Prognostic Role of Pathological Complete Response in Early Stage Epithelial Solid Tumors.

Neoadjuvant chemotherapy was originally designed to convert inoperable cancer. Nowadays, this concept has expanded since it can also offer the possibility to evaluate markers of response such as pathological complete response (pCR) with possible implications in long-term prognostic outcomes. A substantial body of literature tried to evaluate the ability of pCR to fulfill the conditions required to establish a preliminary endpoint, such as pCR, as a surrogate for the final endpoint, the overall survival (OS) but no systematic reviews have been performed yet. In this review we systematically analyzed the prognostic role of pCR in various cancers (breast, gastro-oesophageal, rectal, ovarian, bladder, lung) in which neoadjuvant treatment is a standard of care, evaluating articles published in the English language of phase III or phase II randomized controlled trials and meta-analyses. Since the continue development of immunotherapy in earlier stage, it has also been considered the impact of tumor-infiltrating lymphocyte on pCR.

Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma.

BACKGROUND AND PURPOSE: Glioblastoma (GBM) is the most aggressive and frequent subtype of all malignant gliomas. At the time of recurrence, therapeutic options are lacking. Ortataxel, a second-generation taxane was reported to be effective in pre-clinical and phase I clinical studies. The aim of this study was to evaluate a potential therapeutic activity of ortataxel in patients with GBM recurring after surgery and first line treatment. METHODS: In this phase II study, according to a two stage design, adult patients with histologically confirmed GBM in recurrence after surgery or biopsy, standard radiotherapy and chemotherapy with temozolomide were considered eligible. Patients included were treated with ortataxel 75 mg/m2 i.v. every 3 weeks until disease progression. The primary objective of the study was to evaluate the activity of ortataxel in terms of progression free survival (PFS) at 6 months after the enrollment. PFS, overall survival at 9 months after the enrollment, objective response rate, compliance and safety were evaluated as secondary endpoints. RESULTS: Between Nov 26, 2013 and Dec 12, 2015, 40 patients were recruited across six centres. The number of patients alive and free from progression at 6 months after the enrollment, observed in the first stage was four (11.4%), out of 35 patients included in the analysis, below the minimum number of events (7 out of 33) required to continue the study with the second stage The most important toxicities were neutropenia and hepatotoxicity that occurred in 13.2% of patients and leukopenia that occurred in 15.8% of patients. CONCLUSION: Overall ortataxel treatment fail to demonstrate a significant activity in recurrent GBM patients. However in a limited number of patients the drug produced a benefit that lasted for a long time. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT01989884.

Eribulin Treatment in Patients with Liver Metastatic Breast Cancer: Eight Italian Case Reports.

Liver metastases are very common in metastatic breast cancer (MBC); current treatments for these lesions are based on systemic chemotherapy, endocrine- or human epidermal growth factor receptor 2 (HER2)-targeted therapy, and palliative therapy. However, no standard approach has been clearly identified for second and further chemotherapy lines in MBC patients. In the phase III clinical trial EMBRACE, eribulin was particularly effective in reducing liver lesions and improving both overall survival and progression-free survival in liver MBC patients. In this series, we collected 8 case reports of Italian clinical practice in which eribulin has shown significant efficacy in reducing liver metastases in MBC patients: complete response was reported in 2 patients, and 4 patients achieved partial response. The treatment was well tolerated, thus confirming that eribulin is a suitable therapeutic option for elderly patients and for those who have metastatic HER2-negative disease. In the setting of MBC, the sequencing of therapeutic agents should consider expected response, side effects, tumor characteristics, and patient's preferences, in order to successfully tailor the most appropriate therapy beyond earlier lines.

Eribulin across multiple lines of chemotherapy: a retrospective study on quality of life and efficacy in metastatic breast cancer patients.

