OBJECTIVE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.
METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity.
RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.
CONCLUSIONS: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.
BACKGROUND: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .

BACKGROUND: Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer.
METHODS: We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates.
RESULTS: We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher\'s exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1.
CONCLUSIONS: The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

BACKGROUND: The use of complementary and/or alternative medicine to increase the efficacy and decrease the side effects of current cancer treatment is highly required. In this in-vivo study, we aimed to investigate the anti-tumor activity and probable side effects of a natural treatment, Cyrtopodion scabrum extract (CsE), in a model of tumor bearing mice.
METHODS: We established 28 female CT26-tumor bearing balb/c-mice model. We divided them randomly into four groups (n=7): Negative control received distilled water (DW) and the three treatment groups were administered with 5-FU and two different doses (300 and 600 mg/kg) of the gecko aqueous extract, respectively. The changes in the tumor volumes and weights during and after treatment, along with the blood cell counts; spleen and thymus indices were assessed in the treatment groups. We have also measured the serum TNF-α, VEGF, AST, ALT and GSH, as well as the physical activities of the experimental mice.
RESULTS: We found that the means of tumor weights and volumes in both CsE and 5-FU treated groups were significantly lower than the untreated group (p<0.05). Serum TNF-α and VEGF levels in both CsE treated groups were remarkably lower than 5-FU and untreated groups (p<0.05). The 5-FU treatment caused a remarkably decrease in serum GSH, RBC count, WBC count, thymus index, and spleen index , while CsE treatment maintained these quantities, with no significant changes, compared to the control group. AST and ALT were not significantly changed in none of the treated groups compared to control.
CONCLUSIONS: Altogether, data suggest C. scabrum, as an effective and safe anti-cancer natural source, which could be used as an alternative/complementary medicine for the treatment of patients who suffer from colon cancer.

Odontogenic keratocysts (OKC) are benign, developmental, locally-aggressive odontogenic cystic lesions with a high risk of recurrence. As such, the most effective treatment modalities remain controversial. The mainstay of treatment remains enucleation with or without decompression. The use of adjunctive therapies is widely reported. Our aim was to review our experience of OKCs and therefore identify the treatment modality, if there is any single one, with the lowest rate of recurrence. We also aimed to identify any common themes linking those patients experiencing cystic recurrence. Data were collected on 50 patients treated at UHCW NHS Trust over a 14-year period (2005-2018) via an anonymised database. Surgical pathways were analysed, including details of the location of the cysts and the use of adjunctive therapies, namely; mechanical debridement, cryotherapy, and the use of Carnoy\'s solution. Fifty-six keratocysts, both primary (91%, n = 51) and recurrent (9%, n = 5) were included. A total of 6% of patients had a pre-existing diagnosis of Gorlin-Goltz Syndrome (n = 3). Enucleation was performed in an approximately 3:1 ratio to decompression with secondary enucleation (n = 41:15). Twenty-seven percent of patients had adjunctive therapies (n = 15). There was a 12% recurrence rate (n = 6) found only within the group of primary cysts that had been enucleated only. Notably, there were no recurrences in those cysts that had undergone adjunctive therapy. None of the cysts that underwent initial decompression or marsupialisation recurred. Following surgical intervention, no tertiary recurrent cysts were detected postoperatively. This study demonstrated the advantage of establishing a correct diagnosis prior to definitive treatment. Initial decompression in selected patients followed by enucleation, along with adjunctive therapies showed a benefit in reducing recurrences. However, in the absence of high-quality evidence for the most effective management of odontogenic keratocysts, finding a common approach will remain controversial.

OBJECTIVE: To assess feasibility, complications and efficacy of induction chemotherapy followed by standard chemoradiotherapy in patients with bulky anal canal cancer.
METHODS: Patients with squamous cell carcinoma of the anal canal, staged bulky tumor with or without nodal involvement were prospectively enrolled. Before standard chemoradiotherapy, patients received induction chemotherapy with 3 cycles of 75 mg/m2 cisplatin and 750 mg/m2 5-fluorouracil. Patients were followed-up routinely until recurrence or death.
RESULTS: Seven patients with bulky anal canal cancer were evaluable for this pilot phase of the study. All patients had human papillomavirus-negative disease. Five completed the scheduled induction chemotherapy and all patients completed the programmed concomitant chemoradiotherapy. None had severe hematological toxicity. The majority of patients (6/7) had tumor downsizing after induction treatment. Six months after chemoradiotherapy, complete response was documented in three patients and salvage surgery was performed in two cases. With a median follow-up of 38 months (range=28-48 months), two patients are disease-free survivors.
CONCLUSIONS: Induction chemotherapy has the potential to become a standard approach in patients with bulky human papillomavirus-negative anal canal cancer.

