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Amphotericin B is the most potent antimycotic known to date. However due to its large collateral toxicity, its use, although long standing, had been limited. Many attempts have been made to produce derivatives with reduced collateral damage. The molecular mechanism of polyene has also been closely studied for this purpose and understanding it would contribute to the development of safe derivatives. Our study examined polyene action, including chemical synthesis, electrophysiology, pharmacology, toxicology and molecular dynamics. The results were used to support a novel Amphotericin B derivative with increased selectivity: L-histidine methyl ester of Amphotericin B. We found that this derivative has the same form of action as Amphotericin B, i.e. pore formation in the cell membrane. Its reduced dimerization in solution, when compared to Amphotericin B, is at least partially responsible for its increased selectivity. Here we also present the results of preclinical tests, which show that the derivative is just as potent as Amphotericin B and has increased safety. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: The aim of this single-arm multicenter phase II clinical trial was to assess the feasibility and tolerability of preoperative radiotherapy and simultaneous capecitabine and bevacizumab. Secondary endpoints were downstaging-rate and induction of complete pathological response. Material and methods: Patients with cT3 rectal cancer were eligible. Capecitabine (825mg/sqm twice daily on radiotherapy-days weeks 1–4) and bevacizumab (5mg/kg on days 1, 15 and 29) were administered concurrently to pelvic radiotherapy (1.8Gy daily up to 45Gy in 5weeks). Surgery followed 6–8weeks later. A two-stage trial was designed with early termination at eight patients if more than three patients had experienced a common toxicity criteria ⩾grade 3 according to the NCI CTC guidelines. Results: In the first stage eight patients were enrolled. Median age was 70years (range 55–76) and ECOG PS 0/1 (%) was 87.5/12.5. Major side effects were mostly intestinal bleeding (grade 3, 25%), diarrhea (grade 3, 25%), perianal and abdominal pain (grades 3 and 4, 25%) followed by anemia (grade 3, 12.5%). Tumor downstaging was observed in 37.5% of patients with complete pathological response in two patients (25%). Conclusions: After interim analysis of feasibility and tolerability, accrual was terminated according to protocol due to ⩾grade 3 toxicities in 50% of patients. Complete pathological response was seen in 25% of patients but was accompanied by considerable toxicity. Further clinical trials are needed to clarify the role of bevacizumab in this setting. [Copyright &y& Elsevier]

Simple Summary: Sexual dysfunction (SD) after rectal cancer surgery is common, inadequately discussed, multifactorial and often untreated. It is well known that postoperative SD is caused by nerve damage or vascular injury of the vasa nervosa during surgery or perioperative therapy. The majority of the studies have focused on male dysfunction, missing female data or explored SD only as a secondary outcome. Moreover, the impact on quality of life is rarely described in previous literature. The aim of this study was to evaluate risk factors for worse sexual function and quality of life after multimodal therapy and surgery for locally advanced rectal cancer. Purpose: Sexual function is crucial for the quality of life and can be highly affected by preoperative therapy and surgery. The aim of this study was to identify potential risk factors for poor sexual function and quality of life. Methods: Female patients were asked to complete the Female Sexual Function Index (FSFI-6). Male patients were demanded to answer the International Index of Erectile Function (IIEF-5). Results: In total, 79 patients filled in the questionary, yielding a response rate of 41.57%. The proportion of women was represented by 32.91%, and the median age was 76.0 years (66.0–81.0). Sexual dysfunction appeared in 88.46% of female patients. Severe erectile dysfunction occurred in 52.83% of male patients. Univariate analysis showed female patients (OR: 0.17, 95%CI: 0.05–0.64, p = 0.01), older age (OR: 0.34, 95%CI 0.11–1.01, p = 0.05), tumor localization under 6cm from the anal verge (OR: 4.43, 95%CI: 1.44–13.67, p = 0.01) and extension of operation (APR and ISR) (OR: 0.13, 95%CI: 0.03–0.59, p = 0.01) as significant risk factors for poor outcome. Female patients (OR: 0.12, 95%CI: 0.03–0.62, p = 0.01) and tumors below 6 cm from the anal verge (OR: 4.64, 95%CI: 1.18–18.29, p = 0.03) were shown to be independent risk factors for sexual dysfunction after multimodal therapy in the multivariate analysis. Quality of life was only affected in the case of extensive surgery (p = 0.02). Conclusion: Higher Age, female sex, distal tumors and extensive surgery (APR, ISR) are revealed risk factors for SD in this study. Quality of life was only affected in the case of APR or ISR. [ABSTRACT FROM AUTHOR]

