What Is the Role of Palmitoylethanolamide Co-Ultramicronized with Luteolin on the Symptomatology Reported by Patients Suffering from Long COVID? A Retrospective Analysis Performed by a Group of General Practitioners in a Real-Life Setting.

Long COVID is a recognized post-viral syndrome characterized by neurological, somatic and neuropsychiatric symptoms that might last for long time after SARS-CoV-2 infection. An ever-growing number of patients come to the observation of General Practitioners complaining of mild or moderate symptoms after the resolution of the acute infection. Nine General Practitioners from the Rome area (Italy) performed a retrospective analysis in order to evaluate the role of the supplementation with Palmitoylethanolamide co-ultramicronized with Luteolin (PEALUT) on neurologic and clinical symptoms reported by their patients after COVID-19 resolution. Supplementation with PEALUT helped to improve all patient-reported symptoms, especially pain, anxiety and depression, fatigue, brain fog, anosmia and dysgeusia, leading to an overall improvement in patients' health status. To our knowledge these are the first data presented on Long COVID patients collected in a territorial setting. Despite their preliminary nature, these results highlight the pathogenetic role of "non-resolving" neuroinflammation in Long COVID development and consequently the importance of its control in the resolution of the pathology and put the focus on the General Practitioner as the primary figure for early detection and management of Long COVID syndrome in a real-life setting. Future randomized, controlled, perspective clinical trials are needed to confirm this preliminary observation.

Biglycan expression and clinical outcome in patients with pancreatic adenocarcinoma.

Conflicting results have been reported on the role of extracellular matrix (ECM) proteins in pancreatic cancer. Preclinical studies suggest that the overexpression of biglycan (proteoglycan-I, PG-I), a leucine-rich protein of the ECM, may induce growth arrest of pancreatic cancer cells. The aim of this study was to assess the prognostic role of biglycan expression in pancreatic cancer. We also evaluated MIB-1 and COX-2 expressions (as potential markers of growth and aggressiveness) to better characterize the biology of the tumors. The classical pathological parameters (grading, desmoplasia, perineural, or vascular invasion) as well as molecular determinants of prognosis were examined. MIB-1 (a proliferative index associated with prognosis in most tumors), COX-2, and PG-I expressions were detected by immunohistochemistry and immunofluorescence on tissue samples from 53 patients with pancreatic cancer and reviewed by two independent pathologists. To verify PG-I expression, three rabbit sera (LF104, LF112, and LF121 from NIH, Bethesda, MA, US) were tested. Logrank test and Cox's model were applied for statistical analysis. Out of 53 patients, 40 had stage III and IV pancreatic cancer. Fourteen patients did not express any of the PG-I epitopes. The patients who expressed at least two PG-I epitopes had shorter survival compared to those with single epitope or lacking any expression (28 vs 44 weeks, P = 0.0021). The MIB-1 higher expression predicted shorter survival (25 vs 41 weeks, P = 0.0059). The other parameters were not associated with clinical outcome. Multivariate analyses confirmed PG-I expression and MIB-1 as independent negative prognostic factors. Patients who presented PG-I expression in the ECM had the worse prognosis compared to those who did not. Our results are not in contrast with the hypothesis that ECM proteins are a potential barrier to metastatic spread in localized pancreatic cancer. Rather, we underline the complexity of tumor-stroma interactions in the advanced stage of cancer and the need of further study.

Determinants of recovery from amenorrhea in premenopausal breast cancer patients receiving adjuvant chemotherapy in the taxane era.