This study evaluates efficacy, tolerability and health-related quality of life of eribulin in patients with metastatic breast cancer. Predictive and/or prognostic factors of outcome were also analyzed. Among 44 women receiving eribulin mesylate, one patient had a complete response, 22.7% a partial response and 25% a stable disease. Median overall survival and median progression-free survival were 11.8 and 4.5 months, respectively. Treatment was well tolerated; the most frequent adverse events were neutropenia (52%), leukopenia (50%), fatigue (38%) and alopecia (40%). No significant reductions of health-related quality of life parameters were observed. Disease control during previous chemotherapy lines was related with better outcome with eribulin. In conclusion, eribulin treatment should be considered in a multiple chemotherapy lines strategy in metastatic breast cancer.

Efficacy and activity of treatments after progression from palbociclib plus endocrine therapy in patients with HR+/HER2- metastatic breast cancer: a prospective, monocentric study.

Background: Breast cancer is the most frequent tumour worldwide, and the HR+/HER2- subtype is the most common. For this tumour type, endocrine therapy (ET) is the mainstay of treatment. The association of ET and CDK4/6 inhibitors (CDK4/6i) represents the gold standard for first-line or second-line therapies. However, the optimal therapeutic strategy after CDK4/6i progression is still a matter of debate, with several randomized clinical trials still ongoing. Patients and methods: This is an observational, prospective, real-world study including women with HR+/HER2- metastatic breast cancer progressing to palbociclib plus ET. Patients received either ET or chemotherapy (CT). The primary objective was the evaluation of efficacy of the different therapeutic strategies after palbociclib in terms of median progression-free survival 2. Secondary objectives were the activity of therapeutic strategies measured with the clinical benefit rate, evaluation of the parameters used for the treatment choice, and progression-free survival 1 related to palbociclib plus ET treatment. Results: Overall, 48 patients (median age 53, range 33-78 years) were included. The median progression-free survival 2 was of 5 months in the overall cohort (95% CI 4-48 months) with a statistically significant difference between the two therapeutic strategies adopted (ET versus CT, 10 months versus 5 months, respectively). Regarding secondary objectives, the clinical benefit rate was 55.2% in the CT cohort and 50% in ET. Moreover, women treated with CT had a greater number of visceral metastases and a shorter median progression-free survival 1 than patients who received ET. Conclusions: ET and CT represent two possible therapeutic alternatives for patients progressing on CDK4/6i plus ET. The choice is based on clinical parameters, with a potential preference for ET.

Health-related quality of life and clinical complexity of a real-life cohort of patients with advanced HR+/HER2- breast cancer treated with CDK4/6 inhibitors and endocrine therapy.

Background: Advanced breast cancer (ABC) is characterized by multidimensional clinical complexity that is usually not considered in randomized clinical trials. In the present real-life study, we investigated the link between clinical complexity and quality of life of patients with HR+/HER2- ABC treated with CDK4/6 inhibitors. Methods: We evaluated multimorbidity burden assessed with the Cumulative Illness Rating Scale (CIRS), polypharmacy and patient-reported outcomes (PROs). PROs were assessed at baseline (T0), after 3 months of therapy (T1), and at disease progression (T2) using EORTC QLC-C30 and QLQ-BR23 questionnaires. Baseline PROs and changes between T0 and T1 were evaluated amongst patients with different multimorbidity burden (CIRS <5 and ≥5) and polypharmacy (<2 or ≥2 drugs). Results: From January 2018 to January 2022, we enrolled 54 patients (median age 66 years, IQR 59-74). The median CIRS score was 5 (IQR 2-7), whilst the median number of drugs taken by patients was 2 (IQR 0-4). No changes in QLQ-C30 final scoring between T0 and T1 were observed in the overall cohort (p=0.8944). At T2, QLQ-C30 global score deteriorated with respect to baseline (p=0.0089). At baseline, patients with CIRS ≥5 had worse constipation than patients without comorbidities (p<0.05) and a lower trend in the median QLQ-C30 global score. Patients on ≥2 drugs had lower QLQ-C30 final scores and worse insomnia and constipation (p<0.05). No change in QLQ-C30 final score from T0 to T1 was observed (p>0.05). Conclusion: Multimorbidity and polypharmacy increase the clinical complexity of patients with ABC and may affect baseline PROs. The safety profile of CDK4/6 inhibitors seems to be maintained in this population. Further studies are needed to assess clinical complexity in patients with ABC.This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/.