Purpose: Anastomotic leakage (AL) poses the most serious problem following low anterior resection in patients with rectal cancer independent of surgical approach or technique. The aim of this study was to evaluate risk factors for the occurrence of AL and how they affect the oncological long-term outcome of patients who received neoadjuvant therapy. Methods: A single centre cohort study of 163 consecutive locally advanced rectal cancer patients (cT3, cT4, N +) that received neoadjuvant therapy followed by resection with primary anastomosis between January 1998 and December 2020 were included in this study. Short- and long-term findings were compared between patients with AL (Leakage +) and without AL (Leakage −). Results: A complete follow-up was obtained from 163 patients; thereby, 33 patients (20%) developed an AL. We observed more patients with comorbidities (38% vs. 61%, p = 0.049) which developed a leakage in the course. Permanent stoma rate (36% vs. 18%, p = 0.03) was higher, and time between primary operation and stoma reversal was longer (219 days [172–309] vs. 93 days [50–182], p < 0.001) in this leakage group as well. Tumour distance lower than 6 cm from the anal verge (OR: 2.81 [95%CI: 1.08–7.29], p = 0.04) and comorbidities (OR: 2.22 [95%CI: 1.01–4.90], p = 0.049) was evaluated to be independent risk factors for developing an AL after rectal cancer surgery. Oncological outcome was not influenced by AL nor by other associated risk factors. Conclusion: We could clearly detect the distance of tumour from the anal verge and comorbidities independent risk factors for the occurrence of AL. Oncological findings and long-term outcome were not influenced by these particular risk factors. [ABSTRACT FROM AUTHOR]

Background: In radiation treatment of locally advanced non-small cell lung cancer (LA-NSCLC), 'margins' from internal target volumes to planning target volumes in the range of 12 to 23 mm are reported, and avoiding exposure of the contralateral lung is common practice. We investigated prospectively an approach with tight margins (7 mm) and maximal sparing of the ipsilateral normal lung. Mature results for the first endpoint (pneumonitis) and further toxicities are reported.Methods: Primary tumors were treated by VMAT with 73.8-90.0 Gy in positive correlation to tumor volumes, nodes with 61.2 Gy, a restricted volume of nodes electively with 45 Gy. Fractional doses of 1.8 Gy bid, interval 8 h. Before radiotherapy, two cycles platin-based chemotherapy were given. 12 patients finished maintenance therapy with Durvalumab. Median follow up time for all patients is 19.4 months, for patients alive 27.0 months (3.4-66.5 months).Results: 100 consecutive, unselected patients with LA-NSCLC in stages II through IVA were enrolled (UICC/AJCC, 8th edition). No acute grade 4/5 toxicity occurred. Pneumonitis grade 2 and 3 was observed in 12% and 2% of patients, respectively; lowering the risk of pneumonitis grade ≥ 2 in comparison to the largest study in the literature investigating pneumonitis in LA-NSCLC, is significant (p < 0.0006). Acute esophageal toxicity grade 1, 2 and 3 occurred in 12%, 57% and 3% of patients, respectively. Two patients showed late bronchial stricture/atelectasis grade 2. In two patients with lethal pulmonary haemorrhages a treatment correlation cannot be excluded. Median overall survival for all stage III patients, and for those with 'RTOG 0617 inclusion criteria' is 46.6 and 50.0 months, respectively.Conclusions: Overall toxicity is low. In comparison to results in the literature, maximal sparing the ipsilateral normal lung lowers the risk for pneumonitis significantly.Trial Registration: Ethics committee of Vorarlberg, Austria; EK-0.04-105, Registered 04/09/2017-Retrospectively registered. http://www.ethikkommission-vorarlberg.at. [ABSTRACT FROM AUTHOR]