Chemotherapy-induced amenorrhea occurs in about 20-70% of premenopausal breast cancer patients. Chemotherapy-induced amenorrhea can affect choice of hormonal therapy, fertility, and quality of life of breast cancer survivors. We retrospectively analyzed the incidence of amenorrhea after adjuvant chemotherapy and the subsequent recovery of the menses in 145 breast cancer patients. Age, smoking, alcohol consumption, body mass index, chemotherapy regimen, previous hormonal therapies, and previous childbearing were analyzed as potential predictive factors of ovarian function recovery. Median age was 42 years at the beginning of adjuvant chemotherapy with 30.3% of patients below 40 years of age. The majority (87.6%) of patients received anthracycline-based chemotherapy, 35.2% of patients received a cyclophosphamide-methotrexate-5-fluorouracil regimen and 42.8% received a taxane. The incidence of chemotherapy-induced amenorrhea was 80, and 35.3% of these patients resumed menses after a median of 8 months. In multivariate analysis, younger age (<40 years, P=0.01) and taxane-based chemotherapy (P=0.03) were associated with increased probability of recovery of menses after chemotherapy-induced amenorrhea. In contrast, cyclophosphamide-methotrexate-5-fluorouracil-based chemotherapy (P=0.07) and previous childbearing (P=0.04) were associated with an increased probability of permanent chemotherapy-induced amenorrhea. Recovery of menses after chemotherapy-induced amenorrhea occurs more probably in younger women, with no pregnancies and receiving taxanes.

Neurosurgical management and postoperative whole-brain radiotherapy for colorectal cancer patients with symptomatic brain metastases.

BACKGROUND: New systemic treatments for advanced colorectal cancer have conferred a survival advantage, allowing patients to reach a median survival of almost 2 years. Due to this remarkable life extension, the incidence of brain metastases, though still low, is progressively increasing over time. There is little reported data on the optimal strategy to manage brain lesions from colorectal cancer. METHODS: To explore the role of an aggressive approach to colorectal cancer brain metastases, we retrospectively collected and analyzed data from 30 patients who underwent neurosurgical resection + whole-brain radiotherapy between March 1998 and December 2006. Univariate (logrank) and multivariate (Cox's model) analyses were used to identify prognostic factors. RESULTS: Median age at the time of surgery was 66 years, median ECOG PS was 1, most patients (87%) had concomitant lung and/or liver metastases. Median number of previous chemotherapies was two, with half of the patients being exposed both to oxaliplatin and irinotecan. A median of 27 Gy of radiotherapy were administered to 16 patients after resection. At the time of the analysis, 29 out of 30 patients had died, with a median survival time after brain metastasectomy of 167 days (8-682). Only one patient died within a month from surgery. Median survival was significantly longer in patients who received postsurgical radiotherapy (7.6 vs. 4.7 months, P = 0.014). CONCLUSIONS: Neurosurgical management of symptomatic brain metastases from colorectal cancer is feasible, relatively safe, and offers a chance of prolonged survival. Patients who received radiotherapy after resection experienced a better outcome.

Drug waste minimisation and cost-containment in Medical Oncology: two-year results of a feasibility study.

BACKGROUND: Cost-containment strategies are required to face the challenge of rising drug expenditures in Oncology. Drug wastage leads to economic loss, but little is known about the size of the problem in this field. METHODS: Starting January 2005 we introduced a day-to-day monitoring of drug wastage and an accurate assessment of its costs. An internal protocol for waste minimisation was developed, consisting of four corrective measures: 1. A rational, per pathology distribution of chemotherapy sessions over the week. 2. The use of multi-dose vials. 3. A reasonable rounding of drug dosages. 4. The selection of the most convenient vial size, depending on drug unit pricing. RESULTS: Baseline analysis focused on 29 drugs over one year. Considering their unit price and waste amount, a major impact on expense was found to be attributable to six drugs: cetuximab, docetaxel, gemcitabine, oxaliplatin, pemetrexed and trastuzumab. The economic loss due to their waste equaled 4.8% of the annual drug expenditure. After the study protocol was started, the expense due to unused drugs showed a meaningful 45% reduction throughout 2006. CONCLUSION: Our experience confirms the economic relevance of waste minimisation and may represent a feasible model in addressing this issue.A centralised unit of drug processing, the availability of a computerised physician order entry system and an active involvement of the staff play a key role in allowing waste reduction and a consequent, substantial cost-saving.

Cognitive functions and elderly cancer patients receiving anticancer treatment: a prospective study.