Mismatch repair deficiency as prognostic factor for stage III small bowel adenocarcinoma: A multicentric international study.

BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare cancer with an aggressive behavior. No study has specifically addressed the putative prognostic role of mismatch repair status in stage III SBAs. AIMS: We aimed to investigate whether mismatch repair deficiency is associated with cancer-specific survival in a Western cohort of patients with stage III SBAs. METHODS: In this retrospective multicentric international cohort study, we enrolled 70 patients who underwent surgically resection for stage III SBAs and we analyzed the frequency of mismatch repair deficiency, tested by immunohistochemistry for mismatch repair proteins and by polymerase chain reaction for microsatellite instability, and its association with cancer-specific survival and other clinic-pathologic factors. RESULTS: We found sixteen (23%) patients with mismatch repair deficient adenocarcinoma, without discordance between immunohistochemical and polymerase chain reaction for microsatellite instability analyses. Mismatch repair deficiency proved to be associated with a better outcome both at univariable analysis (hazard ratio: 0.28, 95% confidence interval: 0.08-0.91, p: 0.035) and in bivariable models adjusted for patient age or gender, tumor site, pT4 stage, tumor budding, and perineural invasion. CONCLUSION: This study highlights the importance of testing mismatch repair status to improve prognostic stratification in stage III SBAs.

Perceived risk, illness perception and dispositional optimism related to COVID-19 among oncologic outpatients undergoing in-hospital treatments and healthy controls.

OBJECTIVE: This study aimed to explore risk estimations (perceived risk, dispositional optimism) related to COVID-19 perception and distress in oncologic outpatients undergoing active hospital treatments compared to the general population. DESIGN AND MAIN OUTCOME MEASURES: Data were collected during the Italian lockdown on 150 oncologic outpatients and a sample of 150 healthy subjects. They completed a battery of questionnaires including the Perceived Risk scale, the Brief Illness Perception Questionnaire, the Life Orientation Test- Revised and the Patient Health Questionnaire-4. Descriptive statistics, correlation analysis, and a moderated mediation model were performed to test the study hypotheses. RESULTS: The moderated mediation model attested significant conditional indirect associations of both clinical status and dispositional optimism with distress through the mediation of COVID-19 perceived risk. Healthy individuals and less optimistic people were more likely than others to report higher psychological distress only when they showed neutral or negative COVID-19-related illness perception. CONCLUSIONS: Cancer patients manifest a lower risk perception and a more positive illness representation related to COVID-19 compared to control subjects; the distress level is not associated with the clinical status, but it is moderated by illness perception. Adequate protective behaviors in cancer patients may avoid a dangerous underestimation of objective risks.

Clinical and Biological Variables Influencing Outcome in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Anti-PD-1/PD-L1 Antibodies: A Prospective Multicentre Study.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become the standard of treatment for patients with non-small cell lung cancer (NSCLC). However, there are still many uncertainties regarding the selection of the patient who could benefit more from this treatment. This study aims to evaluate the prognostic and predictive role of clinical and biological variables in unselected patients with advanced NSCLC candidates to receive ICIs. METHODS: This is an observational and prospective study. The primary objective is the evaluation of the relationship between clinical and biological variables and the response to ICIs. Secondary objectives included: safety; assessment of the relationship between clinical and biological parameters/concomitant treatments and progression-free survival at 6 months and overall survival at 6 and 12 months. Nomograms to predict these outcomes have been generated. RESULTS: A total of 166 patients were included. An association with response was found in the presence of the high immunohistochemical PD-L1 expression, squamous cell histotype, and early line of treatment, whereas a higher probability of progression was seen in the presence of anemia, high LDH values and neutrophil/lymphocyte ratio (NLR), pleural involvement, and thrombosis before treatment. The nomogram showed that anemia, PD-L1 expression, NLR, and LDH represented the most informative predictor as regards the three parameters of interest. CONCLUSIONS: In the era of personalized medicine, the results are useful for stratifying the patients and tailoring the treatments, considering both the histological findings and the clinical features of the patients.

Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study.

Non-ampullary small bowel adenocarcinoma is a rare neoplasm with an ominous prognosis, whose incidence is higher in some chronic immuno-inflammatory conditions, such as coeliac and Crohn's disease. Recently, claudin 18.2, a transmembrane protein normally expressed in gastric mucosa, has been recognized as a novel pan-cancer therapeutic target, and several clinical trials with claudin-18-directed drugs have shown promising results on various gastrointestinal malignancies. This is the first study focusing on claudin-18 expression in small bowel adenocarcinomas. The immunohistochemical expression of claudin-18 (clone 43-14A) was assessed in 81 small bowel adenocarcinomas of diverse aetiologies and correlated with several clinico-pathologic features and patient survival. We found that 28% of adenocarcinomas were immunoreactive for claudin-18, with cutoff values of ≥1% at any intensity, while 6% of cancers showed immunoexpression of ≥75% with 2+/3+ score. Moreover, claudin-18 (≥1%) was positively associated with cytokeratin 7 (CK7) and MUC5AC expression, showing CK7+/MUC5AC+ carcinomas the highest rate of positive cases, whereas a negative correlation was found between claudin-18 and CDX2 expression. In addition, some cancer-adjacent dysplastic growths and foci of gastric-type metaplasia in Crohn's disease-associated cases showed claudin-18 immunoreactivity. Survival analysis showed a non-significant trend towards a worse cancer-specific survival for claudin-18-positive cases. A fraction of small bowel adenocarcinomas, mainly sporadic or Crohn's disease-associated, and often exhibiting a non-intestinal immunoprofile, expressed claudin-18, suggesting that claudin-18-directed targeted therapy is worth investigating in such cancers.

The prognostic role of variations in tumour markers (CEA, CA15.3) in patients with metastatic breast cancer treated with CDK4/6 inhibitors.

Tumour markers have no established role in the monitoring of the course of metastatic breast cancer during antineoplastic therapy, yet cancer antigen 15.3 (CA15.3) and carcinoembryonic antigen (CEA) are commonly used in clinical practice to aid in the early detection of progression of disease (PD). In our multicentre, prospective, real-life study, we enrolled 142 consecutive patients with advanced breast cancer receiving endocrine therapy in combination with a CDK4/6 inhibitor from January 2017 to October 2020; 75 patients had PD at the time of database closure. We measured serum marker concentrations at regular 4-month intervals together with radiological tumour response assessments and in cases of clinical suspicion of PD. Appropriate descriptive and inferential statistical methods were used to analyse serum marker level trends amongst prespecified subgroups and at specific time points (baseline, best radiologically documented tumour response and first detection of PD) in the subpopulation of patients with PD at the time of database closure. Notably, the median time from treatment initiation to best tumour response was 4.4 months. We evaluated the presence of an association between baseline CA15.3 and CEA levels and prespecified clinical characteristics but found no clinically meaningful correlation. We assessed marker level variations at the time of best radiologically documented disease response and PD: in the subgroup of patients who responded to treatment before progressing, we detected a statistically significant correlation with tumour marker variation between the time of best response and progression; this finding was not confirmed in the subgroup of patients that did not benefit from treatment. In conclusion, serum tumour marker flares can be useful in the early diagnosis of PD but should not be used as the sole factor prompting a change in treatment strategy without radiological confirmation.

Poorly Cohesive Carcinoma of the Nonampullary Small Intestine: A Distinct Histologic Subtype With Prognostic Significance.

