Occult primary

Occult primary tumors, or cancers of unknown primary (CUPs), are defined as histologically proven metastatic malignant tumors whose primary site cannot be identified during pretreatment evaluation. They have a wide variety of clinical presentations and a poor prognosis in most patients. Patients with occult primary tumors often present with general complaints, such as anorexia and weight loss. Clinical absence of primary tumor, early dissemination, aggressiveness, and unpredictability of metastatic pattern are characteristic of these tumors. Life expectancy is very short, with a median survival of 6 to 9 months. In most patients, occult primary tumors are refractory to systemic treatments, and chemotherapy is only palliative and does not significantly improve long-term survival. However, certain clinical presentations of these tumors are associated with a better prognosis. Special pathologic studies can identify subsets of patients with tumor types that are more responsive to chemotherapy. Treatment options should be individualized for this selected group of patients to achieve improved response and survival rates.     

The Impact of COVID-19 on the Diagnosis and Treatment of Lung Cancer over a 2-Year Period at a Canadian Academic Center

Background: We have recently reported a 35% drop in new lung cancer diagnoses and a 64% drop in lung cancer surgeries during the first year of the pandemic. Methods: The target population was divided into three cohorts: pre-COVID-19 (2019), first year of COVID-19 (2020), and second year of COVID-19 (2021). Results: The number of new lung cancer diagnoses during the second year of the pandemic increased by 75%, with more than 50% being in the advanced/metastatic stage. There was a significant increase in cases with multiple extrathoracic sites of metastases during the pandemic. During the first year of the pandemic, significantly more patients were treated with radiosurgery compared to the pre-COVID-19 year. During the second year, the number of radiosurgery and surgical cases returned to pre-COVID-19 levels. No significant changes were observed in systemic chemotherapy and targeted therapy. No statistical difference was identified in the mean wait time for diagnosis and treatment during the three years of observation. However, the wait time for surgery was prolonged compared to the pre-COVID-19 cohort. Conclusions: The significant drop in new diagnoses of lung cancer during the first year of the pandemic was followed by an almost two-fold increase in the second year, with the increased rate of metastatic disease with multiple extra-thoracic site metastases. Limited access to surgery resulted in the more frequent use of radiosurgery.     

Evolution of the DAZ gene family suggests that Y-linked DAZ plays little, or a limited, role in spermatogenesis but underlines a recent African origin for human populations

The recent transposition to the Y chromosome of the autosomal DAZL1 gene, potentially involved in germ cell development, created a unique opportunity to study the rate of Y chromosome evolution and assess the selective forces that may act upon such genes, and provided a new estimate of the male-to-female mutation rate (alpham). Two different Y- located DAZ sequences were observed in all Old World monkeys, apes and humans. Different DAZ copies originate from independent amplification events in each primate lineage. A comparison of autosomal DAZL1 and Y- linked DAZ intron sequences gave a new figure for male-to-female mutation rates of alpham = 4. It was found that human DAZ exons and introns are evolving at the same rate, implying neutral genetic drift and the absence of any functional selective pressures. We therefore hypothesize that Y-linked DAZ plays little, or a limited, role in human spermatogenesis. The two copies of DAZ in man appear to be due to a relatively recent duplication event (55 000-200 000 years). A worldwide survey of 67 men from five continents representing 19 distinct populations showed that most males have both DAZ variants. This implies a common origin for the Y chromosome consistent with a recent 'out of Africa' origin of the human race.      

A Phase Ib/II Study of Gemcitabine and Docetaxel in Combination With Pazopanib for the Neoadjuvant Treatment of Soft Tissue Sarcomas

Lessons Learned

• Our results highlight some of the challenges in the management of soft tissue sarcomas, which requires close cooperation between surgeons and medical oncologists and a careful selection of patients. The incidence of hepatotoxicity was a concerning finding and had been previously reported in patients treated with pazopanib.
• Although pharmacokinetic analysis was not part of this study, concomitant treatment with pazopanib has been recently reported to increase docetaxel exposure, which may explain the increased toxicity of combination regimens. It remains possible that lower doses of combined gemcitabine, docetaxel, and pazopanib may be tolerable. However, caution should be exercised in future trials investigating similar combinations.