It has been reported that anticancer treatment may cause cognitive impairment. Elderly patients in particular could be at increased risk for treatment-related cognitive deterioration. A consecutive series of cancer out-patients >or=65 years old were prospectively assessed by means of a neuropsychological test Cambridge Cognitive Examination (CAMCOG) test at baseline, and after 3 and 6 months from study entry. Patients were categorized in three groups (group 1, no anticancer treatment; group 2, receiving chemotherapy; group 3, receiving endocrine therapy). Comprehensive geriatric assessment was performed at the three time points evaluation. Sixty-one patients were enrolled (32, 16 and 13, in groups 1, 2, and 3, respectively). At baseline, cognitive function was directly correlated to Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scores and was associated with higher educational level and absence of depression. Overall, cognitive function did not worsen across time in each group. However, more patients in the CT group showed worsening in memory skills, and more patients in the ET and CT group experienced reduction in the attention score.

Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC.

BACKGROUND: Complete surgical resection of gastric cancer is potentially curative, but long-term survival is poor. METHODS: Patients with histologically proven adenocarcinoma of the stomach of stages IB, II, IIIA and B, or IV (T4N2M0) and treated with potentially curative surgery were randomly assigned to follow-up alone or to intravenous treatment with four cycles (repeated every 21 days) of PELF (cisplatin [40 mg/m(2), on days 1 and 5], epirubicin [30 mg/m(2), days 1 and 5], L-leucovorin [100 mg/m(2), days 1-4], and 5-fluorouracil [300 mg/m(2), days 1-4] in a hospital setting. Frequencies and severity of adverse events were determined. Overall survival (OS) and disease-free survival (DFS) were compared between the treatment arms using Kaplan-Meier analysis and a Cox proportional hazards regression model. All statistical tests were two-sided. RESULTS: From January 1995 through September 2000, 258 patients were randomly assigned to chemotherapy (n = 130) or surgery alone (n = 128). Patient characteristics were well balanced between the two arms. Among those who received chemotherapy, grade 3 or 4 toxic effects including vomiting, mucositis, and diarrhea were experienced by 21.1%, 8.4%, and 11.8% of patients, respectively. Leucopenia, anemia, and thrombocytopenia of grade 3 or 4 were experienced by 20.3%, 3.3%, and 4.2% of patients, respectively. After a median follow-up of 72.8 months, 128 patients (49.6%) experienced recurrence and 139 (53.9%) deaths were observed, one toxicity-related. Relative to treatment with surgery alone, adjuvant chemotherapy did not increase disease-free survival (hazard ratio [HR] of recurrence = 0.92; 95% confidence interval [CI] = 0.66 to 1.27) or overall survival (HR of death = 0.90; 95% CI = 0.64 to 1.26). CONCLUSIONS: Our results failed to provide proof of an effect of adjuvant chemotherapy with PELF on overall survival or disease-free survival. The estimated effect of chemotherapy (10% reduction in the hazard of death or relapse) is modest and consistent with the results of meta-analyses of adjuvant chemotherapy without platinum agents.

HEX expression and localization in normal mammary gland and breast carcinoma.

BACKGROUND: The homeobox gene HEX is expressed in several cell types during different phases of animal development. It encodes for a protein localized in both the nucleus and the cytoplasm. During early mouse development, HEX is expressed in the primitive endoderm of blastocyst. Later, HEX is expressed in developing thyroid, liver, lung, as well as in haematopoietic progenitors and endothelial cells. Absence of nuclear expression has been observed during neoplastic transformation of the thyroid follicular cells. Aim of the present study was to evaluate the localization and the function of the protein HEX in normal and tumoral breast tissues and in breast cancer cell lines. METHODS: HEX expression and nuclear localization were investigated by immunohistochemistry in normal and cancerous breast tissue, as well as in breast cancer cell lines. HEX mRNA levels were evaluated by real-time PCR. Effects of HEX expression on Sodium Iodide Symporter (NIS) gene promoter activity was investigated by HeLa cell transfection. RESULTS: In normal breast HEX was detected both in the nucleus and in the cytoplasm. In both ductal and lobular breast carcinomas, a great reduction of nuclear HEX was observed. In several cells from normal breast tissue as well as in MCF-7 and T47D cell line, HEX was observed in the nucleolus. MCF-7 treatment with all-trans retinoic acid enhanced HEX expression and induced a diffuse nuclear localization. Enhanced HEX expression and diffuse nuclear localization were also obtained when MCF-7 cells were treated with inhibitors of histone deacetylases such as sodium butyrate and trichostatin A. With respect to normal non-lactating breast, the amount of nuclear HEX was greatly increased in lactating tissue. Transfection experiments demonstrated that HEX is able to up-regulate the activity of NIS promoter. CONCLUSION: Our data indicate that localization of HEX is regulated in epithelial breast cells. Since modification of localization occurs during lactation and tumorigenesis, we suggest that HEX may play a role in differentiation of the epithelial breast cell.