Purpose: Various forms of GAFCHROMIC® film have been used for several years as radiographic media for measuring dose distributions. GAFCHROMIC® EBT (GC-EBT) film is particularly useful for clinical dose ranges. This thin film dosimeter develops a blue color (λmax approximately 635 nm) when irradiated with ionizing radiation. Methods: Temperature controlled photospectrometry was used to assess temperature related readout changes in GC-EBT type film dosimetry. For observing clinical impact of findings, multiple scan studies with rising flat bed scanner temperature were performed. Results: The whole optical spectrum in the observed wavelength range of 450–700 nm shows a distinct spectrum shift linear with temperature toward lower wavelengths when readout temperature is increased. In addition, absorption decreases in maximum regions and increases in minimum regions of the absorbance spectrum. The most pronounced wavelength dependent readout differences occur in the slopes of the spectrum curves. Absorption readout differences of -1%/°C for a 2.7 Gy irradiated film piece at a readout wavelength of approximately 650 nm can be found. The readout difference is strongly dependent on readout light spectral characteristic, irradiation dose, and temperature. Readout difference can be positive or negative. Characteristic temperature behavior patterns are present for each color channel of a flat bed scanner. All described effects are reversible within the measurement accuracy of this study. Conclusions: When using unsuitable readout light, careful control of the readout temperature is necessary in order to obtain consistent and accurate results. Adapted GC-EBT type film dosimetry guidelines are presented. Temperature dependent readout differences on a flat bed scanner can be avoided when using scanner bed temperature as a fixed dosimetry parameter. [ABSTRACT FROM AUTHOR]

Induction chemotherapy (ICT) with cisplatin (P), 5-FU (F) and taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial, and toxicity and/or delay of radiotherapy (RT) may reduce the potential benefit of this treatment regimen. Here, we report the results of a randomised phase II trial comparing TPF with TP + cetuximab (C). In this trial, 100 patients with locally advanced stage III or IV SCCHN were included in the analysis. Patients were randomly assigned to either TPF-ICT (N = 49) or TPC-ICT (N = 51), both followed by RT + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished. On an intention-to-treat basis, the ORR (complete remission + partial remission) was 74.5% in the TPC arm compared with 63.3% in the TPF arm (p = 0.109). OS was similar in both arms 400 days after treatment was initiated (86.1% [95% confidence interval {CI}, 73.0–93.1%] in the TPC arm and 78.5% [95% CI, 63.7–87.8%] in the TPF arm). TPC resulted in slightly less serious adverse events and in less haematological, but more skin toxicities. Two patients randomised in the TPC arm died during ICT and RT. Four patients in the TPF arm died after completion of RT. No delay from the end of ICT to RT + C was observed. A total of 83.1% of patients (80% in the TPC arm; 86% in the TPF arm) received RT without dose reduction and/or modification. TPC-containing ICT for patients with locally advanced SCCHN was found to be an effective and tolerable one-day regimen. Further prospective evidence from larger trials is warranted. • Phase II randomised trial comparing two induction chemotherapy (ICT) regimens. • Substitution of 5-FU with cetuximab in docetaxel- and cisplatin-containing ICT. • Both regimens result in similar response rates. • Cetuximab-containing ICT is a less laborious one-day treatment option. • Results in decreased haematological, but increased cutaneous toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To determine the efficacy and feasibility of induction chemotherapy (ICT) with docetaxel, cisplatin and 5-fluorouracil followed by radiotherapy and cetuximab (C) in patients with locally advanced head and neck cancer. Patients and methods: Forty-nine previously untreated patients with local advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) received three courses of ICT consisting of docetaxel 75mg/m2 day 1, cisplatin 75mg/m2 day 1 and infusional 5-fluorouracil 750mg/m2/day on days 1–5 followed by radiotherapy plus C at 250mg/m2/week (after an initial loading dose of 400mg/m2). Results: After completion of ICT 44 of 49 patients received radiotherapy plus C. Three months after therapy completion tumour response was observed in 33 patients and after two years, 25 patients were in complete remission (CR). The most common grade 4 toxicity during the whole treatment period was dermatitis (30%), followed by mucositis (27%) and neutropenia (17%) without fever. One toxic related death was observed during ICT. Two-year progression-free survival (PFS) rate was 59% and two-year overall survival (OS) rate was 63%, respectively. Conclusion: Concurrent radiotherapy plus C after three courses of ICT was feasible and was associated with promising CR, PFS and OS rates. Further optimisation of dose and sequence is warranted. [Copyright &y& Elsevier]