Poorly cohesive carcinomas (PCCs) are neoplasms characterized by a dyshesive cell invasion pattern featuring single-cell or cord-like stromal infiltration. Although they have been extensively studied in the stomach and other digestive system organs, limited data regarding nonampullary small bowel poorly cohesive carcinomas (SB-PCCs) are hitherto available. The aims of our study were to analyze the clinicopathologic and immunophenotypical features of SB-PCCs (PCC pattern accounting for >50% of the neoplasm) and to compare them with small bowel adenocarcinomas (SBAs), not otherwise specified (SBAs-NOS) and with cancers with a histologically distinct PCC component accounting for 10% to 50% of the neoplasm (mixed-poorly-cohesive-glandular-SBAs). Fifteen SB-PCCs were identified and compared with 95 SBAs-NOS and 27 mixed-poorly-cohesive-glandular-SBAs. Most SB-PCCs (67%) were composed of <10% of signet-ring cells, and all but 1 SB-PCCs exhibited loss of membranous expression of E-cadherin. Compared with SBAs-NOS, SB-PCCs showed a significantly younger patient age at diagnosis, and a stronger association with Crohn disease, and both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs featured a higher rate of lymphovascular and perineural invasion and a lower percentage of mismatch repair-deficient cases. Importantly, the cancer-specific survival of SB-PCC (hazard ratio: 3.81; 95% confidence interval: 1.90-7.64; P<0.001) and mixed-poorly-cohesive-glandular-SBA (4.12; 2.20-7.71; P<0.001) patients was significantly worse compared with SBAs-NOS cases. This study provides objective evidence to the World Health Organization (WHO) 2019 introduction of SB-PCC as a distinctive subtype of nonampullary SBA, by virtue of its unique clinical and histologic features, and suggests that both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs should be separated from SBAs-NOS.

Patterns of treatment and outcome of palbociclib plus endocrine therapy in hormone receptor-positive/HER2 receptor-negative metastatic breast cancer: a real-world multicentre Italian study.

BACKGROUND: The CDK4/6 inhibitor palbociclib combined with endocrine therapy (ET) has proven to prolong progression-free survival (PFS) in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Few data are available regarding the efficacy of such a regimen outside the clinical trials. PATIENTS AND METHODS: This is a multicentre prospective real-world experience aimed at verifying the outcome of palbociclib plus ET in an unselected population of MBC patients. The primary aim was the clinical benefit rate (CBR); secondary aims were the median PFS, overall survival (OS) and safety. Patients received palbociclib plus letrozole 2.5 mg (cohort A) or fulvestrant 500 mg (cohort B). RESULTS: In total, 191 patients (92 in cohort A, 99 in cohort B) were enrolled and treated, and 182 were evaluable for the analysis. Median age was 62 years (range 47-79); 54% had visceral involvement; 28% of patients had previously performed one treatment line (including chemotherapy and ET), 22.6% two lines and 15.9% three. An overall response rate of 34.6% was observed with 11 (6.0%) complete responses and 52 (28.6%) partial responses. Stable disease was achieved by 78 patients (42.9%) with an overall CBR of 59.8%. At a median follow-up of 24 months (range 6-32), median PFS was 13 months without significant differences between the cohorts. When analysed according to treatment line, PFS values were significantly prolonged when palbociclib-based therapy was administered as first-line treatment (14.0 months), to decrease progressively in second and subsequent lines (11.7 and 6.7 months, respectively). Median OS was 25 months, ranging from 28.0 months in 1st line to 18.0 and 13.0 months in 2nd and subsequent lines, respectively. CONCLUSIONS: Our data indicate that palbociclib plus ET is active and safe in HR+/HER2- MBC, also suggesting a better performance of the combinations in earlier treatment lines.

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer.