Identification of clinical prognostic factors in patients with unknown primary tumors treated with a platinum-based combination.

OBJECTIVE: The aim of this study was to evaluate patient and tumor characteristics in 102 patients with unknown primary tumors (UPT) prospectively treated with a combination of carboplatin, doxorubicin, and etoposide, to identify clinical variables predictive of response and survival. PATIENTS AND METHODS: The association between clinical characteristics and outcome was evaluated by univariate and multivariate analysis: chi(2) test and logistic regression analysis were used to study variables predictive of response, and survival analysis, comparison of survival curves and Cox multiple regression analysis to study variables predictive of survival. RESULTS: We obtained 26.5% objective responses (95% confidence interval: 18.2-36.1%) and a median survival of 9 months (95% confidence interval: 7-11 months). Several variables were associated with response to treatment and survival at univariate analysis. At multivariate analysis the number of tumor sites, bone/visceral involvement and epithelial tumor markers were significantly predictive of response; presence of pain, serum alkaline phosphatase, carboplatin AUC and response to treatment were significantly associated with survival. CONCLUSIONS: The identification of variables that can predict prognosis and response to treatment in patients with UPT may be useful to offer aggressive treatment to sensitive subsets of patients and provide therapeutic alternatives to those with a low probability of benefiting from standard treatment. In our patients the use of carboplatin AUC higher than 6 and response to treatment were the most important factors associated with prognosis, together with presence of pain and serum alkaline phosphatase. However, larger series and identification of new disease markers are necessary to better define predictive and prognostic variables in UPT patients.

Topoisomerase IIalpha and APE/ref-1 are associated with pathologic response to primary anthracycline-based chemotherapy for breast cancer.

The aim of this study was to evaluate the role of several biological and histological markers (topoisomerase IIalpha, MIB-1, E2F, apoptotic index, APE/ref-1, p53, Her-2/neu, estrogen and porgesterone receptors, and histological grading) as predictors of pathologic response after anthracycline-based chemotherapy for breast cancer. A series of 50 consecutive breast cancer patients receiving anthracycline-based primary chemotherapy were retrospectively studied. Biological markers were assessed by immunohistochemistry (and by TUNEL assay for apoptotic index) in pre-treatment core biopsies and post-treatment surgical samples. The expression of topoisomerase IIalpha, E2F, MIB-1, estrogen and progesterone receptors decreased, while APE/ref-1 staining increased after treatment. Higher topoisomerase IIalpha (P=0.007) and lower APE/ref-1 (P=0.04) expression were associated with better pathologic response.

Tumor shrinkage evaluation during and after preoperative doxorubicin and cyclophosphamide followed by docetaxel in patients with breast cancer.

AIM: To evaluate the relative activity of the sequential administration of doxorubicin and cyclophosphamide (AC) followed by docetaxel alone, as primary systemic therapy in patients with breast cancer, using an in vivo chemosensitivity predictive assay. PATIENTS AND METHODS: Patients with stage II-III breast cancer received two cycles of AC (60/600 mg/m2 every 3 weeks) followed by two cycles of docetaxel (100 mg/m2 every 3 weeks). All patients underwent comprehensive breast imaging prior to chemotherapy, after two AC and after docetaxel. RESULTS: Forty-two patients were accrued and evaluated by intention-to-treat analysis. After two cycles of AC, the median tumor shrinkage was 18.3%, whereas treatment with docetaxel provided an additional median tumor shrinkage of 34.2%. Pathological complete remission was observed in 5 patients (11.9%), whereas 26 patients (61.9%) experienced a partial response. CONCLUSION: The relative contribution of docetaxel to tumor mass reduction seemed to be greater than that of AC. However, the slow rate of tumor shrinkage observed may indicate that the activity of the first 2 cycles of AC is carried over into the part of treatment with docetaxel.

Galectin-3 expression in non-small cell lung carcinoma.