Background.

For extremity soft tissue sarcomas (STS), surgical resection remains the standard of care, and the addition of chemotherapy is controversial. This was a phase Ib/II trial of neoadjuvant therapy for patients with STS.

Methods.

Patients with high grade, extremity STS of >8 cm and amenable to definitive resection were treated with up to four 21-day cycles of 900 mg/m² gemcitabine on days 1 and 8, 75 mg/m² docetaxel on day 8, and 400 mg of pazopanib daily (GDP), followed by surgery and, if indicated, radiation therapy. Primary and secondary endpoints (phase Ib portion) were the safety and rate of pathologic response.

Results.

The trial was discontinued because of slow accrual after inclusion of five patients (leiomyosarcoma: two; undifferentiated pleomorphic sarcoma: three). Two patients completed four treatment cycles: one underwent surgery and one had insufficient response and received additional therapies. Three patients discontinued treatment because of toxicity. Grade 3 adverse events included hypertension, fatigue, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, hoarseness, and myelotoxicity. There were no complete or partial responses. One patient had ≥90% pathologic response. Among four patients who underwent resection, three remain free of disease, and one patient eventually relapsed.

Conclusion.

GDP combination used in the neoadjuvant setting resulted in significant toxicity; despite pathologic responses, no objective responses occurred.     

Hyperbilirubinemia guideline adherence in Russia illustrates universal challenges

Guidelines for management of newborn hyperbilirubinemia have existed in Russia for many years. We sought to determine the degree to which management of hyperbilirubinemia in Russia meets three existing clinical protocols. We performed a cross-sectional chart review in a government-run, academic hospital in an urban setting in Moscow, Russia. Subjects were admitted to Level II nursery at Hospital No.13, were not transferred to a Level III nursery, did not die during hospitalization, and had at least one pairing of total serum bilirubin (TSB) and clinical evaluation of jaundice. We measured physician adherence to three available guidelines based upon TSB levels at which phototherapy and exchange transfusions were performed. We identified 594 infants and 1,924 pairings. Despite availability of TSB to inform decision-making, physicians did not follow the protocols. Under Russian and U.S. guidelines, physicians often failed to start phototherapy, started phototherapy unnecessarily, and missed recommended exchange transfusions. Despite a resource-poor setting, guideline adherence in Russia was remarkably similar to that of U.S. physicians. The data illustrate the challenge of overcoming physician behavior to standardize practice, and raise questions about the presumed higher quality of care in a more developed medical system. A new framework for guideline implementation is needed, and many of the necessary tools already exist.     

Advances in Adjuvant Therapy of Gastrointestinal Stromal Tumors

The Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma of the gastrointestinal tract. Major prognostic indices in the evaluation and management of GIST include the size, location and tumor mitotic rate. The discovery of the mutation in the tyrosine kinase receptor c-KIT (CD117) revolutionized the treatment of GIST in the early twenty-first century. Since the first case report of the success of the tyrosine kinase inhibitor (TKI) imatinib, in the treatment of a female patient with metastatic GIST, the paradigm of treatment of this tumor has evolved tremendously. The initial use in metastatic GISTs has progressed to use of the TKI in both the adjuvant and neoadjuvant settings. It is now standard of care for patients with complete resection of primary localized GIST, with high risk of recurrence, to have at least one year of adjuvant imatinib. Recent SSGVXIII study shows that patients benefit from extended duration of therapy.     

Resource utilization for peritoneal catheter placement

We reviewed hospitalization data for our large regional peritoneal dialysis (PD) program between January 1, 1997, and November 30, 1998, to determine the impact of inpatient PD catheter placement, by using Toronto Western II catheters placed under general anesthesia. Of 106 catheter placements, 80 were elective in previously identified renal failure patients. In elective cases, mean length of hospital stay was 6.75 days (SD, 7.01), median 4.5 days. These Canadian data are similar to those from the American Health Cost and Utilization Project. Evidently surgical PD catheter placement even in elective, planned circumstances involves a significant use of hospital resources. Current published reports do not outline hospital resource requirements or complication rates for this method.