Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm?

The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient\u27s outcomes. In that regard, CUP patients’ outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology of CUP has two main hypotheses. One is that CUP is a subgroup of a given primary cancer, where the primary is present but cannot be seen due to its small size. The other, the “true” CUP hypothesis, states that CUP share features that make them a specific entity, whatever their tissue of origin. A true biological signature has not yet been described, but chromosomal instability is a hallmark of poor prognosis CUP group. Precision oncology, despite achieving identifying the putative origin of the CUP, so far failed to globally improve outcomes of patients. Targeting molecular pathways based on molecular analysis in CUP management is under investigation. Immunotherapy has not shown ground-breaking results, to date. Accrual is also a crucial issue in CUP trials. Herein we review CUP history, biological features and remaining questions in CUP biology, the two main approaches of molecular oncology in CUP management, in order to draw perspectives in the enormous challenge of improving CUP patient outcomes

Patterns of Disease Progression and Outcome of Patients With Testicular Seminoma Who Relapse After Adjuvant or Curative Radiation Therapy.

PURPOSE Radiation therapy is a possible treatment strategy for patients with testicular seminoma after orchiectomy in clinical stage I or II disease. Little is known about the outcome of patients who experience a relapse after radiation therapy. METHODS AND MATERIALS Data from 61 patients who relapsed after adjuvant or curative radiation therapy from 17 centers in 11 countries were collected and retrospectively analyzed. Primary outcomes were disease-free and overall survival. Secondary outcomes were time to relapse, stage at relapse, treatment for relapse, and rate of febrile neutropenia during chemotherapy for relapse. RESULTS With a median follow-up of 9.9 years (95% confidence interval [CI], 7.5-10.9), we found a 5-year disease-free survival of 90% (95% CI, 79-95) and a 5-year overall survival of 98% (95% CI, 89-100). Sixty-six percent of patients had stage III disease at time of relapse and 93% of patients fell into the good prognosis group per the International Germ Cell Cancer Collaborative Group classification. The median time to relapse after radiation therapy was 15.6 months (95% CI, 12-23). Twenty-two (36%) patients relapsed more than 2 years after radiation therapy and 7 (11.5%) patients relapsed more than 5 years after radiation therapy. One-third of relapses was detected owing to patients' symptoms, whereas two-thirds of relapses were detected during routine follow-up. The majority (93%) of cases were treated with cisplatin-based chemotherapy. The rate of febrile neutropenia during chemotherapy was 35%. Five patients experienced a second relapse. At last follow-up, 55 patients (90%) were alive without disease. Only 1 patient died owing to disease progression. CONCLUSIONS Cisplatin-based chemotherapy for patients with seminoma who have relapsed after treatment with radiation therapy alone leads to excellent outcomes. Patients and physicians should be aware of possible late relapses after radiation therapy

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic:A Survey of International Expertise Centers

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). MATERIALS AND METHODS: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. RESULTS: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. CONCLUSION: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

ONE YEAR OF BIOSIMILAR FILGRASTIM IN ROUTINE CLINICAL PRACTICE

Objectives: The use of biosimilar filgrastim has been debated for the limited experience at the time of the approval. We performed a retrospective data analysis of 52 patients who underwent and completed a chemotherapy line for advanced solid tumour and received primary (n=46) or secondary (n=6) prophylaxis with biosimilar filgrastim (Zarzio®). Methods: All hospital day patients with an expected risk of FN >20% (n=21) or FN risk < 20% at high risk for infection (n=25), received 3 days (days 2−4) primary prophylaxis with subcutaneous bolus injections of Zarzio® 300 μg/die. Uneligible patients who developed severe neutropenia after the first cycle, received secondary prophylaxis. Blood tests were performed at the nadir and the day before chemotherapy. The primary end-point was to evaluate the efficacy and tolerability of Zarzio® in terms of severe neutropenia or overall FN incidence and duration. Results: Our retrospective data analysis involved 52 patients (median age 59.2 years) with fifteen aged ≥65 years and median body weight of 70 kg who received a total of 243 chemotherapy cycles (median 4.6 cycles/patient) and 651 Zarzio® administrations (median 12.5 administrations/patient). Severe neutropenia was recorded in 29/452 blood tests. None of the patients developed FN. Two patients received prophylactic antibiotics for severe neutropenia. None of the patients delayed the treatment for bone marrow toxicity. Conclusion: Our data confirmed the efficacy and safety of Zarzio® in routine clinical practice. The use of a three days schedule is actually under debate; longer schedule (5 up to 10 days) could improve the outcome