Galectins are a family of animal beta-galactoside-binding lectins involved in malignant transformation and progression. The present study evaluated the immunohistochemical expression of galectin-3 in a consecutive series of 81 radically resected non-small cell lung carcinomas (NSCLCs). The main pattern of galectin-3 expression was cytoplasmic (median percentage of cells with cytoplasmic positivity: 80.0%). The median percentage of tumor cells with nuclear and cytoplasmic co-expression of galectin-3 was 3.5%. No cases with exclusive nuclear immunostaining were observed. Functional interaction between galectin-3 and the thyroid transcription factor-1 (TTF-1) was previously demonstrated by cotransfection experiments. In the present study, concomitant expression of nuclear galectin-3 and TTF-1 was independently associated with a worse clinical outcome (HR 2.0; P = 0.01).

BRCA2 germline mutations in primary cancer of the fallopian tube.

Germline mutations of BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. It has been recently reported that BRCA1/2 mutations may also predispose to fallopian tube cancer. We report the presence of germline BRCA2 gene mutations in three out of four subjects with fallopian tube cancer diagnosed in a two-year time span at our clinic. The mothers of two of these women suffered from breast or ovarian carcinoma. These results suggest on one hand that in patients with a history suggestive for a heredofamilial breast/ovarian cancer syndrome fallopian tube carcinoma is associated with high risk of BRCA2 mutation, and on the other hand that in patients/individuals with germline BRCA2 gene mutations in whom a prophylactic oophorectomy is performed, removal of fallopian tubes may be considered.

Proteomic evaluation of core biopsy specimens from breast lesions.

Analysis of tumour samples by a proteomic technology, which combines two-dimensional gel electrophoresis and mass spectrometry analysis, is a promising approach for molecular characterization of cancer. Proteomic analysis of neoplasms is usually performed on surgical material. The possibility to perform proteomic analysis on pre-operative samples might be useful for diagnostic purposes or for determination of tumour sensitivity to therapy. In this study, we report how tissues from core biopsy of breast lesions can be routinely used to obtain accurate protein expression profiles by proteomic analysis. Protein profiles from fibroadenomas were compared to those from ductal infiltrating carcinomas. By using mass spectrometry, identification of proteins overexpressed in carcinomas with respect to fibroadenomas was obtained. Thus, our study provides a methodology to perform proteomic analysis on pre-operative samples of breast lesions.

The role of levamisole in the adjuvant treatment of stage III colon cancer patients: a randomized trial of 5-fluorouracil and levamisole versus 5-fluorouracil alone.

Adjuvant 5-fluorouracil (5FU) and levamisole (Lev) have been considered standard treatment for stage III colon cancer patients. However, the uncertain contribution of Lev to the efficacy of treatment has led many oncologists to prefer the 5FU/leucovorin combination. To establish the role of Lev, we conducted a randomized trial comparing the 5FU/Lev combination with 5FU alone in patients with Dukes' C colon cancer. Patients with stage III colon cancer were randomized to receive 5FU alone (450 mg/m2 i.v. bolus daily for 5 days and then, beginning at day 28, weekly for 48 weeks) or the same plus Lev (50 mg orally three times/day for 3 days, repeated every 2 weeks for 1 year). From December 1994 to March 1998, 92 patients were assigned to receive 5FU/Lev, and 93 were assigned to receive 5FU alone. Leukopenia and hepatic toxicity were more frequent in patients receiving 5FU/Lev as compared with those receiving 5FU (respectively, p = 0.003 and p = 0.039), whereas other toxicities were equivalent and mild in both arms. After a median follow-up time of 48 months, 80 patients have had recurrences (40 in each arm) and no advantages in terms of disease-free survival and overall survival could be demonstrated for the combination arm. The addition of Lev to 5FU does not seem to be relevant for the clinical activity of this adjuvant regimen, whereas toxicity related to Lev should be considered when an adjuvant treatment for stage III colon cancer patients is proposed.

Role of mammography, ultrasound and large core biopsy in the diagnostic evaluation of papillary breast lesions.

