugs could not be definitely proven. Unspecific cytotoxicity might have a confounding effect.

Prostate-Specific Membrane Antigen in Anaplastic and Poorly Differentiated Thyroid Cancer-A New Diagnostic and Therapeutic Target?

Several studies have demonstrated an expression of the prostate-specific membrane antigen (PSMA) in the cancer-related neovasculature of thyroid malignancies. Due to the poor prognosis and limited therapeutic options for patients with anaplastic (ATC) and poorly differentiated (PDTC) thyroid carcinoma, the aim of our study was to investigate the theranostic approach of PSMA expression in these patients. The PSMA uptake on Gallium-68 (68Ga)-PSMA-positron emission tomography/computed tomography (PET/CT) and glucose uptake on F-18-Fluordeoxyglucose (18F-FDG)-PET/CTs were analysed in two ATC and six PDTC patients. The PSMA expression in corresponding patients' tissue samples was detected by immunohistochemistry. In addition, various tissue sections from 22 ATC and six PDTC patients were examined concerning PSMA expression. 68Ga-PSMA-PET/CT showed heterogeneous PSMA expression among patients and lesions. Six of the eight analyzed patients (two ATC, four PDTC) showed increased glucose metabolism without increased PSMA uptake after PET/CT. In one patient (PDTC), 18F-FDG-PET/CT tracer uptake was positive and 68Ga-PSMA-PET/CT showed heterogeneous results. Another patient (PDTC) evidenced only PSMA-positive lesions and received two cycles of Lutetium-177 (177Lu)-PSMA therapy, which kept his disease stable for seven months. There was a correlation between immunohistochemical PSMA expression and uptake on 68Ga-PMSA-PET/CT in three of the examined patients. Twenty-seven of the analyzed 39 ATC and 13 of the analyzed 22 PDTC tissue sections showed a strong PSMA expression. Considering the rarity of PDTC and ATC, which is the reason for the small patient population we studied, the findings of this study confirm the high diagnostic sensitivity and superiority of 18F-FDG-PET/CT in comparison to 68Ga-PSMA-PET/CT in the diagnosis of ATC and PDTC. However, it can be suggested that 68Ga-PMSA-PET/CT can be considered as a beneficial adjunct to the well-established 18F-FDG-PET/CT for a few individual selected patients with ATC and PDTC to detect lesions not discovered by 18F-FDG-PET/CT and to determine patients' eligibility for a radioligand therapy. Radiolabelled PSMA-ligands may, in the future, represent a theranostic approach with only minor side effects for a few individual selected patients with ATC and PDTC who need alternative treatment options in case of progression when established therapies are no longer effective. However, due to the small sample size of our collective, larger studies are needed to allow for a final evaluation on the significance of PSMA-targeted diagnostic and therapy for ATC and PDTC.