Background: Postoperative morbidity remains a significant clinical problem and may alter long-term outcome particularly after neoadjuvant chemoradiation in patients with locally advanced low rectal cancer. The aim of the present study was to identify a potential long-term effect of postoperative morbidity.Methods: Analysis of prospectively collected data of 90 consecutive patients who underwent neoadjuvant chemoradiation and curative mesorectal excision for locally advanced (cT3/4, Nx, M0/1) adenocarcinoma of the mid and lower third of the rectum during a 7-year period (1996-2002).Results: Major postoperative complications occurred in 17.8% and minor complications in 26.6% of patients. Hospital mortality and 30-day mortality was 0%. Infectious complications were seen in 34.5%. The leading causes of infectious complications were anastomotic leakage and perineal wound infection. Postoperative morbidity was statistically significantly associated with gender (P < 0.05), pre-therapeutic haemoglobin level (P < 0.05), ASA score (P < 0.05), hospitalisation (P < 0.001) and clinical long-time course (P < 0.01). Moreover, early postoperative morbidity was proven as an independent prognostic factor concerning disease-free (P < 0.05) and overall survival (P < 0.05).Conclusion: Early postoperative morbidity in patients with preoperative chemoradiation due to locally advanced low rectal cancer is demonstrated as an independent prognosticator. Gender, pre-therapeutic haemoglobin level and ASA score indicate patients at risk for early postoperative complications and may therefore serve as predictive features. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The effectiveness of modified radical neck dissection with concomitant chemoradiotherapy in patients with N2/3 advanced head and neck cancer was evaluated. Study design and setting: Retrospective study of 35 patients treated at the University Hospital, Medical University, Innsbruck. The treatment consisted of a split course radiation up to 70Gy with concomitant chemotherapy with Mytomicin C and 5-fluorouracil. Neck dissection and/or tumor resection was performed between the two cycles of radiation and chemotherapy. Results: The 2-year progression-free survival was 64%, locoregional control 92% and overall survival 55. Observed toxicities included mucositis (grade 3, 35%; grade 4, 16%), neutropenia (grade 4, 28%), and thrombocytopenia (grade 4, 26%). No complications related to modified radical neck dissection were observed. Conclusion: Intermittent neck dissection was highly effective in controlling the neck disease. Mitomycin C-based chemoradiotherapy for treatment of locally advanced cancer seems to be an option to cisplatin-based regimens. [Copyright &y& Elsevier]

Purpose: Clinical trials demonstrated the efficacy and safety of intravenous (i.v.) or subcutaneous (s.c.) amifostine for reducing xerostomia and mucositis after radiotherapy or radiochemotherapy for head-and-neck cancer. This randomized, double-blinded, placebo-controlled, phase III study evaluated the efficacy and safety of i.v. amifostine during radiochemotherapy for head-and-neck cancer. Methods and Materials: Patients from European and American study centers received i.v. amifostine 300 mg/m2 (n = 67) or placebo (n = 65) before carboplatin 70 mg/m2 and radiotherapy on Days 1 to 5 and 21 to 25, and i.v. amifostine 200 mg/m2 or placebo before radiotherapy on other days. Results: Toxicity incidences were (amifostine, placebo, p value): Grade 2 or higher acute xerostomia (39%, 34%, 0.715), Grade 3 or higher acute mucositis (39%, 22%, 0.055), Grade 2 or higher late xerostomia (37%, 24%, 0.235), and Grade 3 or higher treatment-related adverse events (42%, 20%, 0.008). One-year rates of locoregional failure, progression-free survival, and overall survival were not significantly different between treatments. Conclusions: The used amifostine doses were not able to reduce the toxicity of simultaneous radiochemotherapy for head-and-neck cancer. The safety of amifostine and the lack of tumor protection were consistent with previous studies. [Copyright &y& Elsevier]