BACKGROUND: It is well recognized that distinguishing benign from malignant papillary lesions of the breast may pose challenging diagnostic problems. To prospectively evaluate the potential role of mammography, ultrasound and image-guided core biopsy in the diagnosis of papillary lesions of the breast. METHODS: 1,442 women consecutively underwent 14-gauge core biopsy and in 51 cases (3.5%) a diagnosis of papillary lesion was formulated. Both radiologists and pathologists independently expressed their degree of suspicion of malignancy (not suspicious, low, moderate, high) on the basis of radiological and core biopsy findings, respectively. Surgical excision of the lesion was used as gold standard and diagnostic agreement was assessed by the kappa statistic. RESULTS: At surgery, 19 of the 49 (38.7%) resected cases had a diagnosis of malignancy. A poor agreement was found between mammography and core biopsy results in the categorization of suspicion of malignancy (k = 0.03). Similar data were obtained between ultrasound and core biopsy (k = 0.07). A poor agreement was also observed between radiological and surgical results (k < 0.20). In contrast, a good agreement was found between core biopsy and surgical samples (k > 0.70). However, 5 (26%) out of the 19 malignant cases at surgery were judged as benign or probably benign on core biopsy. Depending on how the categories of suspicion on core biopsy were set up, the range of sensitivity was 74-89%, whereas specificity ranged from 91 to 97%. CONCLUSIONS: Image-guided large core biopsy allows for a correct diagnosis in the majority of papillary lesions. However, its sensitivity is not good enough for surgical excision to be avoided.

Predictors of short-term survival and progression to chemotherapy in patients with advanced colorectal cancer treated with 5-fluorouracil-based regimens.

The aim of this study was to assess in patients with advanced colorectal cancer which factors were associated with short-term survival (6 months or less) and progression to first-line 5-fluorouracil (5-FU) chemotherapy. Three hundred twenty-one consecutive nonselected patients with advanced colorectal cancer were treated with conventional 5-FU-based regimens as first-line treatment from 1988 to 1999. Factors related to patient, tumor, or treatment were analyzed by univariate and multivariate logistic regression analysis by comparing short survivors (SS, those who survived or= 2) (p = 0.015), elevated (>or=5 microg/l) serum carcinoembryonic antigen (CEA) (p = 0.015), and more than one site of metastatic disease (p < 0.001). Progression to first-line chemotherapy (p < 0.001) was also a strong factor associated with short survival in multivariate analysis; factors predictive of progression were elevated CEA (p = 0.027) and diffuse metastatic disease (p = 0.029). Our data indicate the relevance of some clinical prognostic factors (younger age, poor performance status, elevated CEA, site of primary, number of metastatic sites, resistance to chemotherapy) as independent factors associated with poor survival and progression to first-line chemotherapy in patients with metastatic colorectal cancer treated with conventional 5-FU regimens. Patients identified by these factors as having a poor prognosis and low probability of response to treatment should be considered either for more aggressive regimens or supportive care only: conventional 5-FU treatments do not impact on response or survival.

Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression.

PURPOSE: The relationship between germ-line mutations of hMSH2 and hMLH1, microsatellite instability (MSI), and loss of DNA mismatch repair (MMR) gene expression were studied to formulate an effective selection protocol for patients with suspected hereditary nonpolyposis colorectal cancer who should be offered genetic testing. PATIENTS AND METHODS: Patients eligible for germ-line analysis of hMLH1 and hMSH2 were selected. Tumor specimens were obtained to assess MSI and loss of MMR gene expression. RESULTS: Among 37 patients who participated in the study, two hMSH2 and two hMLH1 missense mutations (11%) were detected, none of which was found in a panel of 60 healthy volunteers. High MSI was found in five tumors (19%) and low MSI in 10 tumors (39%); 12 tumors (46%) were microsatellite stable. Four tumors demonstrated loss of hMLH1, and three tumors demonstrated loss of hMSH2 protein expression. CONCLUSION: No relationship was found between MMR gene mutations and MSI; low or no MSI was found in the four patients with germ-line mutations, and none of the five patients with high MSI demonstrated abnormalities of MMR genes. On the contrary, loss of hMLH1 or hMSH2 expression was found in the tumors from three of the four patients demonstrating germ-line mutations. These data suggest that germ-line mutations of the MMR gene can occur in people with MSI-negative tumors. Sensitive clinical criteria and the study of MMR gene expression may be useful to identify this subset of patients.