Biosimilar filgrastim in routine clinical practice: a single centre experience.

Introduction: The use of recombinant human granulocyte colony-stimulating factors (rh-G-CSF) has significantly increased the ability to maintain effective schedules and doses of chemotherapy regimens with severe medullary toxicity. However, despite numerous guidelines, the use of rh-G-CSFs in clinical practice is often suboptimal, occurring on a non-systematic case-by-case basis. The availability of biosimilar filgrastim at significantly reduced costs may allow more patients to benefit from growth factor support with comparable results to the originator filgrastim in terms of febrile neutropenia (FN) risk reduction. We performed a retrospective data analysis of 42 patients who underwent chemotherapy for advanced solid tumours and received primary prophylaxis with biosimilar filgrastim (Zarzio®). Methods: All hospital day patients with an expected risk of FN >20% based on their scheduled chemotherapy regimen received 3 days (days 2−4) primary prophylaxis with subcutaneous bolus injections of Zarzio® 300 μg. Patients with FN < 20% and poor bone marrow reserve or other severe co-morbidities and at high risk for infection also received primary prophylaxis. Blood tests were performed at the nadir and the day before the next cycle of treatment. Patients were usually asked to repeat each test in the same laboratory. The primary end-point was the efficacy and tolerability of primary prophylaxis with Zarzio® in terms of severe neutropenia and overall FN incidence and duration in unselected cancer patients in routine clinical practice. Treatment related toxicity (predominantly muscle-skeletal events) was evaluated through the NCI CTC 3.0. Results: We analysed data from 42 patients (male, n=14; female n=28) with advanced solid tumours (breast, n=15; endometrial/ovarian, n=7; non-small-cell lung, n=6; gastric, n=5; others, n=9) who received primary prophylaxis with Zarzio® for FN. Median age was 58 years (range: 26−82), with one-third of patients (n=14) aged ≥65 years. Median body weight was 68 kg (range 44−101). Eighteen patients received primary prophylaxis because of an FN risk >20% and 24 because of associated co-morbidities. A total of 185 chemotherapy cycles was administered (median 4.4 cycles/patient). Zarzio® was administered 538 times (median 12 administrations/patient). Severe neutropenia (ANC ≤ 1100 x 109/L) was recorded in 24/401 blood tests. None of the patients developed FN. Musculoskeletal event (arthralgia, myalgia, bone pain) after Zarzio® administration were as expected ; two patients reported cutaneous rash and one patient had hypotension. There were no significant differences between the elderly population (aged ≥65 years) and patients aged <65 years in terms of toxicity or severe neutropenic events (11 versus 13 events, OR: 0.57, 95% CI 0.24−1.31, p= 0.18). Conclusion: Our retrospective analysis in unselected patients confirmed the efficacy and safety profile of Zarzio® in routine clinical practice. No patients developed FN or had delayed treatment because of severe neutropenia. Elderly patients (33.3% of the study population) did not differ significantly from other patients in terms of treatment tolerability and efficacy

Osteoarthritis Pain in Old Mice Aggravates Neuroinflammation and Frailty: The Positive Effect of Morphine Treatment