While docetaxel/cisplatin/5-fluorouracil (DCF) outperforms CF in first-line gastric adenocarcinoma, toxicity remains an issue.
This multicenter phase II trial randomized chemonaïve metastatic gastric adenocarcinoma patients to fractionated weekly DCF (D 40 mg/m2 , C 35 mg/m², F 1800 mg/m² over 24 h, on days 1 and 8 every 3 weeks, arm (1) or fortnightly DCF (D 50 mg/m2 , C 50 mg/m², F 2000 mg/m² over 48 h every 2 weeks, arm (2). Prophylactic granulocyte colony-stimulating factor (G-CSF) was not allowed. The primary endpoint was the rate of febrile neutropenia within the first six treatment weeks (early FN).
A total of 106 eligible patients were recruited. The early and overall FN rates were 9.5% and 17% in arm 1, respectively, and 5.9% and 8% in arm 2, respectively. Grade ≥3 toxicities occurred in 81% of patients in arm 1 and 90% of patients in arm 2, the most common being neutropenia (33% vs. 61%), fatigue (27% vs. 25%), vomiting (21% vs. 12%), anorexia (19% vs. 18%), and diarrhea (17% vs. 10%). Median progression-free survival and overall survival were 5.1 (95% CI, 3.2-6.5) and 8.2 months (95% CI, 6.0-14.5), respectively, in arm 1 and 5.2 (95% CI, 3.0-6.9) and 11.9 months (95% CI, 7.4-15.9), respectively, in arm 2.
Fractionated weekly and fortnightly DCF regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G-CSF.

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.

Current systemic dosages of chemotherapeutic drugs such as gemcitabine, 5-FU, cisplatin, doxorubicin are administered every 7 days over 4 cycles due to systemic toxicity. An increase in potency of the drugs will result in dosage reduction with more frequent administration and efficacy increase. Hence, we investigated how the drugs potency can be increased by combining with bromelain and N-acetylcysteine. Tumour cells (5,000/well) were seeded into a 96 well plate and treated 24 hrs later with either single agents or in combinations at various concentrations. Cell survival was assessed by the sulforhodamine B assay after 72 hours of exposure. LD 50 was determined for each treatment and the Combination Index (CI) was assessed to determine synergy using Tallarida\'s method. CI indicated that synergy was dependent on the concentration of the agents used and was cell line specific. For bromelain and N-acetylcysteine, certain ratio of the two agents gave very good synergy that was prevalent in almost all cell lines. Gemcitabine and 5-FU and doxorubicin reacted favourably with most concentrations of bromelain and NAC investigated. Cisplatin and oxaliplatin were not very compatible with NAC. A value of CI <0.5 indicated that the current clinical chemotherapeutic dosage can be dramatically reduced. Bromelain with NAC showed synergy in all tumour cell lines and acting synergistically with chemotherapeutic drugs. Synergistic combinations resulting in considerable dosage reduction of chemotherapeutic agents may enable more frequent treatment with higher efficacy.

BACKGROUND: Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor used to prevent neutropenia, is not indicated for administration within 24 h of completion of chemotherapy. The safety of administering pegfilgrastim in gastrointestinal cancer chemotherapy regimens containing continuous intravenous infusion of 5-fluorouracil (5-FUCI) on the day of completion of 5-fluorouracil has not been adequately studied.
METHODS: An institutional review board-approved retrospective analysis of patients with a gastrointestinal malignancy receiving pegfilgrastim on the final day of 5-FUCI was conducted. The primary end point was to determine the incidence of grade 3 and grade 4 neutropenia and febrile neutropenia when pegfilgrastim was administered on the final day of 5-FUCI. The secondary endpoint was to determine rate of dose reductions and treatment delays.
RESULTS: A total of 300 patients were reviewed from January 2010 to May 2017. The most common cancers were colorectal (25%) and pancreatic (60%), with 77% of patients having late stage disease. The risk of a patient developing grade 3 neutropenia was 0.010 (95% CI 0.002-0.029) and grade 4 neutropenia was 0.007 (95% CI 0.001-0.024). The risk of febrile neutropenia was 0.007 (95% CI 0.001-0.024). The risks of treatment delay and treatment reduction were 0.013 (95% CI 0.004-0.034) and 0.010 (95% CI 0.002-0.029), respectively.
CONCLUSIONS: The low risk of grade 3 and grade 4 neutropenia, febrile neutropenia, as well as dose delays and/or reduction suggests that pegfilgrastim can be administered on the final day of 5-FUCI. Limitations of this study were that it was retrospective in nature and was conducted at a single institution.

To investigate the role of induction chemotherapy (IC) followed by definitive chemoradiotherapy in people with anal canal cancer with bulky disease at diagnosis.
We assessed patient acceptability and treatment feasibility of IC in patients with bulky anal canal malignant lesions.
Theoretical IC advantages may include tumor downsizing and early micrometastasis eradication, without affecting compliance with subsequent standard chemoradiotherapy regimens, as a result of improvement of oxygenation and higher intramural concentration of cytotoxic drugs.
The study design should be proven feasible, with a satisfactory patient acceptance rate and an optimized work flow. To our knowledge, this study is the first trial to investigate the use of IC in the population of patients with bulky anal canal cancer.