Prostate cancer (PC) is the most common male cancer in Western Countries. In recent years, the treatment of relapsed or metastatic disease had benefited by the introduction of a variety of new different drugs. In consideration of the relative long survival of PC patients, side effects of these drugs must be considered and monitored. In this review, we analyzed the newly developed therapies for PC treatment, describing the mechanism of action, the metabolism and latest clinical trials that led to the approval of these drugs in clinical practice. We then evaluated the cardiovascular and renal side effects from pivotal phase III and II studies and meta-analyses. Cardiovascular side effects are the most frequent, in particular hypertension, while renal toxicity is rarer and not well described in literature. Therefore, there is a need to better define the effects of these therapies, in order to personalize patient treatment on the basis of their comorbidities and preferences, in addition to their symptoms and disease load.

Bilateral Breast Metastases from Epstein-Barr Virus-Associated Gastric Cancer during Pregnancy: Is There a Method to Its Madness?

Breast metastases of extramammary malignant neoplasms are rare, with an incidence of 0.3%-2.7% among all malignant mammary tumors. Breast metastases from gastric carcinoma are very rare (<0.1%), and this event is even rarer during pregnancy. Herein, we describe a 39-year-old Caucasian woman with a history of an Epstein-Barr virus-associated gastric carcinoma (EBVaGC) that was characterized by prominent tumor infiltrating lymphocytes. Three years after undergoing radical surgery, the patient developed bilateral breast nodules during her pregnancy. A breast biopsy was performed, and histology confirmed a diagnosis of EBVaGC; tumor cells showed positivity for cytokeratin 8/18 and E-cadherin, and negativity for cytokeratin 7, cytokeratin 20, cytokeratin 5/6, caudal type homebox 2, androgen receptor, mammaglobin, gross cystic disease fluid protein-15, and estrogen and progesterone receptors. We also discuss the main diagnostic pitfalls. To our knowledge, this is the first report of an EBVaGC with lymphoid stroma that developed breast metastases during pregnancy.

Role of androgen receptor expression in early stage ER+/PgR-/HER2- breast cancer.

BACKGROUND: Progesterone receptor (PgR) negative breast cancer (BC) is an aggressive subtype with poor prognosis and reduced response to endocrine treatments. Several studies have suggested that androgen receptor (AR) expression is associated with a favorable tumor biology, longer recurrence free survival (RFS), and overall survival. In the literature no data exist regarding the role of AR expression in early stage estrogen receptor (ER)+/PgR- BCs. The aim of this study was to evaluate the prognostic role of AR expression in this setting. PATIENTS AND METHODS: This is a monocentric retrospective study in which 208 patients who underwent surgical intervention for ER+/PgR-/Human Epidermal growth factor Receptor 2 (HER2)- BC were included. The primary objective was to analyze the relationship between AR expression and RFS. RESULTS: At a median follow-up of 77 months, 75 patients (36%) had a disease relapse (all sites included). AR expression was significantly higher in patients who did not relapse compared with those who relapsed with an impact on RFS (hazard ratio [HR] = 0.99, p = 0.025). Patients with AR expression ⩾80% had a lower risk of relapse compared with those with AR <80% (HR = 0.53, p = 0.008). In addition, breast tumors with higher AR expression had good biological features (low ki67 and nuclear grade) compared with BCs with lower AR expression, at least partly explaining the different outcome. CONCLUSIONS: The results of this study support the potential prognostic role of AR in patients with ER+/PgR- BCs and may contribute to the identification of subgroups of high-risk patients.

Impact of COVID-19 Outbreak on Cancer Patient Care and Treatment: Data from an Outpatient Oncology Clinic in Lombardy (Italy).