Knee osteoarthritis is a common cause of pain and disability in old subjects. Pain may predispose to the development of frailty. Studies on mechanisms underlying pain in osteoarthritis models during aging are lacking. In this work, we used the monosodium iodoacetate model of osteoarthritis in adult (11-week-old) and old (20-month-old) C57BL/6J mice to compare hypersensitivity, locomotion, neuroinflammation, and the effects of morphine treatment. After osteoarthritis induction in adult and old mice, weight-bearing asymmetry, mechanical allodynia, and thermal hyperalgesia similarly developed, while locomotion and frailty were more affected in old than in adult animals. When behavioral deficits were present, the animals were treated for 7 days with morphine. This opioid counteracts the behavioral alterations and the frailty index worsening both in adult and old mice. To address the mechanisms that underlie pain, we evaluated neuroinflammatory markers and proinflammatory cytokine expression in the sciatic nerve, DRGs, and spinal cord. Overexpression of cytokines and glia markers were present in osteoarthritis adult and old mice, but the activation was qualitatively and quantitatively more evident in aged mice. Morphine was able to counteract neuroinflammation in both age groups. We demonstrate that old mice are more vulnerable to pain&rsquo;s detrimental effects, but prompt treatment is successful at mitigating these effects

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design

BACKGROUND Carcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. MATERIALS AND METHODS Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined. RESULTS A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabyte of DNA; 34 patients (11.6%) had a TMB greater or equal to 16 mutations per megabyte. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 or 303 specimens; 19.6% had a score of >16%. CONCLUSIONS Thirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 IMPLICATIONS FOR PRACTICE: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, like programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment

Randomized controlled trial of remote endarterectomy versus endovascular intervention for TransAtlantic Inter-Society Consensus II D femoropopliteal lesions

ObjectiveThis study evaluated outcomes of remote endarterectomy (RE) vs endovascular (ENDO) interventions on TransAtlantic Inter-Societal Consensus (TASC)-II D femoropopliteal lesions and identified factors predictive of restenosis.MethodsFrom October 2004 to December 2008, 95 patients with TASC-II D lesions were randomized 1:1 to receive RE of the superficial femoral artery (SFA) with end point stenting (51 patients) or ENDO, consisting of subintimal angioplasty with stenting (44 patients). The groups were balanced for age, sex, atherosclerotic risk factors, and comorbidities. Categoric data were analyzed with χ2 tests, and time to event provided two-sided P values with a level of significance at .05 and 95% confidence intervals (CIs). Survival curves for primary patency were plotted using the Kaplan-Meier method. Univariate analysis for diabetes, hypertension, dyslipidemia, smoking, and critical ischemia was performed according to the Cox proportional hazards model.ResultsThe mean follow-up was 52.5 months (range, 35-75 months). Five RE patients and four ENDO patients were lost to follow-up (censored). Primary patency was 76.5% (39 of 51) in RE and 56.8% (25 of 44) in ENDO (hazard ratio [HR], 2.6; 95% CI, 0.99-4.2; P = .05) at 24 months and was 62.7% (32 of 46) in RE and 47.7% (21 of 40) in ENDO (HR, 1.89; 95% CI, 0.94-3.78; P = .07) at 36 months. Assisted primary patency was 70.6% (36 of 51) in RE and 52.3% (23 of 44) in ENDO (HR, 2.45; 95% CI, 1.20-5.02; P = .01). Secondary patency overlapped the primary comparison data at 12 and 24 months; at 36 months, there was a slight but significative advantage for RE (HR, 2.26; 95% CI, 1.05-4.86; P = .03). Univariate analysis demonstrated that hypercholesterolemia and critical limb ischemia (CLI) were significantly related to patency failure, whereas diabetes was significant only in ENDO. These factors (hypercholesterolemia and CLI) were independent predictors of patency on Cox multivariate analysis.ConclusionsRE is a safe, effective, and durable procedure for TASC-II D lesions. Our data demonstrate a significantly higher primary, assisted primary, and secondary patency of RE vs ENDO procedures. Furthermore, overall secondary patency rates remain within the standard limits, although preoperative CLI and dyslipidemia continue to be associated with worse outcomes. Taken together, these data suggest that RE should be considered better than an endovascular procedure in SFA long-segment occlusion treatment