Lombardy was the first area in Italy to have an outbreak of coronavirus disease 19 (COVID-19) at the beginning of 2020. In this context, cancer has been reported as a major risk factor for adverse outcomes and death, so oncology societies have quickly released guidelines on cancer care during the pandemic. The aim of this study was to investigate the management of cancer patients and oncological treatments during the COVID-19 pandemic and to describe the containment measures performed in our outpatient clinic at Pavia (Lombardy). A comparison with the same period of the four previous years (2019, 2018, 2017, and 2016) was also performed. Using our electronic databases, we evaluated the number and characteristics of patients accessing the hospital for anticancer drug infusion from 24 February, 2020 to 30 April, 2020 and the number of radiological exams performed. Although a significant reduction in access for therapy was seen when compared with 2019 (2590 versus 2974, access rate ratio (ARR) = 0.85, p < 0.001), no significant differences in access numbers and ARR was evident between 2020 and 2018, 2017, or 2016 (2590 versus 2626 (ARR = 0.07), 2660 (ARR = 0.99), and 2694 (ARR = 0.96), respectively, p > 0.05). In 2020, 63 patients delayed treatment: 38% for "pandemic fear", 18% for travel restrictions, 13% for quarantine, 18% for flu syndrome other than COVID-19, and 13% for worsening of clinical conditions and death. Only 7/469 patients developed COVID-19. A significant reduction in radiological exams was found in 2020 versus all the other years considered (211 versus 360, 355, 385, 390 for the years 2020, 2019, 2018, 2017, and 2016, respectively, p < 0.001). The low incidence of COVID-19 among our cancer patients, along with the hospital policy to control infection, enabled safe cancer treatment and a continuum of care in most patients, while a small fraction of patients experienced a therapeutic delay due to patient-related reasons.

Small Bowel Adenocarcinomas Featuring Special AT-Rich Sequence-Binding Protein 2 (SATB2) Expression and a Colorectal Cancer-Like Immunophenotype: A Potential Diagnostic Pitfall.

Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn's disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7-/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7-/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7-/CK20- or CK7-/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20- or CK7+/CK20+ cancers (p = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7-/CK20- cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.

The PI3K/AKT/mTOR and CDK4/6 Pathways in Endocrine Resistant HR+/HER2- Metastatic Breast Cancer: Biological Mechanisms and New Treatments.

Endocrine-based treatments are the normal standard-of-care in women with hormone receptor-positive/Human Epidermal growth factor Receptor 2-negative metastatic breast cancer. Despite the well-known efficacy of these drugs as first-line therapies, about 50% of women develop endocrine resistance and disease progression. The treatment of these patients has represented one of the most important research fields in the last few years, with several multicenter phase II/III trials published or still ongoing. Novel therapies, such as cyclin-dependent kinase (CDK)4/6 and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, have significantly changed the prognosis of patients progressing to a previous endocrine treatment, allowing a great benefit in terms of progression-free survival and, in some cases, of overall survival. However, identifying response predictors is essential for the rational use of these drugs to avoid unnecessary toxicity and costs, and to ensure the optimal therapeutic sequence is used. In this review, we analyze the PI3K/AKT/mTOR and CDK4/6 pathways and their roles in endocrine resistant metastatic breast cancer. We then focus on the new treatments developed and the roles of these drugs in overcoming endocrine resistance, describing the latest clinical trials that led to the approval of the drugs in clinical practice.

Non-traumatic splenic rupture in amyloidosis as a rare evolution of multiple myeloma.

We report the case of a 64-year-old man with a diagnosis of IgG lambda multiple myeloma (MM) symptomatic for bone lesions for which he received autologous stem cell transplant after induction treatment and high-dose melphalan, thalidomide and lenalidomide therapy. Twelve years after the diagnosis, he had an unexpected and acute onset of abdominal pain with signs of hypovolemic shock. A computed tomography scan was immediately performed and demonstrated a splenic rupture. A splenectomy was performed but, a week after, the patient developed an acute respiratory distress syndrome and died. After histological exam of the spleen, non-traumatic spleen rupture due to amyloidosis was our final diagnosis. This event is potentially fatal and rare in patients with MM; clinicians should be aware of this potential course of the disease and monitor patients also for amyloid induced organ damages.